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Notaro M, Borghetti M, Bresesti C, Giacca G, Kerzel T, Mercado CM, Beretta S, Monti M, Merelli I, Iaia S, Genua M, Annoni A, Canu T, Cristofori P, Degl'Innocenti S, Sanvito F, Rancoita PMV, Ostuni R, Gregori S, Naldini L, Squadrito ML. In vivo armed macrophages curb liver metastasis through tumor-reactive T-cell rejuvenation. Nat Commun 2025; 16:3471. [PMID: 40216735 PMCID: PMC11992024 DOI: 10.1038/s41467-025-58369-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Accepted: 03/18/2025] [Indexed: 04/14/2025] Open
Abstract
Despite recent progress in cancer treatment, liver metastases persist as an unmet clinical need. Here, we show that arming liver and tumor-associated macrophages in vivo to co-express tumor antigens (TAs), IFNα, and IL-12 unleashes robust anti-tumor immune responses, leading to the regression of liver metastases. Mechanistically, in vivo armed macrophages expand tumor reactive CD8+ T cells, which acquire features of progenitor exhausted T cells and kill cancer cells independently of CD4+ T cell help. IFNα and IL-12 produced by armed macrophages reprogram antigen presenting cells and rewire cellular interactions, rescuing tumor reactive T cell functions. In vivo armed macrophages trigger anti-tumor immunity in distinct liver metastasis mouse models of colorectal cancer and melanoma, expressing either surrogate tumor antigens, naturally occurring neoantigens or tumor-associated antigens. Altogether, our findings support the translational potential of in vivo armed liver macrophages to expand and rejuvenate tumor reactive T cells for the treatment of liver metastases.
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Affiliation(s)
- Marco Notaro
- Vector Engineering and In vivo Tumor Targeting Unit, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| | - Maristella Borghetti
- Vector Engineering and In vivo Tumor Targeting Unit, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| | - Chiara Bresesti
- Vector Engineering and In vivo Tumor Targeting Unit, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Giovanna Giacca
- Vector Engineering and In vivo Tumor Targeting Unit, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| | - Thomas Kerzel
- Vector Engineering and In vivo Tumor Targeting Unit, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Carl Mirko Mercado
- Vector Engineering and In vivo Tumor Targeting Unit, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Stefano Beretta
- BioInformatics Core, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Marco Monti
- BioInformatics Core, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Ivan Merelli
- BioInformatics Core, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Silvia Iaia
- Mechanisms of Peripheral Tolerance Unit and Immune Core, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Marco Genua
- Genomics of the Innate Immune System Unit, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Andrea Annoni
- Mechanisms of Peripheral Tolerance Unit and Immune Core, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Tamara Canu
- Preclinical Imaging Facility, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Patrizia Cristofori
- GLP Test Facility, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Sara Degl'Innocenti
- GLP Test Facility, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Francesca Sanvito
- GLP Test Facility, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Pathology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | | | - Renato Ostuni
- Vita-Salute San Raffaele University, Milan, Italy
- Genomics of the Innate Immune System Unit, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Silvia Gregori
- Mechanisms of Peripheral Tolerance Unit and Immune Core, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Luigi Naldini
- Vita-Salute San Raffaele University, Milan, Italy
- Targeted Cancer Gene Therapy Unit, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Mario Leonardo Squadrito
- Vector Engineering and In vivo Tumor Targeting Unit, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy.
- Vita-Salute San Raffaele University, Milan, Italy.
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Pagano D, Barresi V, Tropea A, Galvano A, Bazan V, Caldarella A, Sani C, Pompeo G, Russo V, Liotta R, Scuderi C, Mercorillo S, Barbera F, Di Lorenzo N, Jukna A, Carradori V, Rizzo M, Gruttadauria S, Peluso M. Clinical Validation of a Machine Learning-Based Biomarker Signature to Predict Response to Cytotoxic Chemotherapy Alone or Combined with Targeted Therapy in Metastatic Colorectal Cancer Patients: A Study Protocol and Review. Life (Basel) 2025; 15:320. [PMID: 40003728 PMCID: PMC11857289 DOI: 10.3390/life15020320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Revised: 02/12/2025] [Accepted: 02/14/2025] [Indexed: 02/27/2025] Open
Abstract
Metastatic colorectal cancer (mCRC) is a severe condition with high rates of illness and death. Current treatments are limited and not always effective because the cancer responds differently to drugs in different patients. This research aims to use artificial intelligence (AI) to improve treatment by predicting which therapies will work best for individual patients. By analyzing large sets of patient data and using machine learning, we hope to create a model that can identify which patients will respond to chemotherapy, either alone or combined with other targeted treatments. The study will involve dividing patients into training and validation sets to develop and test the models, avoiding overfitting. Various machine learning algorithms, like random survival forest and neural networks, will be integrated to develop a highly accurate and stable predictive model. The model's performance will be evaluated using statistical measures such as sensitivity, specificity, and the area under the curve (AUC). The aim is to personalize treatments, improve patient outcomes, reduce healthcare costs, and make the treatment process more efficient. If successful, this research could significantly impact the medical community by providing a new tool for better managing and treating mCRC, leading to more personalized and effective cancer care. In addition, we examine the applicability of learning methods to biomarker discovery and therapy prediction by considering recent narrative publications.
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Affiliation(s)
- Duilio Pagano
- Department for the Treatment and Study of Abdominal Diseases and Abdominal Transplantation, Istituto di Ricovero e Cura a Carattere Scientifico-Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione (IRCCS-ISMETT), University of Pittsburgh Medical Center (UPMC), 90127 Palermo, Italy; (D.P.); (A.T.); (R.L.); (F.B.); (N.D.L.); (A.J.); (M.R.)
| | - Vincenza Barresi
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (V.B.); (C.S.); (S.M.)
| | - Alessandro Tropea
- Department for the Treatment and Study of Abdominal Diseases and Abdominal Transplantation, Istituto di Ricovero e Cura a Carattere Scientifico-Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione (IRCCS-ISMETT), University of Pittsburgh Medical Center (UPMC), 90127 Palermo, Italy; (D.P.); (A.T.); (R.L.); (F.B.); (N.D.L.); (A.J.); (M.R.)
| | - Antonio Galvano
- Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy; (A.G.); (V.B.)
| | - Viviana Bazan
- Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy; (A.G.); (V.B.)
| | - Adele Caldarella
- Tuscany Cancer Registry, Clinical Epidemiology Unit, ISPRO-Study, Prevention and Oncology Network Institute, 50139 Florence, Italy;
| | - Cristina Sani
- Cancer Prevention Laboratory, ISPRO-Study, Prevention and Oncology Network Institute, 50139 Florence, Italy; (C.S.); (G.P.)
| | - Gianpaolo Pompeo
- Cancer Prevention Laboratory, ISPRO-Study, Prevention and Oncology Network Institute, 50139 Florence, Italy; (C.S.); (G.P.)
| | - Valentina Russo
- Research and Development Branch, Cancer Prevention Laboratory, ISPRO-Study, Prevention and Oncology Network Institute, 50139 Florence, Italy; (V.R.); (V.C.); (M.P.)
| | - Rosa Liotta
- Department for the Treatment and Study of Abdominal Diseases and Abdominal Transplantation, Istituto di Ricovero e Cura a Carattere Scientifico-Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione (IRCCS-ISMETT), University of Pittsburgh Medical Center (UPMC), 90127 Palermo, Italy; (D.P.); (A.T.); (R.L.); (F.B.); (N.D.L.); (A.J.); (M.R.)
| | - Chiara Scuderi
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (V.B.); (C.S.); (S.M.)
| | - Simona Mercorillo
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (V.B.); (C.S.); (S.M.)
| | - Floriana Barbera
- Department for the Treatment and Study of Abdominal Diseases and Abdominal Transplantation, Istituto di Ricovero e Cura a Carattere Scientifico-Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione (IRCCS-ISMETT), University of Pittsburgh Medical Center (UPMC), 90127 Palermo, Italy; (D.P.); (A.T.); (R.L.); (F.B.); (N.D.L.); (A.J.); (M.R.)
| | - Noemi Di Lorenzo
- Department for the Treatment and Study of Abdominal Diseases and Abdominal Transplantation, Istituto di Ricovero e Cura a Carattere Scientifico-Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione (IRCCS-ISMETT), University of Pittsburgh Medical Center (UPMC), 90127 Palermo, Italy; (D.P.); (A.T.); (R.L.); (F.B.); (N.D.L.); (A.J.); (M.R.)
| | - Agita Jukna
- Department for the Treatment and Study of Abdominal Diseases and Abdominal Transplantation, Istituto di Ricovero e Cura a Carattere Scientifico-Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione (IRCCS-ISMETT), University of Pittsburgh Medical Center (UPMC), 90127 Palermo, Italy; (D.P.); (A.T.); (R.L.); (F.B.); (N.D.L.); (A.J.); (M.R.)
| | - Valentina Carradori
- Research and Development Branch, Cancer Prevention Laboratory, ISPRO-Study, Prevention and Oncology Network Institute, 50139 Florence, Italy; (V.R.); (V.C.); (M.P.)
| | - Monica Rizzo
- Department for the Treatment and Study of Abdominal Diseases and Abdominal Transplantation, Istituto di Ricovero e Cura a Carattere Scientifico-Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione (IRCCS-ISMETT), University of Pittsburgh Medical Center (UPMC), 90127 Palermo, Italy; (D.P.); (A.T.); (R.L.); (F.B.); (N.D.L.); (A.J.); (M.R.)
| | - Salvatore Gruttadauria
- Department for the Treatment and Study of Abdominal Diseases and Abdominal Transplantation, Istituto di Ricovero e Cura a Carattere Scientifico-Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione (IRCCS-ISMETT), University of Pittsburgh Medical Center (UPMC), 90127 Palermo, Italy; (D.P.); (A.T.); (R.L.); (F.B.); (N.D.L.); (A.J.); (M.R.)
- Department of General Surgery and Medical-Surgical Specialties, University of Catania, 95123 Catania, Italy
| | - Marco Peluso
- Research and Development Branch, Cancer Prevention Laboratory, ISPRO-Study, Prevention and Oncology Network Institute, 50139 Florence, Italy; (V.R.); (V.C.); (M.P.)
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Fei F, Lu P, Ni J. Peripheral blood CD8 + CD28+ T cells as predictive biomarkers for treatment response in metastatic colorectal cancer. Biomarkers 2025; 30:10-22. [PMID: 39989261 DOI: 10.1080/1354750x.2024.2435867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Accepted: 11/24/2024] [Indexed: 02/25/2025]
Abstract
BACKGROUND Colorectal cancer (CRC) is a substantial global health burden, with treatment outcomes significantly influenced by the interaction between the immune system and the tumor microenvironment. OBJECTIVE This study aims to investigate the role of peripheral blood immune cell subpopulations, particularly CD8+ CD28+ T cells, in predicting treatment response in metastatic CRC patients receiving bevacizumab combined with chemotherapy. METHODS A cohort of 45 CRC patients was analyzed. Flow cytometry was utilized to assess immune cell subpopulations. RESULTS Higher CD8+ CD28+ T cell counts were associated with better treatment responses, including improved objective response rates. In a murine CRC model, the combination therapy significantly inhibited tumor growth and enhanced immune cell function. CONCLUSION These findings highlight the importance of CD8+ CD28+ T cells as potential biomarkers for predicting treatment outcomes in CRC. They also suggest that bevacizumab, when combined with chemotherapy, can modulate immune function and improve clinical efficacy.
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Affiliation(s)
- Fei Fei
- Department of Oncology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi Medical Center, Nanjing Medical University, Wuxi, China
| | - Peihua Lu
- Department of Oncology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi Medical Center, Nanjing Medical University, Wuxi, China
| | - Jingyi Ni
- Department of Oncology, Affiliated Tumor Hospital of Nantong University, Nantong, China
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Abedizadeh R, Majidi F, Khorasani HR, Abedi H, Sabour D. Colorectal cancer: a comprehensive review of carcinogenesis, diagnosis, and novel strategies for classified treatments. Cancer Metastasis Rev 2024; 43:729-753. [PMID: 38112903 DOI: 10.1007/s10555-023-10158-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Accepted: 11/27/2023] [Indexed: 12/21/2023]
Abstract
Colorectal cancer is the third most common and the second deadliest cancer worldwide. To date, colorectal cancer becomes one of the most important challenges of the health system in many countries. Since the clinical symptoms of this cancer appear in the final stages of the disease and there is a significant golden time between the formation of polyps and the onset of cancer, early diagnosis can play a significant role in reducing mortality. Today, in addition to colonoscopy, minimally invasive methods such as liquid biopsy have received much attention. The treatment of this complex disease has been mostly based on traditional treatments including surgery, radiotherapy, and chemotherapy; the high mortality rate indicates a lack of success for current treatment methods. Moreover, disease recurrence is another problem of traditional treatments. Recently, new approaches such as targeted therapy, immunotherapy, and nanomedicine have opened new doors for cancer treatment, some of which have already entered the market, and many methods have shown promising results in clinical trials. The success of immunotherapy in the treatment of refractory disease, the introduction of these methods into neoadjuvant therapy, and the successful results in tumor shrinkage without surgery have made immunotherapy a tough competitor for conventional treatments. It seems that the combination of those methods with such targeted therapies will go through promising changes in the future of colorectal cancer treatment.
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Affiliation(s)
- Roya Abedizadeh
- Department of Cancer Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Isar 11, Babol, 47138-18983, Iran
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Bani-Hashem Square, Tehran, 16635-148, Iran
| | - Fateme Majidi
- Department of Cancer Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Isar 11, Babol, 47138-18983, Iran
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Bani-Hashem Square, Tehran, 16635-148, Iran
| | - Hamid Reza Khorasani
- Department of Cancer Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Isar 11, Babol, 47138-18983, Iran
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Bani-Hashem Square, Tehran, 16635-148, Iran
| | - Hassan Abedi
- Department of Internal Medicine, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran.
| | - Davood Sabour
- Department of Cancer Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Isar 11, Babol, 47138-18983, Iran.
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Bani-Hashem Square, Tehran, 16635-148, Iran.
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Pollini T, Tran T, Wong P, Adam MA, Alseidi A, Corvera C, Hirose K, Nakakura E, Warren R, Maker VK, Maker AV. Improved survival of patients receiving immunotherapy and chemotherapy following curative-intent resection of colorectal liver metastases. J Gastrointest Surg 2024; 28:246-251. [PMID: 38445916 DOI: 10.1016/j.gassur.2023.12.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Accepted: 12/25/2023] [Indexed: 03/07/2024]
Abstract
BACKGROUND Despite significant advancements in the treatment of patients with colorectal liver metastases (CRLMs), only a minority will experience long-term survival. This study aimed to determine the effect of chemotherapy (CT) and immunotherapy (IT) compared with that of CT alone on patient survival after surgical resection. METHODS Patients undergoing curative-intent liver resection followed by adjuvant systemic therapy for stage IV colon cancer were identified using the National Cancer Database. Patients were stratified into type of therapy (CT alone vs CT + IT) and microsatellite status. Propensity score-weighted analysis was performed through 1:1 matching based on the nearest neighbor method. RESULTS Of 9943 patients who underwent resection of CRLMs, 7971 (80%) received systemic adjuvant therapy. Of 7971 patients, 1432 (18%) received a combination of CT and IT. Microsatellite status was not associated with overall survival (OS). Adjuvant CT + IT was associated with increased 3-year OS compared with that of CT alone in both the unmatched cohort (55% vs 48%, respectively; P < .001) and matched cohort (52% vs 48%, respectively; P = .050). On multivariate analysis, older age, positive resection margins, and KRAS mutation were independent predictors of poor survival, whereas the administration of adjuvant CT + IT was an independent predictor of improved survival. CONCLUSION IT combined with CT was associated with improved survival compared with that of CT alone after curative-intent resection of CRLMs, regardless of microsatellite instability status. Clinical trials to determine optimal patient selection, IT regimen, and long-term efficacy to improve outcomes of patients with CRLMs are warranted.
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Affiliation(s)
- Tommaso Pollini
- Division of Surgical Oncology, Department of Surgery, University of California San Francisco, San Francisco, California, United States
| | - Thuy Tran
- Division of Surgical Oncology, Department of Surgery, City of Hope Comprehensive Cancer Center, Duarte, California, United States; Department of Surgery, University of Illinois at Chicago, Chicago, Illinois, United States
| | - Paul Wong
- Division of Surgical Oncology, Department of Surgery, University of California San Francisco, San Francisco, California, United States
| | - Mohamed A Adam
- Division of Surgical Oncology, Department of Surgery, University of California San Francisco, San Francisco, California, United States
| | - Adnan Alseidi
- Division of Surgical Oncology, Department of Surgery, University of California San Francisco, San Francisco, California, United States
| | - Carlos Corvera
- Division of Surgical Oncology, Department of Surgery, University of California San Francisco, San Francisco, California, United States
| | - Kenzo Hirose
- Division of Surgical Oncology, Department of Surgery, University of California San Francisco, San Francisco, California, United States
| | - Eric Nakakura
- Division of Surgical Oncology, Department of Surgery, University of California San Francisco, San Francisco, California, United States
| | - Robert Warren
- Division of Surgical Oncology, Department of Surgery, University of California San Francisco, San Francisco, California, United States
| | - Vijay K Maker
- Department of Surgery, University of Illinois at Chicago, Chicago, Illinois, United States
| | - Ajay V Maker
- Division of Surgical Oncology, Department of Surgery, University of California San Francisco, San Francisco, California, United States.
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Dao V, Heestand G. Beyond EGFR inhibitors in advanced colorectal cancer: Targeting BRAF and HER2. Curr Probl Cancer 2023; 47:100960. [PMID: 37285606 DOI: 10.1016/j.currproblcancer.2023.100960] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 04/14/2023] [Accepted: 04/18/2023] [Indexed: 06/09/2023]
Abstract
The addition of antiepidermal growth factor receptor (EGFR) monoclonal antibodies, cetuximab or panitumumab, to conventional chemotherapy has improved clinical outcomes for rat sarcoma virus (RAS) wild-type advanced colorectal cancer patients, however, durable responses and 5-year overall survival rates remain limited. BRAF V600E somatic mutation and human epidermal growth factor receptor (HER2) amplification/overexpression have been separately implicated in primary resistance to anti-EGFR therapeutic strategies via aberrant activation of the mitogen-activated protein kinase (MAPK) signaling pathway, resulting in poorer outcomes. In addition to being a negative predictive biomarker for anti-EGFR therapy, BRAF V600E mutation and HER2 amplification/overexpression serve as positive predictors of response to therapies targeting these respective tumor promoters. This review will highlight key clinical studies that support the rational use of v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) and HER2-targeted therapies, often in combination with other targeted agents, cytotoxic chemotherapy, and immune checkpoint inhibitors. We discuss current challenges with BRAF and HER2-targeted therapies in metastatic colorectal cancer and potential opportunities for improvement.
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Affiliation(s)
- Vinh Dao
- Department of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, California; Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, California
| | - Gregory Heestand
- Department of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, California.
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Saber R, Henault D, Messaoudi N, Rebolledo R, Montagnon E, Soucy G, Stagg J, Tang A, Turcotte S, Kadoury S. Radiomics using computed tomography to predict CD73 expression and prognosis of colorectal cancer liver metastases. J Transl Med 2023; 21:507. [PMID: 37501197 PMCID: PMC10375693 DOI: 10.1186/s12967-023-04175-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Accepted: 04/30/2023] [Indexed: 07/29/2023] Open
Abstract
BACKGROUND Finding a noninvasive radiomic surrogate of tumor immune features could help identify patients more likely to respond to novel immune checkpoint inhibitors. Particularly, CD73 is an ectonucleotidase that catalyzes the breakdown of extracellular AMP into immunosuppressive adenosine, which can be blocked by therapeutic antibodies. High CD73 expression in colorectal cancer liver metastasis (CRLM) resected with curative intent is associated with early recurrence and shorter patient survival. The aim of this study was hence to evaluate whether machine learning analysis of preoperative liver CT-scan could estimate high vs low CD73 expression in CRLM and whether such radiomic score would have a prognostic significance. METHODS We trained an Attentive Interpretable Tabular Learning (TabNet) model to predict, from preoperative CT images, stratified expression levels of CD73 (CD73High vs. CD73Low) assessed by immunofluorescence (IF) on tissue microarrays. Radiomic features were extracted from 160 segmented CRLM of 122 patients with matched IF data, preprocessed and used to train the predictive model. We applied a five-fold cross-validation and validated the performance on a hold-out test set. RESULTS TabNet provided areas under the receiver operating characteristic curve of 0.95 (95% CI 0.87 to 1.0) and 0.79 (0.65 to 0.92) on the training and hold-out test sets respectively, and outperformed other machine learning models. The TabNet-derived score, termed rad-CD73, was positively correlated with CD73 histological expression in matched CRLM (Spearman's ρ = 0.6004; P < 0.0001). The median time to recurrence (TTR) and disease-specific survival (DSS) after CRLM resection in rad-CD73High vs rad-CD73Low patients was 13.0 vs 23.6 months (P = 0.0098) and 53.4 vs 126.0 months (P = 0.0222), respectively. The prognostic value of rad-CD73 was independent of the standard clinical risk score, for both TTR (HR = 2.11, 95% CI 1.30 to 3.45, P < 0.005) and DSS (HR = 1.88, 95% CI 1.11 to 3.18, P = 0.020). CONCLUSIONS Our findings reveal promising results for non-invasive CT-scan-based prediction of CD73 expression in CRLM and warrant further validation as to whether rad-CD73 could assist oncologists as a biomarker of prognosis and response to immunotherapies targeting the adenosine pathway.
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Affiliation(s)
- Ralph Saber
- MedICAL Laboratory, Polytechnique Montréal, Montréal, H3T 1J4, Canada
- Imaging and Engineering Axis, Centre de recherche du Centre Hospitalier de l'Université de Montréal/Institut du cancer de Montréal, 900 rue Saint-Denis R10.430, Montréal, QC, H2X 0A9, Canada
| | - David Henault
- Cancer Axis, Centre de recherche du Centre Hospitalier de l'Université de Montréal/Institut du cancer de Montréal, 900 rue Saint-Denis, Room R10.430, Montréal, QC, H2X 0A9, Canada
- Hepato-Pancreato-Biliary Surgery and Liver Transplantation Service, Centre hospitalier de l'Université de Montréal, 1000, rue Saint-Denis, Montréal, QC, H2X 0C1, Canada
| | - Nouredin Messaoudi
- Cancer Axis, Centre de recherche du Centre Hospitalier de l'Université de Montréal/Institut du cancer de Montréal, 900 rue Saint-Denis, Room R10.430, Montréal, QC, H2X 0A9, Canada
- Hepato-Pancreato-Biliary Surgery and Liver Transplantation Service, Centre hospitalier de l'Université de Montréal, 1000, rue Saint-Denis, Montréal, QC, H2X 0C1, Canada
- Department of Surgery, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel) and Europe Hospitals, Brussels, Belgium
| | - Rolando Rebolledo
- Cancer Axis, Centre de recherche du Centre Hospitalier de l'Université de Montréal/Institut du cancer de Montréal, 900 rue Saint-Denis, Room R10.430, Montréal, QC, H2X 0A9, Canada
- Hepato-Pancreato-Biliary Surgery and Liver Transplantation Service, Centre hospitalier de l'Université de Montréal, 1000, rue Saint-Denis, Montréal, QC, H2X 0C1, Canada
| | - Emmanuel Montagnon
- Imaging and Engineering Axis, Centre de recherche du Centre Hospitalier de l'Université de Montréal/Institut du cancer de Montréal, 900 rue Saint-Denis R10.430, Montréal, QC, H2X 0A9, Canada
| | - Geneviève Soucy
- Pahology Department, Centre hospitalier de l'Université de Montréal, 1000, rue Saint-Denis, Montréal, QC, H2X 0C1, Canada
| | - John Stagg
- Cancer Axis, Centre de recherche du Centre Hospitalier de l'Université de Montréal/Institut du cancer de Montréal, 900 rue Saint-Denis, Room R10.430, Montréal, QC, H2X 0A9, Canada
| | - An Tang
- Imaging and Engineering Axis, Centre de recherche du Centre Hospitalier de l'Université de Montréal/Institut du cancer de Montréal, 900 rue Saint-Denis R10.430, Montréal, QC, H2X 0A9, Canada
- Department of Radiology, Radiation Oncology and Nuclear Medicine, Université de Montréal, Montréal, H3T 1J4, Canada
| | - Simon Turcotte
- Cancer Axis, Centre de recherche du Centre Hospitalier de l'Université de Montréal/Institut du cancer de Montréal, 900 rue Saint-Denis, Room R10.430, Montréal, QC, H2X 0A9, Canada.
- Hepato-Pancreato-Biliary Surgery and Liver Transplantation Service, Centre hospitalier de l'Université de Montréal, 1000, rue Saint-Denis, Montréal, QC, H2X 0C1, Canada.
| | - Samuel Kadoury
- MedICAL Laboratory, Polytechnique Montréal, Montréal, H3T 1J4, Canada.
- Imaging and Engineering Axis, Centre de recherche du Centre Hospitalier de l'Université de Montréal/Institut du cancer de Montréal, 900 rue Saint-Denis R10.430, Montréal, QC, H2X 0A9, Canada.
- Department of Computer and Software Engineering, Institute of Biomedical Engineering, Polytechnique Montréal, Montréal, H3T 1J4, Canada.
- Department of Radiology, Radiation Oncology and Nuclear Medicine, Université de Montréal, Montréal, H3T 1J4, Canada.
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8
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Tsai KY, Chang YJ, Huang CY, Prince GMSH, Chen HA, Makondi PT, Shen YR, Wei PL. Novel heavily fucosylated glycans as a promising therapeutic target in colorectal cancer. J Transl Med 2023; 21:505. [PMID: 37496011 PMCID: PMC10373344 DOI: 10.1186/s12967-023-04363-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Accepted: 07/16/2023] [Indexed: 07/28/2023] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is highly prevalent and lethal globally, and its prognosis remains unsatisfactory. Drug resistance is regarded as the main cause of treatment failure leading to tumor recurrence and metastasis. The overexpression of fucosylated epitopes, which are usually modifications of glycoproteins, was reported to occur in various epithelial cancers. However, the effects of treatments that target these antigens in colorectal cancer remain unclear. METHODS This study investigated the expression of heavily fucosylated glycans (HFGs) in 30 clinical samples from patients with CRC and other normal human tissues. The complement-dependent cytotoxicity was explored in vitro through treatment with anti-HFG monoclonal antibody (mAb) alone or in combination with chemotherapeutic agents. In vivo inhibitory effects were also examined using a xenograft mouse model. RESULTS Immunohistochemistry staining and western blotting revealed that HFG expression was higher in human colorectal cancer tissues than in normal tissues. In DLD-1 and SW1116 cells, which overexpress fucosylated epitopes, anti-HFG mAb produced observable cytotoxic effects, especially when it was combined with chemotherapeutic agents. The xenograft model also demonstrated that anti-HFG mAb had potent and dose-dependent inhibitory effects on colorectal tumor growth. CONCLUSIONS As a novel cancer antigen, HFGs are a promising treatment target, and the implementation of anti-HFG mAb treatment for CRC warrants further investigation.
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Affiliation(s)
- Kuei-Yen Tsai
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan
- Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City, 235041, Taiwan
| | - Yu-Jia Chang
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan
- Cancer Research Center and Translational Laboratory, Department of Medical Research, Taipei Medical University Hospital, Taipei Medical University, Taipei, 11031, Taiwan
- Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei, 11696, Taiwan
- Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, 116, Taiwan
| | - Chien-Yu Huang
- School of Medicine, National Tsing Hua University, Hsinchu, 30013, Taiwan
- Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu, 30013, Taiwan
| | - G M Shazzad Hossain Prince
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan
| | - Hsin-An Chen
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan
- Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City, 235041, Taiwan
| | | | - Ying-Rou Shen
- Research Department, GlycoNex Inc., New Taipei City, 22175, Taiwan
| | - Po-Li Wei
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan.
- Cancer Research Center and Translational Laboratory, Department of Medical Research, Taipei Medical University Hospital, Taipei Medical University, Taipei, 11031, Taiwan.
- Division of Colorectal Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei Medical University, 252 Wuxing Street, Sinyi District, Taipei, 11031, Taiwan.
- Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, 11031, Taiwan.
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9
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Zhang Z, Zhang Y, Liu C, Shao J, Chen Y, Zhu Y, Zhang L, Qin B, Kong Z, Wang X, Wang Y, Huang D, Liu L, Zhou Y, Tao R, Yang Z, Liu M, Zhao W. A real-world study of immune checkpoint inhibitors in advanced triple-negative breast cancer. CANCER INNOVATION 2023; 2:172-180. [PMID: 38089401 PMCID: PMC10686160 DOI: 10.1002/cai2.70] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 03/08/2023] [Accepted: 03/16/2023] [Indexed: 10/15/2024]
Abstract
Background Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer. Immune checkpoint inhibitors (ICIs) have been widely used to treat various tumors and have changed the landscape of tumor management, but the data from real-world studies of ICIs for TNBC treatment remain limited. The aim of this study was to evaluate the efficacy of ICIs in the treatment of patients with advanced TNBC in a real-world setting and to explore possible correlates. Methods The clinical data of advanced TNBC patients who received ICI treatment in the Chinese People's Liberation Army (PLA) General Hospital were collected. Treatment responses, outcomes and adverse events (AEs) were assessed. Results Eighty-one patients were included in the study. The confirmed objective response rate (ORR) was 32.1%, and the disease control rate (DCR) was 64.2%. The median progression-free survival (PFS) was 4.2 months, and the median overall survival (OS) was 11.0 months. PFS and OS were longer in patients who achieved clinical benefit from ICIs and shorter in patients who received later-line ICIs and higher levels of inflammation; specifically, patients with higher TILs had longer PFS. Overall AEs were tolerable. Conclusions ICIs are effective in the treatment of advanced TNBC, and the adverse reactions are tolerable. A panel of biomarkers including LDH, ALP, and bNLR were identified to predict the efficacies of ICIs in TNBC treatment.
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Affiliation(s)
| | - Yadi Zhang
- Nankai University School of MedicineTianjinChina
| | | | | | - Yimeng Chen
- Department of Medical OncologyXi'an Jiaotong UniversityXi'anShaanxiChina
| | - Yimin Zhu
- Department of Medical Oncology, Fifth Medical CenterGeneral Hospital of the Chinese People's Liberation ArmyBeijingChina
| | - Li Zhang
- Department of Medical Oncology, First Medical CenterGeneral Hospital of the Chinese People's Liberation ArmyBeijingChina
| | - Boyu Qin
- Department of Medical Oncology, Fifth Medical CenterGeneral Hospital of the Chinese People's Liberation ArmyBeijingChina
| | | | - Xixi Wang
- Nankai University School of MedicineTianjinChina
| | | | | | - Liqun Liu
- Medical School of Chinese PLABeijingChina
| | - Yuxin Zhou
- Medical School of Chinese PLABeijingChina
| | - Ran Tao
- Department of Medical Oncology, First Medical CenterGeneral Hospital of the Chinese People's Liberation ArmyBeijingChina
| | - Zengjie Yang
- Cancer Biology ProgramFox Chase Cancer CenterPhiladelphiaPennsylvaniaUSA
| | - Mei Liu
- Department of Pathology, First Medical CenterGeneral Hospital of the Chinese People's Liberation ArmyBeijingChina
| | - Weihong Zhao
- Department of Medical Oncology, First Medical CenterGeneral Hospital of the Chinese People's Liberation ArmyBeijingChina
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10
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Vulasala SSR, Sutphin PD, Kethu S, Onteddu NK, Kalva SP. Interventional radiological therapies in colorectal hepatic metastases. Front Oncol 2023; 13:963966. [PMID: 37324012 PMCID: PMC10266282 DOI: 10.3389/fonc.2023.963966] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Accepted: 05/19/2023] [Indexed: 06/17/2023] Open
Abstract
Colorectal malignancy is the third most common cancer and one of the prevalent causes of death globally. Around 20-25% of patients present with metastases at the time of diagnosis, and 50-60% of patients develop metastases in due course of the disease. Liver, followed by lung and lymph nodes, are the most common sites of colorectal cancer metastases. In such patients, the 5-year survival rate is approximately 19.2%. Although surgical resection is the primary mode of managing colorectal cancer metastases, only 10-25% of patients are competent for curative therapy. Hepatic insufficiency may be the aftermath of extensive surgical hepatectomy. Hence formal assessment of future liver remnant volume (FLR) is imperative prior to surgery to prevent hepatic failure. The evolution of minimally invasive interventional radiological techniques has enhanced the treatment algorithm of patients with colorectal cancer metastases. Studies have demonstrated that these techniques may address the limitations of curative resection, such as insufficient FLR, bi-lobar disease, and patients at higher risk for surgery. This review focuses on curative and palliative role through procedures including portal vein embolization, radioembolization, and ablation. Alongside, we deliberate various studies on conventional chemoembolization and chemoembolization with irinotecan-loaded drug-eluting beads. The radioembolization with Yttrium-90 microspheres has evolved as salvage therapy in surgically unresectable and chemo-resistant metastases.
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Affiliation(s)
- Sai Swarupa R. Vulasala
- Department of Radiology, University of Florida College of Medicine, Jacksonville, FL, United States
| | - Patrick D. Sutphin
- Division of Interventional Radiology, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Samira Kethu
- Department of Microbiology and Immunology, College of Arts and Sciences, University of Miami, Coral Gables, FL, United States
| | - Nirmal K. Onteddu
- Department of Hospital Medicine, Flowers Hospital, Dothan, AL, United States
| | - Sanjeeva P. Kalva
- Division of Interventional Radiology, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
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11
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Jiao S, Guan X, Niu H, Ma X, Wang K, Liu E, Zhang W, Wei R, Sun P, Chen Y, Wang X. The tumor characteristics, treatment strategy, and prognosis in colorectal cancer patients with synchronous liver metastasis in China and the USA. Int J Colorectal Dis 2023; 38:140. [PMID: 37219592 DOI: 10.1007/s00384-023-04398-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/03/2023] [Indexed: 05/24/2023]
Abstract
PURPOSE This study performed an analysis of clinicopathological characteristics, surgical treatment strategy, and survival for CRC patients with LM between China and the USA. METHODS The CRC patients with simultaneous LM were identified from the Surveillance, Epidemiology, and End Results (SEER) registry and the Chinese National Cancer Center (CNCC) database from 2010 to 2017. We assessed 3-year cancer-specific survival (CSS) according to surgical treatment strategy and time period. RESULTS Differences in patient age, gender, primary tumor location, tumor grade, tumor histology, and tumor stage were observed between the USA and China. Compared to the USA, a larger proportion of patients in China underwent both primary site resection (PSR) and hepatic resection (HR) (35.1% vs 15.6%, P < 0.001), and fewer patients underwent only PSR in China (29.1% vs 45.1%, P < 0.001). From 2010 to 2017, the proportion of patient who underwent both PSR and HR has increased from 13.9% to 17.4% in the USA and from 25.4% to 39.4% in China. The 3-year CSS were increasing over time in both the USA and China. The 3-year CSS of patients receiving HR and PSR were significantly higher than those receiving only PSR and patients treated with no surgery in the USA and China. There were no significant differences of 3-year CSS between the USA and China after adjustment (P = 0.237). CONCLUSIONS Despite the distinctions of tumor characteristics and surgical strategy in patients with LM between the USA and China, increased adoption of HR has contributed to the profound improvements of survival during recent decade.
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Affiliation(s)
- Shuai Jiao
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xu Guan
- Department of Colorectal Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100021, China.
| | - Haitao Niu
- Department of Colorectal Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100021, China
| | - Xiaolong Ma
- Department of Colorectal Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Kaifeng Wang
- Department of Colorectal Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100021, China
| | - Enrui Liu
- Department of Colorectal Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100021, China
| | - Weiyuan Zhang
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Ran Wei
- Department of Colorectal Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100021, China
| | - Peng Sun
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, 518116, China
| | - Yinggang Chen
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, 518116, China.
| | - Xishan Wang
- Department of Colorectal Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100021, China.
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12
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Boughriba R, Sahraoui G, Chaar I, Weslati M, Ayed K, Ounissi D, Hazgui M, Bouraoui S, Gati A. Significant association of MCP1 rs1024611 and CCR2 rs1799864 polymorphisms with colorectal cancer and liver metastases susceptibility and aggressiveness: A case-control study. Cytokine 2023; 167:156193. [PMID: 37149962 DOI: 10.1016/j.cyto.2023.156193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 02/07/2023] [Accepted: 03/26/2023] [Indexed: 05/09/2023]
Abstract
BACKGROUND The MCP-1/CCR2 axis is one of the major chemokine signaling pathways that play a crucial role in the tumor microenvironment and has been involved in triggering various tumor progression mechanisms, such as increasing the immunosuppressive cells recruitment and promoting tumor cell proliferation and invasiveness. AIM The current study investigated the association of MCP1 (rs1024611) and CCR2 (rs1799864) genes variants with the risk as well as prognosis of colorectal cancer (CRC) and colorectal liver metastases (CRLM). SUBJECTS AND METHODS A retrospective cohort study involved 408 patients (284 CRC and 124 CRLM), and 284 healthy control was conducted. Genotyping of selected polymorphisms was performed by PCR-RFLP assays and confirmed by microchip and capillary electrophoresis. RESULTS The results highlighted a positive association between MCP1 rs1024611 (non-AA) and CCR2 rs1799864 (GA) genotypes with increased CRC and CRLM risk. Correlation between SNPs and clinicopathological characteristics revealed a positive association between MCP1 rs1024611 and CCR2 rs1799864 (dominant model) and CRC poor prognosis features. Kaplan-Meier survival analysis revealed a significant association between MCP1 rs1024611 non-AA carriers and decreased survival rate. Neoadjuvant treatment showed an improvement in CRC and CRLM survival rates among carriers of MCP1 and CCR2 wild-type genotype. FOLFIRI chemotherapy exhibits reduced survival rates for patients who carried mutated genotypes of MCP1 and CCR2 polymorphisms. CONCLUSION Considering our results, we suggest That both MCP1 and CCR2 polymorphisms may constitute independent factors for CRC and CRLM occurrence and can be helpful targets for an efficient therapeutic approach.
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Affiliation(s)
- Rahma Boughriba
- Laboratory of Genetic, Immunology and Human Pathology, Faculty of Sciences of Tunis, University of Tunis El Manar (UTM), 2092 Tunis, Tunisia; Unit of Colorectal Cancer Research UR12SP14, Mongi Slim Hospital, Sidi Daoud, La Marsa, 2046 Tunis, Tunisia
| | - Ghada Sahraoui
- Department of Pathological Anatomy and Cytology of Salah Azaiez Oncology Institute, Bab Saadoun 1029 Tunis, Tunisia; Medical School of Tunis, University of Tunis El Manar, 15 rue Djebel Lakhdhar, La Rabta, 1007 Tunis, Tunisia
| | - Ines Chaar
- Unit of Colorectal Cancer Research UR12SP14, Mongi Slim Hospital, Sidi Daoud, La Marsa, 2046 Tunis, Tunisia
| | - Marwa Weslati
- Unit of Colorectal Cancer Research UR12SP14, Mongi Slim Hospital, Sidi Daoud, La Marsa, 2046 Tunis, Tunisia
| | - Khouloud Ayed
- Laboratory of Genetic, Immunology and Human Pathology, Faculty of Sciences of Tunis, University of Tunis El Manar (UTM), 2092 Tunis, Tunisia
| | - Donia Ounissi
- Unit of Colorectal Cancer Research UR12SP14, Mongi Slim Hospital, Sidi Daoud, La Marsa, 2046 Tunis, Tunisia
| | - Mariem Hazgui
- Unit of Colorectal Cancer Research UR12SP14, Mongi Slim Hospital, Sidi Daoud, La Marsa, 2046 Tunis, Tunisia
| | - Saadia Bouraoui
- Unit of Colorectal Cancer Research UR12SP14, Mongi Slim Hospital, Sidi Daoud, La Marsa, 2046 Tunis, Tunisia; Medical School of Tunis, University of Tunis El Manar, 15 rue Djebel Lakhdhar, La Rabta, 1007 Tunis, Tunisia
| | - Asma Gati
- Laboratory of Genetic, Immunology and Human Pathology, Faculty of Sciences of Tunis, University of Tunis El Manar (UTM), 2092 Tunis, Tunisia.
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13
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Said SS, Ibrahim WN. Cancer Resistance to Immunotherapy: Comprehensive Insights with Future Perspectives. Pharmaceutics 2023; 15:pharmaceutics15041143. [PMID: 37111629 PMCID: PMC10141036 DOI: 10.3390/pharmaceutics15041143] [Citation(s) in RCA: 44] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 03/24/2023] [Accepted: 03/31/2023] [Indexed: 04/08/2023] Open
Abstract
Cancer immunotherapy is a type of treatment that harnesses the power of the immune systems of patients to target cancer cells with better precision compared to traditional chemotherapy. Several lines of treatment have been approved by the US Food and Drug Administration (FDA) and have led to remarkable success in the treatment of solid tumors, such as melanoma and small-cell lung cancer. These immunotherapies include checkpoint inhibitors, cytokines, and vaccines, while the chimeric antigen receptor (CAR) T-cell treatment has shown better responses in hematological malignancies. Despite these breakthrough achievements, the response to treatment has been variable among patients, and only a small percentage of cancer patients gained from this treatment, depending on the histological type of tumor and other host factors. Cancer cells develop mechanisms to avoid interacting with immune cells in these circumstances, which has an adverse effect on how effectively they react to therapy. These mechanisms arise either due to intrinsic factors within cancer cells or due other cells within the tumor microenvironment (TME). When this scenario is used in a therapeutic setting, the term “resistance to immunotherapy” is applied; “primary resistance” denotes a failure to respond to treatment from the start, and “secondary resistance” denotes a relapse following the initial response to immunotherapy. Here, we provide a thorough summary of the internal and external mechanisms underlying tumor resistance to immunotherapy. Furthermore, a variety of immunotherapies are briefly discussed, along with recent developments that have been employed to prevent relapses following treatment, with a focus on upcoming initiatives to improve the efficacy of immunotherapy for cancer patients.
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Affiliation(s)
- Sawsan Sudqi Said
- Department of Biomedical Sciences, College of Health Sciences, QU Health, Qatar University, Doha P.O. Box 2713, Qatar
| | - Wisam Nabeel Ibrahim
- Department of Biomedical Sciences, College of Health Sciences, QU Health, Qatar University, Doha P.O. Box 2713, Qatar
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14
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Shi R, Zhou X, Pang L, Wang M, Li Y, Chen C, Ning H, Zhang L, Yue G, Qiu L, Zhao W, Qi Y, Wu Y, Gao Y. Peptide vaccine from cancer-testis antigen ODF2 can potentiate the cytotoxic T lymphocyte infiltration through IL-15 in non-MSI-H colorectal cancer. Cancer Immunol Immunother 2023; 72:985-1001. [PMID: 36251028 DOI: 10.1007/s00262-022-03307-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 10/10/2022] [Indexed: 03/20/2023]
Abstract
About 85% of patients with colorectal cancer (CRC) have the non-microsatellite instability-high (non-MSI-H) subtype, and many cannot benefit from immune checkpoint blockade. A potential reason for this is that most non-MSI-H colorectal cancers are immunologically "cold" due to poor CD8+ T cell infiltration. In the present study, we screened for potential cancer-testis antigens (CTAs) by comparing the bioinformatics of CD8+ T effector memory (Tem) cell infiltration between MSI-H and non-MSI-H CRC. Two ODF2-derived epitope peptides, P433 and P609, displayed immunogenicity and increased the proportion of CD8+ T effector memory (Tem) cells in vitro and in vivo. The adoptive transfer of peptide pool-induced CTLs inhibited tumor growth and enhanced CD8+ T cell infiltration in tumor-bearing NOD/SCID mice. The mechanistic study showed that knockdown of ODF2 in CRC cells promoted interleukin-15 expression, which facilitated CD8+ T cell proliferation. In conclusion, ODF2, a CTA, was negatively correlated with CD8+ T cell infiltration in "cold" non-MSI-H CRC and was selected based on the results of bioinformatics analyses. The corresponding HLA-A2 restricted epitope peptide induced antigen-specific CTLs. Immunotherapy targeting ODF2 could improve CTA infiltration via upregulating IL-15 in non-MSI-H CRC. This tumor antigen screening strategy could be exploited to develop therapeutic vaccines targeting non-MSI-H CRC.
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Affiliation(s)
- Ranran Shi
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Xiuman Zhou
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, 518107, China
| | - Liwei Pang
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Mingshuang Wang
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Yubing Li
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Chunxia Chen
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Haoming Ning
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Lihan Zhang
- Department of Integrated Chinse and Western Medicine, Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Guangxing Yue
- Department of Integrated Chinse and Western Medicine, Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Lu Qiu
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, 518107, China
| | - Wenshan Zhao
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China
- Henan Key Laboratory of Bioactive Macromolecules, Zhengzhou University, Zhengzhou, 450001, China
- International Joint Laboratory for Protein and Peptide Drugs of Henan Province, Zhengzhou University, Zhengzhou, 450001, China
| | - Yuanming Qi
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China
- Henan Key Laboratory of Bioactive Macromolecules, Zhengzhou University, Zhengzhou, 450001, China
- International Joint Laboratory for Protein and Peptide Drugs of Henan Province, Zhengzhou University, Zhengzhou, 450001, China
| | - Yahong Wu
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China.
- Henan Key Laboratory of Bioactive Macromolecules, Zhengzhou University, Zhengzhou, 450001, China.
- International Joint Laboratory for Protein and Peptide Drugs of Henan Province, Zhengzhou University, Zhengzhou, 450001, China.
| | - Yanfeng Gao
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China.
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, 518107, China.
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15
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Jeong KY. Challenges to addressing the unmet medical needs for immunotherapy targeting cold colorectal cancer. World J Gastrointest Oncol 2023; 15:215-224. [PMID: 36908316 PMCID: PMC9994045 DOI: 10.4251/wjgo.v15.i2.215] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 12/18/2022] [Accepted: 01/09/2023] [Indexed: 02/14/2023] Open
Abstract
With the establishment of the immune surveillance mechanism since the 1950s, attempts have been made to activate the immune system for cancer treatment through the discovery of various cytokines or the development of antibodies up to now. The fruits of these efforts have contributed to the recognition of the 3rd generation of anticancer immunotherapy as the mainstream of cancer treatment. However, the limitations of cancer immunotherapy are also being recognized through the conceptual establishment of cold tumors recently, and colorectal cancer (CRC) has become a major issue from this therapeutic point of view. Here, it is emphasized that non-clinical strategies to overcome the immunosuppressive environment and clinical trials based on these basic investigations are being made on the journey to achieve better treatment outcomes for the treatment of cold CRC.
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Affiliation(s)
- Keun-Yeong Jeong
- Research and Development Center, PearlsinMires, Seoul 03690, South Korea
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16
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Nguyen HM, Gaikwad S, Oladejo M, Paulishak W, Wood LM. Targeting Ubiquitin-like Protein, ISG15, as a Novel Tumor Associated Antigen in Colorectal Cancer. Cancers (Basel) 2023; 15:1237. [PMID: 36831577 PMCID: PMC9954464 DOI: 10.3390/cancers15041237] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2022] [Revised: 02/11/2023] [Accepted: 02/13/2023] [Indexed: 02/17/2023] Open
Abstract
Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in both men and women in the United States. While immune checkpoint inhibitor (ICI) therapy is demonstrating remarkable clinical responses, the resistance and immune-related toxicities associated with ICIs demonstrate the need to develop additional immunotherapy options for CRC patients. Cancer vaccines represent a safe and promising treatment approach for CRC. As previously developed tumor-associated antigen (TAA)-based cancer vaccines for CRC are not demonstrating promising results, we propose that interferon-stimulated gene 15 (ISG15) is a novel TAA and therapeutic target for CRC. Our work demonstrates the anti-tumor efficacy of a Listeria-based vaccine targeting ISG15, designated Lm-LLO-ISG15, in an immunocompetent CRC murine model. The Lm-LLO-ISG15-mediated anti-tumor response is associated with an increased influx of functional T cells, higher production of multiple intracellular cytokines response, a lower number of regulatory T cells, and a greater ratio of effector to regulatory T cells (Teff/Treg) in the tumor microenvironment.
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Affiliation(s)
| | | | | | | | - Laurence M. Wood
- Department of Immunotherapeutics and Biotechnology, Jerry H Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Abilene, TX 79601, USA
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17
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Le DT, Diaz LA, Kim TW, Van Cutsem E, Geva R, Jäger D, Hara H, Burge M, O'Neil BH, Kavan P, Yoshino T, Guimbaud R, Taniguchi H, Élez E, Al-Batran SE, Boland PM, Cui Y, Leconte P, Marinello P, André T. Pembrolizumab for previously treated, microsatellite instability–high/mismatch repair–deficient advanced colorectal cancer: final analysis of KEYNOTE-164. Eur J Cancer 2023; 186:185-195. [PMID: 37141828 DOI: 10.1016/j.ejca.2023.02.016] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Accepted: 02/16/2023] [Indexed: 02/26/2023]
Abstract
BACKGROUND Pembrolizumab demonstrated durable clinical benefit and manageable safety in previously treated advanced or metastatic microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) colorectal cancer (CRC) in the phase 2 KEYNOTE-164 study. Results from the final analysis are presented. METHODS Eligible patients had unresectable or metastatic MSI-H/dMMR CRC and ≥2 prior systemic therapies (cohort A) or ≥1 prior systemic therapy (cohort B). Patients received pembrolizumab 200 mg intravenously every 3 weeks for ≤35 cycles. The primary end-point was objective response rate (ORR) assessed per Response Evaluation Criteria in Solid Tumors, version 1.1 by blinded independent central review. Secondary end-points included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety and tolerability. RESULTS Sixty-one patients in cohort A and 63 patients in cohort B were enroled; median follow-up was 62.2 months and 54.4 months, respectively. ORR was 32.8% (95% CI, 21.3%-46.0%) in cohort A and 34.9% (95% CI, 23.3%-48.0%) in cohort B. Median DOR was not reached (NR) in either cohort. Median PFS was 2.3 months (95% CI, 2.1-8.1) in cohort A and 4.1 months (95% CI, 2.1-18.9) in cohort B. Median OS was 31.4 months (95% CI, 21.4-58.0) in cohort A and 47.0 months (95% CI, 19.2-NR) in cohort B. No new safety signals were observed. Nine patients who initially responded experienced disease progression off therapy and received second-course pembrolizumab. Six patients (66.7%) completed an additional 17 cycles of pembrolizumab, and 2 patients achieved a partial response. CONCLUSIONS Pembrolizumab continued to show durable antitumor activity, prolonged OS, and manageable safety in patients with previously treated MSI-H/dMMR CRC. CLINICAL TRIAL REGISTRY INFORMATION ClinicalTrials.gov, NCT02460198.
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Affiliation(s)
- Dung T Le
- Oncology, Sidney Kimmel Comprehensive Cancer Center at John Hopkins University, Baltimore, MD, USA.
| | - Luis A Diaz
- Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Oncology, Asan Medical Center, Seoul, Republic of Korea
| | - Tae Won Kim
- Oncology, Asan Medical Center, Seoul, Republic of Korea; University of Ulsan, Ulsan, Republic of Korea
| | - Eric Van Cutsem
- Digestive Oncology, University Hospitals Gasthuisberg, Leuven and KU Leuven, Leuven, Belgium
| | - Ravit Geva
- Oncology Division, Tel Aviv Sourasky Medical Center, Tel Aviv-Yafo, Israel
| | - Dirk Jäger
- Medical Oncology, University Medical Center Heidelberg, National Center for Tumor Diseases, Heidelberg, Germany
| | - Hiroki Hara
- Gastroenterology, Saitama Cancer Center, Saitama, Japan
| | - Matthew Burge
- Cancer Care Services, Royal Brisbane Hospital, Brisbane, Queensland, Australia
| | - Bert H O'Neil
- Oncology, Community North Cancer Center, Indianapolis, IN, USA
| | - Petr Kavan
- Oncology, McGill University, Montreal, Quebec, Canada
| | - Takayuki Yoshino
- Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Rosine Guimbaud
- Digestive Medical Oncology, Centre Hospitalier Universitaire de Toulouse, Toulouse, France
| | | | - Elena Élez
- Medical Oncology, Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Institute of Oncology, Barcelona, Spain; Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Salah-Eddin Al-Batran
- Krankenhaus Nordwest, University Cancer Center (UCT), Frankfurt, Germany; Institute of Clinical Cancer Research (IKF), Frankfurt, Germany
| | - Patrick M Boland
- Medical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
| | - Yi Cui
- Biostatistician Oncology, MSD China, Beijing, China
| | | | | | - Thierry André
- Sorbonne Université, INSERM, Unité Mixte de Recherche Scientifique 938 and SIRIC CURAMUS, Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Paris, France; Medical Oncology Department, Hôpital Saint-Antoine, Paris, France
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18
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Yao Y, Li Z, Zhao R. Editorial: Supramolecular cancer therapeutic biomaterials. Front Chem 2023; 11:1162103. [PMID: 36936528 PMCID: PMC10020698 DOI: 10.3389/fchem.2023.1162103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 02/27/2023] [Indexed: 03/06/2023] Open
Affiliation(s)
- Yong Yao
- School of Chemistry and Chemical Engineering, Nantong University, Nantong, China
| | - Zhengtao Li
- Department of Chemistry, National University of Singapore, Singapore, Singapore
| | - Ruibo Zhao
- Department of Materials, Imperial College London, London, United Kingdom
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19
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Shasha T, Gruijs M, van Egmond M. Mechanisms of colorectal liver metastasis development. Cell Mol Life Sci 2022; 79:607. [PMID: 36436127 PMCID: PMC9701652 DOI: 10.1007/s00018-022-04630-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 11/11/2022] [Accepted: 11/13/2022] [Indexed: 11/28/2022]
Abstract
Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide, largely due to the development of colorectal liver metastases (CRLM). For the establishment of CRLM, CRC cells must remodel their tumor-microenvironment (TME), avoid the immune system, invade the underlying stroma, survive the hostile environment of the circulation, extravasate into the liver, reprogram the hepatic microenvironment into a permissive pre-metastatic niche, and finally, awake from a dormant state to grow out into clinically detectable CRLM. These steps form part of the invasion-metastasis cascade that relies on reciprocal interactions between the tumor and its ever-changing microenvironment. Such interplay provides a strong rational for therapeutically targeting the TME. In fact, several TME constituents, such as VEGF, TGF-β coreceptor endoglin, and CXCR4, are already targeted in clinical trials. It is, however, of utmost importance to fully understand the complex interactions in the invasion-metastasis cascade to identify novel potential therapeutic targets and prevent the establishment of CRLM, which may ultimately greatly improve patient outcome.
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Affiliation(s)
- Tal Shasha
- Molecular Cell Biology and Immunology, Amsterdam UMC Location Vrije Universiteit Amsterdam, De Boelelaan 1117, Amsterdam, The Netherlands
- Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, The Netherlands
- Amsterdam Institute for Infection and Immunity, Cancer Immunology, Amsterdam, The Netherlands
| | - Mandy Gruijs
- Molecular Cell Biology and Immunology, Amsterdam UMC Location Vrije Universiteit Amsterdam, De Boelelaan 1117, Amsterdam, The Netherlands
- Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, The Netherlands
- Amsterdam Institute for Infection and Immunity, Cancer Immunology, Amsterdam, The Netherlands
| | - Marjolein van Egmond
- Molecular Cell Biology and Immunology, Amsterdam UMC Location Vrije Universiteit Amsterdam, De Boelelaan 1117, Amsterdam, The Netherlands.
- Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, The Netherlands.
- Amsterdam Institute for Infection and Immunity, Cancer Immunology, Amsterdam, The Netherlands.
- Amsterdam UMC Location Vrije Universiteit Amsterdam, Surgery, De Boelelaan 1117, Amsterdam, The Netherlands.
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20
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Russo V, Lallo E, Munnia A, Spedicato M, Messerini L, D’Aurizio R, Ceroni EG, Brunelli G, Galvano A, Russo A, Landini I, Nobili S, Ceppi M, Bruzzone M, Cianchi F, Staderini F, Roselli M, Riondino S, Ferroni P, Guadagni F, Mini E, Peluso M. Artificial Intelligence Predictive Models of Response to Cytotoxic Chemotherapy Alone or Combined to Targeted Therapy for Metastatic Colorectal Cancer Patients: A Systematic Review and Meta-Analysis. Cancers (Basel) 2022; 14:4012. [PMID: 36011003 PMCID: PMC9406544 DOI: 10.3390/cancers14164012] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 07/26/2022] [Accepted: 08/12/2022] [Indexed: 12/24/2022] Open
Abstract
Tailored treatments for metastatic colorectal cancer (mCRC) have not yet completely evolved due to the variety in response to drugs. Therefore, artificial intelligence has been recently used to develop prognostic and predictive models of treatment response (either activity/efficacy or toxicity) to aid in clinical decision making. In this systematic review, we have examined the ability of learning methods to predict response to chemotherapy alone or combined with targeted therapy in mCRC patients by targeting specific narrative publications in Medline up to April 2022 to identify appropriate original scientific articles. After the literature search, 26 original articles met inclusion and exclusion criteria and were included in the study. Our results show that all investigations conducted on this field have provided generally promising results in predicting the response to therapy or toxic side-effects. By a meta-analytic approach we found that the overall weighted means of the area under the receiver operating characteristic (ROC) curve (AUC) were 0.90, 95% C.I. 0.80-0.95 and 0.83, 95% C.I. 0.74-0.89 in training and validation sets, respectively, indicating a good classification performance in discriminating response vs. non-response. The calculation of overall HR indicates that learning models have strong ability to predict improved survival. Lastly, the delta-radiomics and the 74 gene signatures were able to discriminate response vs. non-response by correctly identifying up to 99% of mCRC patients who were responders and up to 100% of patients who were non-responders. Specifically, when we evaluated the predictive models with tests reaching 80% sensitivity (SE) and 90% specificity (SP), the delta radiomics showed an SE of 99% and an SP of 94% in the training set and an SE of 85% and SP of 92 in the test set, whereas for the 74 gene signatures the SE was 97.6% and the SP 100% in the training set.
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Affiliation(s)
- Valentina Russo
- Research and Development Branch, Regional Cancer Prevention Laboratory, ISPRO-Study, Prevention and Oncology Network Institute, 50139 Florence, Italy
| | - Eleonora Lallo
- Research and Development Branch, Regional Cancer Prevention Laboratory, ISPRO-Study, Prevention and Oncology Network Institute, 50139 Florence, Italy
| | - Armelle Munnia
- Research and Development Branch, Regional Cancer Prevention Laboratory, ISPRO-Study, Prevention and Oncology Network Institute, 50139 Florence, Italy
| | - Miriana Spedicato
- Research and Development Branch, Regional Cancer Prevention Laboratory, ISPRO-Study, Prevention and Oncology Network Institute, 50139 Florence, Italy
| | - Luca Messerini
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
| | - Romina D’Aurizio
- Institute of Informatics and Telematics, National Research Council, 56124 Pisa, Italy
| | - Elia Giuseppe Ceroni
- Institute of Informatics and Telematics, National Research Council, 56124 Pisa, Italy
| | - Giulia Brunelli
- Institute of Informatics and Telematics, National Research Council, 56124 Pisa, Italy
| | - Antonio Galvano
- Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy
| | - Antonio Russo
- Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy
| | - Ida Landini
- Department of Health Sciences, University of Florence, 50139 Florence, Italy
| | - Stefania Nobili
- Department of Neurosciences, Imaging and Clinical Sciences, “G. D’Annunzio” Chieti-Pescara, 66100 Chieti, Italy
| | - Marcello Ceppi
- Clinical Epidemiology Unit, IRCCS-Ospedale Policlinico San Martino, 16131 Genova, Italy
| | - Marco Bruzzone
- Clinical Epidemiology Unit, IRCCS-Ospedale Policlinico San Martino, 16131 Genova, Italy
| | - Fabio Cianchi
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
| | - Fabio Staderini
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
| | - Mario Roselli
- Medical Oncology Unit, Department of Systems Medicine, Tor Vergata University, 00133 Rome, Italy
| | - Silvia Riondino
- Medical Oncology Unit, Department of Systems Medicine, Tor Vergata University, 00133 Rome, Italy
| | - Patrizia Ferroni
- BioBIM (InterInstitutional Multidisciplinary Biobank), IRCCS San Raffaele Roma, 00166 Rome, Italy
- Department of Human Sciences & Quality of Life Promotion, San Raffaele Roma Open University, 00166 Rome, Italy
| | - Fiorella Guadagni
- BioBIM (InterInstitutional Multidisciplinary Biobank), IRCCS San Raffaele Roma, 00166 Rome, Italy
- Department of Human Sciences & Quality of Life Promotion, San Raffaele Roma Open University, 00166 Rome, Italy
| | - Enrico Mini
- Department of Health Sciences, University of Florence, 50139 Florence, Italy
| | - Marco Peluso
- Research and Development Branch, Regional Cancer Prevention Laboratory, ISPRO-Study, Prevention and Oncology Network Institute, 50139 Florence, Italy
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21
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Line PD. Liver transplantation for colorectal secondaries: on the way to validation. Curr Opin Organ Transplant 2022; 27:329-336. [PMID: 36354259 DOI: 10.1097/mot.0000000000000977] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
PURPOSE OF REVIEW Liver transplantation for nonresectable colorectal liver metastases (CRLMs) is an emerging field within transplant oncology. This review summarizes recent developments within this field. RECENT FINDINGS More stringent selection criteria can yield 5-year survival rates that are similar to conventional indications for liver transplantation. Response to chemotherapy, low carcinoembryonic antigen levels, limited tumor volume and stable disease with observation time exceeding 12 months are fundamental requirements in this context. Radiomic analysis of pre transplant PET/computed tomography scans to determine metabolic tumor volume (MTV) in the liver seems particularly promising with regards to prediction of a favorable tumor biology. MTV values below 70 cm3 are associated with excellent long-term survival after transplantation, whereas the MTV threshold for liver resection seem far smaller. Recent studies put into question whether technical nonresectability per se is a valid inclusion criterion for liver transplantation. In patients with high hepatic tumor burden, but otherwise favorable prognostic features as assessed by the Oslo score, liver transplantation could possibly give a clinically relevant survival benefit compared with liver resection. SUMMARY Liver transplantation is feasible treatment option in highly selected patients with nonresectable CRLMs. Robust and stringent selection criteria should be applied according to international consensus guidelines.
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Affiliation(s)
- Pål-Dag Line
- Department of Transplantation Medicine, Oslo University Hospital
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
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22
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Li J, Chen D, Shen M. Tumor Microenvironment Shapes Colorectal Cancer Progression, Metastasis, and Treatment Responses. Front Med (Lausanne) 2022; 9:869010. [PMID: 35402443 PMCID: PMC8984105 DOI: 10.3389/fmed.2022.869010] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Accepted: 02/24/2022] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most devastating diseases that accounts for numerous deaths worldwide. Tumor cell-autonomous pathways, such as the oncogenic signaling activation, significantly contribute to CRC progression and metastasis. Recent accumulating evidence suggests that the CRC microenvironment also profoundly promotes or represses this process. As the roles of the tumor microenvironment (TME) in CRC progression and metastasis is gradually uncovered, the importance of these non-cell-autonomous signaling pathways is appreciated. However, we are still at the beginning of this TME function exploring process. In this review, we summarize the current understanding of the TME in CRC progression and metastasis by focusing on the gut microbiota and host cellular and non-cellular components. We also briefly discuss TME-remodeling therapies in CRC.
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Affiliation(s)
- Jun Li
- Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI, United States
| | - Dawei Chen
- Wayne State University School of Medicine, Detroit, MI, United States
| | - Minhong Shen
- Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI, United States
- Department of Oncology, Wayne State University School of Medicine and Tumor Biology and Microenvironment Research Program, Barbara Ann Karmanos Cancer Institute, Detroit, MI, United States
- *Correspondence: Minhong Shen,
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23
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Wang J, Kang Y, Li Y, Sun L, Zhang J, Qian S, Luo K, Jiang Y, Sun L, Xu F. Gasdermin D in Different Subcellular Locations Predicts Diverse Progression, Immune Microenvironment and Prognosis in Colorectal Cancer. J Inflamm Res 2021; 14:6223-6235. [PMID: 34858044 PMCID: PMC8630373 DOI: 10.2147/jir.s338584] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Accepted: 11/02/2021] [Indexed: 12/23/2022] Open
Abstract
Background Pyroptosis is a type of cell death that causes an immune reaction. Gasdermin D (GSDMD), as an executor of pyroptosis, has become an attractive target in cancer research. However, the clinical significance of GSDMD expression in different subcellular locations remains unclear. Methods GSDMD was detected by immunohistochemistry in 178 cases of colorectal cancer with follow-up information. General data and information on systemic inflammatory indicators were collected from case records, and the clinicopathological parameters were reviewed by microscopy. CD3+, CD4+, and CD8+ T lymphocytes, CD20+ B lymphocytes, and CD68+ macrophages were detected by immunohistochemistry. Univariate survival analysis (Kaplan–Meier method, Log rank test) and a multivariate Cox proportional hazard model were used to analyze the impact of GSDMD on overall survival. Results Survival analysis showed that high expression of cytoplasmic GSDMD was an independent favorable indicator for prognosis (P=0.027) and improved the efficacy of chemotherapy (P=0.012). Positive cytoplasmic GSDMD expression indicated lower probability of distant metastasis (P=0.024), yet nuclear GSDMD expression predicted deeper infiltration depth (P=0.007). Membranous GSDMD expression positively correlated with CD68+ macrophages in tumor center (P=0.002) and CD8+ lymphocytes in tumor invasive front (P=0.007). However, nuclear GSDMD was negatively related to CD68+ macrophages in tumor invasive front (P<0.001) and CD8+ lymphocytes in tumor center (P=0.069). Cytoplasmic GSDMD was associated with more CD3+ lymphocytes both in tumor center (P=0.066) and tumor invasive front (P=0.008). Moreover, positive membranous GSDMD indicated a lower neutrophil-to-lymphocyte ratio (P=0.013). Conclusion GSDMD subcellular localization patterns are related to CRC progression and immune reaction, and should be investigated in future studies.
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Affiliation(s)
- Jiahui Wang
- Department of Pathology and Pathophysiology, and Department of General Surgery of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China.,Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China
| | - Yixin Kang
- Department of Pathology and Pathophysiology, and Department of General Surgery of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China.,Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China
| | - Yuxuan Li
- Department of Pathology and Pathophysiology, and Department of General Surgery of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China.,Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China
| | - Liang Sun
- Department of Pathology and Pathophysiology, and Department of General Surgery of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China.,Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China
| | - Jun Zhang
- Department of Pathology and Pathophysiology, and Department of General Surgery of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China.,Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China
| | - Senmi Qian
- Department of Pathology and Pathophysiology, and Department of General Surgery of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China.,Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China
| | - Ke Luo
- Department of Pathology and Pathophysiology, and Department of General Surgery of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China
| | - Yi Jiang
- Department of Statistics, School of Mathematical Sciences, Anhui University, Hefei, Anhui, People's Republic of China
| | - Lichao Sun
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Fangying Xu
- Department of Pathology and Pathophysiology, and Department of General Surgery of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China.,Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China
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24
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Kobori T, Tanaka C, Tameishi M, Urashima Y, Ito T, Obata T. Role of Ezrin/Radixin/Moesin in the Surface Localization of Programmed Cell Death Ligand-1 in Human Colon Adenocarcinoma LS180 Cells. Pharmaceuticals (Basel) 2021; 14:ph14090864. [PMID: 34577564 PMCID: PMC8467328 DOI: 10.3390/ph14090864] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 08/23/2021] [Accepted: 08/26/2021] [Indexed: 12/30/2022] Open
Abstract
Programmed cell death ligand-1 (PD-L1), an immune checkpoint protein highly expressed on the cell surface in various cancer cell types, binds to programmed cell death-1 (PD-1), leading to T-cell dysfunction and tumor survival. Despite clinical successes of PD-1/PD-L1 blockade therapies, patients with colorectal cancer (CRC) receive little benefit because most cases respond poorly. Because high PD-L1 expression is associated with immune evasion and poor prognosis in CRC patients, identifying potential modulators for the plasma membrane localization of PD-L1 may represent a novel therapeutic strategy for enhancing the efficacy of PD-1/PD-L1 blockade therapies. Here, we investigated whether PD-L1 expression in human colorectal adenocarcinoma cells (LS180) is affected by ezrin/radixin/moesin (ERM), functioning as scaffold proteins that crosslink plasma membrane proteins with the actin cytoskeleton. We observed colocalization of PD-L1 with all three ERM proteins in the plasma membrane and detected interactions involving PD-L1, the three ERM proteins, and the actin cytoskeleton. Furthermore, gene silencing of ezrin and radixin, but not of moesin, substantially decreased the expression of PD-L1 on the cell surface without affecting its mRNA level. Thus, in LS180 cells, ezrin and radixin may function as scaffold proteins mediating the plasma membrane localization of PD-L1, possibly by post-translational modification.
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Affiliation(s)
- Takuro Kobori
- Laboratory of Clinical Pharmaceutics, Faculty of Pharmacy, Osaka Ohtani University, Tondabayashi, Osaka 584-8540, Japan; (T.K.); (C.T.); (M.T.); (Y.U.)
| | - Chihiro Tanaka
- Laboratory of Clinical Pharmaceutics, Faculty of Pharmacy, Osaka Ohtani University, Tondabayashi, Osaka 584-8540, Japan; (T.K.); (C.T.); (M.T.); (Y.U.)
| | - Mayuka Tameishi
- Laboratory of Clinical Pharmaceutics, Faculty of Pharmacy, Osaka Ohtani University, Tondabayashi, Osaka 584-8540, Japan; (T.K.); (C.T.); (M.T.); (Y.U.)
| | - Yoko Urashima
- Laboratory of Clinical Pharmaceutics, Faculty of Pharmacy, Osaka Ohtani University, Tondabayashi, Osaka 584-8540, Japan; (T.K.); (C.T.); (M.T.); (Y.U.)
| | - Takuya Ito
- Laboratory of Natural Medicines, Faculty of Pharmacy, Osaka Ohtani University, Tondabayashi, Osaka 584-8540, Japan;
| | - Tokio Obata
- Laboratory of Clinical Pharmaceutics, Faculty of Pharmacy, Osaka Ohtani University, Tondabayashi, Osaka 584-8540, Japan; (T.K.); (C.T.); (M.T.); (Y.U.)
- Correspondence: ; Tel.: +81-721-24-9371
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