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Sato H, Meng S, Hara T, Tsuji Y, Arao Y, Sasaki K, Kobayashi S, di Luccio E, Hirotsu T, Satoh T, Doki Y, Eguchi H, Ishii H. Tissue-Resident Memory T Cells in Gastrointestinal Cancers: Prognostic Significance and Therapeutic Implications. Biomedicines 2024; 12:1342. [PMID: 38927549 PMCID: PMC11202222 DOI: 10.3390/biomedicines12061342] [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: 04/26/2024] [Revised: 06/05/2024] [Accepted: 06/12/2024] [Indexed: 06/28/2024] Open
Abstract
Gastrointestinal cancers, which include a variety of esophageal and colorectal malignancies, present a global health challenge and require effective treatment strategies. In the evolving field of cancer immunotherapy, tissue-resident memory T cells (Trm cells) have emerged as important players in the immune response within nonlymphoid tissues. In this review, we summarize the characteristics and functions of Trm cells and discuss their profound implications for patient outcomes in gastrointestinal cancers. Positioned strategically in peripheral tissues, Trm cells have functions beyond immune surveillance, affecting tumor progression, prognosis, and response to immunotherapy. Studies indicate that Trm cells are prognostic markers and correlate positively with enhanced survival. Their presence in the tumor microenvironment has sparked interest in their therapeutic potential, particularly with respect to immune checkpoint inhibitors, which may improve cancer treatment. Understanding how Trm cells work will not only help to prevent cancer spread through effective treatment but will also contribute to disease prevention at early stages as well as vaccine development. The role of Trm cells goes beyond just cancer, and they have potential applications in infectious and autoimmune diseases. This review provides a thorough analysis of Trm cells in gastrointestinal cancers, which may lead to personalized and effective cancer therapies.
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Affiliation(s)
- Hiromichi Sato
- Department of Medical Data Science, Center of Medical Innovation and Translational Research, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita 565-0871, Japan; (H.S.)
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita 565-0871, Japan
| | - Sikun Meng
- Department of Medical Data Science, Center of Medical Innovation and Translational Research, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita 565-0871, Japan; (H.S.)
| | - Tomoaki Hara
- Department of Medical Data Science, Center of Medical Innovation and Translational Research, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita 565-0871, Japan; (H.S.)
| | - Yoshiko Tsuji
- Department of Medical Data Science, Center of Medical Innovation and Translational Research, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita 565-0871, Japan; (H.S.)
| | - Yasuko Arao
- Department of Medical Data Science, Center of Medical Innovation and Translational Research, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita 565-0871, Japan; (H.S.)
| | - Kazuki Sasaki
- Department of Medical Data Science, Center of Medical Innovation and Translational Research, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita 565-0871, Japan; (H.S.)
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita 565-0871, Japan
| | - Shogo Kobayashi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita 565-0871, Japan
| | - Eric di Luccio
- Hirotsu Bio Science Inc., Chiyoda-Ku, Tokyo 102-0094, Japan
| | | | - Taroh Satoh
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita 565-0871, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita 565-0871, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita 565-0871, Japan
| | - Hideshi Ishii
- Department of Medical Data Science, Center of Medical Innovation and Translational Research, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita 565-0871, Japan; (H.S.)
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Singvogel K, Schittek B. Dormancy of cutaneous melanoma. Cancer Cell Int 2024; 24:88. [PMID: 38419052 PMCID: PMC10903048 DOI: 10.1186/s12935-024-03278-5] [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: 10/09/2023] [Accepted: 02/19/2024] [Indexed: 03/02/2024] Open
Abstract
Many cancer-related deaths including melanoma result from metastases that develop months or years after the initial cancer therapy. Even the most effective drugs and immune therapies rarely eradicate all tumor cells. Instead, they strongly reduce cancer burden, permitting dormant cancer cells to persist in niches, where they establish a cellular homeostasis with their host without causing clinical symptoms. Dormant cancers respond poorly to most drugs and therapies since they do not proliferate and hide in niches. It therefore remains a major challenge to develop novel therapies for dormant cancers. In this review we focus on the mechanisms regulating the initiation of cutaneous melanoma dormancy as well as those which are involved in reawakening of dormant cutaneous melanoma cells. In recent years the role of neutrophils and niche components in reawakening of melanoma cells came into focus and indicate possible future therapeutic applications. Sophisticated in vitro and in vivo melanoma dormancy models are needed to make progress in this field and are discussed.
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Affiliation(s)
- Kathrin Singvogel
- Division of Dermatooncology, Department of Dermatology, University of Tübingen, Liebermeisterstr. 25, D -72076 , Tübingen, Germany
| | - Birgit Schittek
- Division of Dermatooncology, Department of Dermatology, University of Tübingen, Liebermeisterstr. 25, D -72076 , Tübingen, Germany.
- Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tübingen, Tübingen, Germany.
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Li J, Yang C, Zheng Y. Identification of a tissue resident memory CD8 T cell-related risk score signature for colorectal cancer, the association with TME landscapes and therapeutic responses. Front Genet 2023; 13:1088230. [PMID: 36685946 PMCID: PMC9845416 DOI: 10.3389/fgene.2022.1088230] [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: 11/03/2022] [Accepted: 12/12/2022] [Indexed: 01/05/2023] Open
Abstract
Backgrounds: The tissue resident memory CD8 T cell (Trm) constitutes an important component of the local immunity. In the context of malignant tumors, mounting evidence also supports the potential anti-tumor property of this cell subset. Therefore, identification of Trm marker genes and exploration of the causative effect of Trm in shaping tumor microenvironment (TME) heterogeneity might provide novel insights for the comprehensive management of cancer patients. Methods: By dissecting a single T cell transcriptome dataset, we acquired marker genes for Trm, which were latter applied to bulk RNA sequencing profiles of two large colorectal cancer (CRC) patient cohorts downloaded from TCGA and GEO databases. First, colorectal cancer patients were divided into different Trm clusters using consensus clustering algorithm. Then, we established a Trm-related gene (TRMRG) risk score signature and tested its efficacy in predicting prognosis for colorectal cancer patients. Moreover, a sequence of rigorous and robust analyses were also carried out to investigate the potential role of Trm-related gene risk score in tumor microenvironment remodeling and therapeutic utility of it in colorectal cancer treatment. Results: A total of 49 Trm marker genes were identified by analyzing single cell RNA sequencing profiles. First, colorectal cancer patients were successfully classified into two Trm clusters with significant heterogeneity in functional enrichment patterns and tumor microenvironment landscapes. Then, we developed a Trm-related gene risk score signature and divided patients into different risk levels. High risk patients were characterized by attenuated immunogenicity, weakened sensitivity to immunotherapy, as well as adverse clinical outcomes. While low risk patients with advantages in survival exhibited increased immunogenicity, stronger metabolic activity and improved immunotherapeutic responses. Conclusion: Through combinatorial analysis of single cell and bulk RNA sequencing data, the present study identified Trm to play a non-negligible role in regulating the complexity and heterogeneity of tumor microenvironment for colorectal cancer. Moreover, the Trm-related gene risk score signature developed currently was corroborated to be tightly correlated with prognosis and therapeutic responses of colorectal cancer patients, thus exhibiting potential application value for clinical practice.
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Tolstykh EI, Degteva MO, Vozilova AV, Akleyev AV. Approaches to Cytogenetic Assessment of the Dose due to Radiation Exposure of the Gut-Associated Lymphoid Tissue. BIOL BULL+ 2022. [DOI: 10.1134/s1062359022110206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/17/2023]
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Plunkett KR, Armitage JD, Inderjeeth AJ, McDonnell AM, Waithman J, Lau PKH. Tissue-resident memory T cells in the era of (Neo) adjuvant melanoma management. Front Immunol 2022; 13:1048758. [PMID: 36466880 PMCID: PMC9709277 DOI: 10.3389/fimmu.2022.1048758] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 10/13/2022] [Indexed: 10/10/2023] Open
Abstract
Tissue-resident memory T (TRM) cells have emerged as key players in the immune control of melanoma. These specialized cells are identified by expression of tissue retention markers such as CD69, CD103 and CD49a with downregulation of egress molecules such as Sphingosine-1-Phosphate Receptor-1 (S1PR1) and the lymphoid homing receptor, CD62L. TRM have been shown to be integral in controlling infections such as herpes simplex virus (HSV), lymphocytic choriomeningitis virus (LCMV) and influenza. More recently, robust pre-clinical models have also demonstrated TRM are able to maintain melanoma in a dormant state without progression to macroscopic disease reminiscent of their ability to control viral infections. The discovery of the role these cells play in anti-melanoma immunity has coincided with the advent of immune checkpoint inhibitor (ICI) therapy which has revolutionized the treatment of cancers. ICIs that target programmed death protein-1 (PD-1) and cytotoxic T lymphocyte antigen-4 (CTLA-4) have led to substantial improvements in outcomes for patients with metastatic melanoma and have been rapidly employed to reduce recurrences in the resected stage III setting. While ICIs mediate anti-tumor activity via CD8+ T cells, the specific subsets that facilitate this response is unclear. TRM invariably exhibit high expression of immune checkpoints such as PD-1, CTLA-4 and lymphocyte activating gene-3 (LAG-3) which strongly implicates this CD8+ T cell subset as a crucial mediator of ICI activity. In this review, we present pre-clinical and translational studies that highlight the critical role of TRM in both immune control of primary melanoma and as a key CD8+ T cell subset that mediates anti-tumor activity of ICIs for the treatment of melanoma.
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Affiliation(s)
- Kai R. Plunkett
- School of Biomedical Sciences, University of Western Australia, Nedlands, WA, Australia
- Telethon Kids Institute, University of Western Australia, Nedlands, WA, Australia
| | - Jesse D. Armitage
- School of Biomedical Sciences, University of Western Australia, Nedlands, WA, Australia
- Telethon Kids Institute, University of Western Australia, Nedlands, WA, Australia
| | | | - Alison M. McDonnell
- Telethon Kids Institute, University of Western Australia, Nedlands, WA, Australia
| | - Jason Waithman
- School of Biomedical Sciences, University of Western Australia, Nedlands, WA, Australia
- Telethon Kids Institute, University of Western Australia, Nedlands, WA, Australia
| | - Peter K. H. Lau
- Melanoma Discovery Laboratory, Harry Perkins Institute of Medical Research, Nedlands, WA, Australia
- Department of Medical Oncology, Sir Charles Gairdner Hospital, Nedlands, WA, Australia
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Yenyuwadee S, Sanchez-Trincado Lopez JL, Shah R, Rosato PC, Boussiotis VA. The evolving role of tissue-resident memory T cells in infections and cancer. SCIENCE ADVANCES 2022; 8:eabo5871. [PMID: 35977028 PMCID: PMC9385156 DOI: 10.1126/sciadv.abo5871] [Citation(s) in RCA: 79] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Accepted: 07/05/2022] [Indexed: 06/12/2023]
Abstract
Resident memory T cells (TRM) form a distinct type of T memory cells that stably resides in tissues. TRM form an integral part of the immune sensing network and have the ability to control local immune homeostasis and participate in immune responses mediated by pathogens, cancer, and possibly autoantigens during autoimmunity. TRM express residence gene signatures, functional properties of both memory and effector cells, and remarkable plasticity. TRM have a well-established role in pathogen immunity, whereas their role in antitumor immune responses and immunotherapy is currently evolving. As TRM form the most abundant T memory cell population in nonlymphoid tissues, they are attractive targets for therapeutic exploitation. Here, we provide a concise review of the development and physiological role of CD8+ TRM, their involvement in diseases, and their potential therapeutic exploitation.
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Affiliation(s)
- Sasitorn Yenyuwadee
- Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
- Department of Dermatology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Jose Luis Sanchez-Trincado Lopez
- Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
- Laboratory of Immunomedicine, School of Medicine, Complutense University of Madrid, Ave Complutense S/N, 28040 Madrid, Spain
| | - Rushil Shah
- Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
- Cornell University, Ithaca, NY 14850 , USA
| | - Pamela C Rosato
- The Geisel School of Medicine at Dartmouth, Lebanon, NH 03755, USA
| | - Vassiliki A Boussiotis
- Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
- Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
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Toh JWT, Ferguson AL, Spring KJ, Mahajan H, Palendira U. Cytotoxic CD8+ T cells and tissue resident memory cells in colorectal cancer based on microsatellite instability and BRAF status. World J Clin Oncol 2021; 12:238-248. [PMID: 33959477 PMCID: PMC8085513 DOI: 10.5306/wjco.v12.i4.238] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 03/14/2021] [Accepted: 04/05/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Recent studies in non-colorectal malignancy have associated T resident memory (TRM) cells with improved patient survival. It is unknown if TRM plays a role in colorectal cancer (CRC).
AIM To examine the potential role of TRM cells in providing immunogenicity in CRC stratified by microsatellite instability (MSI) and BRAF status.
METHODS Patients with known MSI and BRAF mutation status were eligible for inclusion in this study. CRC tumour sections stained with haematoxylin and eosin were microscopically reviewed and the images scanned prior to assessment for location of invading edge and core of tumour. Sequential sections were prepared for quantitative multiplex immunohistochemistry (IHC) staining. Opal Multiplex IHC staining was performed with appropriate positive and negative controls and imaged using a standard fluorescent microscope fitted with a spectral scanning camera (Mantra) in conjunction with Mantra snap software. Images were unmixed and annotated in inForm 2.2.0. Statistical analysis was performed using Graphpad Prism Version 7 and Stata Version 15.
RESULTS Seventy-two patients with known MSI and BRAF status were included in the study. All patients were assessed for MSI by IHC and high resolution capillary electrophoresis testing and 44 of these patients successfully underwent quantitative multiplex IHC staining. Overall, there was a statistically significant increase in CD8+ TRM cells in the MSI (BRAF mutant and wild type) group over the microsatellite stable (MSS) group. There was a statistically significant difference in CD8+ TRM between high level MSI (MSI-H):BRAF mutant [22.57, 95% confidence interval (CI): 14.31-30.84] vs MSS [8.031 (95%CI: 4.698-11.36)], P = 0.0076 andMSI-H:BRAF wild type [16.18 (95%CI: 10.44-21.93)] vs MSS [8.031 (95%CI: 4.698-11.36)], P = 0.0279. There was no statistically significant difference in CD8 T cells (both CD8+CD103- and CD8+CD103+TRM) between MSI-H: BRAF mutant and wild type CRC.
CONCLUSION This study has shown that CD8+ TRM are found in greater abundance in MSI-H CRC, both BRAF mutant and MSI-H:BRAF wild type, when compared with their MSS counterpart. CD8+ TRM may play a role in the immunogenicity in MSI-H CRC (BRAF mutant and BRAF wild type). Further studies should focus on the potential immunogenic qualities of TRM cells and investigate potential immunotherapeutic approaches to improve treatment and survival associated with CRC.
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Affiliation(s)
- James Wei Tatt Toh
- Division of Surgery and Anaesthesia, Department of Colorectal Surgery, Westmead Hospital, Westmead Clinical School, The University of Sydney, Ingham Institute for Applied Medical Research, Westmead 2145, NSW, Australia
| | - Angela L Ferguson
- Department of Infectious Diseases and Immunology, School of Medical Sciences, Faculty of Medicine and Health, Human Viral & Cancer Immunology, Centenary Institute, Charles Perkin Centre, The University of Sydney, Sydney 2000, NSW, Australia
| | - Kevin J Spring
- Medical Oncology Group, Ingham Institute for Applied Medical Research, Liverpool Hospital, Liverpool Clinical School, University of Western Sydney, South Western Clinical School UNSW, Liverpool 2170, NSW, Australia
| | - Hema Mahajan
- Department of Anatomical Pathology, ICPMR, Westmead Hospital, Westmead 2145, NSW, Australia
| | - Umaimainthan Palendira
- Department of Immunology and Infectious Diseases, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney 2000, NSW, Australia
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Hamilton SE, Badovinac VP, Beura LK, Pierson M, Jameson SC, Masopust D, Griffith TS. New Insights into the Immune System Using Dirty Mice. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2020; 205:3-11. [PMID: 32571979 PMCID: PMC7316151 DOI: 10.4049/jimmunol.2000171] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Accepted: 05/04/2020] [Indexed: 02/06/2023]
Abstract
The mouse (Mus musculus) is the dominant organism used to investigate the mechanisms behind complex immunological responses because of their genetic similarity to humans and our ability to manipulate those genetics to understand downstream function. Indeed, our knowledge of immune system development, response to infection, and ways to therapeutically manipulate the immune response to combat disease were, in large part, delineated in the mouse. Despite the power of mouse-based immunology research, the translational efficacy of many new therapies from mouse to human is far from ideal. Recent data have highlighted how the naive, neonate-like immune system of specific pathogen-free mice differs dramatically in composition and function to mice living under barrier-free conditions (i.e., "dirty" mice). In this review, we discuss major findings to date and challenges faced when using dirty mice and specific areas of immunology research that may benefit from using animals with robust and varied microbial exposure.
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Affiliation(s)
- Sara E Hamilton
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455
- Microbiology, Immunology, and Cancer Biology Ph.D. Program, University of Minnesota, Minneapolis, MN 55455
- Center for Immunology, University of Minnesota, Minneapolis, MN 55455
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455
| | - Vladimir P Badovinac
- Department of Pathology, University of Iowa, Iowa City, IA 52242
- Department of Microbiology and Immunology, University of Iowa, Iowa City, IA 52242
- Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, IA 52242
| | - Lalit K Beura
- Department of Molecular Microbiology and Immunology, Brown University, Providence, RI 02912
| | - Mark Pierson
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455
| | - Stephen C Jameson
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455
- Microbiology, Immunology, and Cancer Biology Ph.D. Program, University of Minnesota, Minneapolis, MN 55455
- Center for Immunology, University of Minnesota, Minneapolis, MN 55455
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455
| | - David Masopust
- Microbiology, Immunology, and Cancer Biology Ph.D. Program, University of Minnesota, Minneapolis, MN 55455
- Center for Immunology, University of Minnesota, Minneapolis, MN 55455
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455
- Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55455
| | - Thomas S Griffith
- Microbiology, Immunology, and Cancer Biology Ph.D. Program, University of Minnesota, Minneapolis, MN 55455;
- Center for Immunology, University of Minnesota, Minneapolis, MN 55455
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455
- Department of Urology, University of Minnesota, Minneapolis, MN 55455; and
- Minneapolis Veterans Affairs Health Care System, Minneapolis, MN 55417
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