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1
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Naskar S, Sriraman N, Sarkar A, Mahajan N, Sarkar K. Tumor antigen presentation and the associated signal transduction during carcinogenesis. Pathol Res Pract 2024; 261:155485. [PMID: 39088877 DOI: 10.1016/j.prp.2024.155485] [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: 01/13/2024] [Revised: 07/17/2024] [Accepted: 07/22/2024] [Indexed: 08/03/2024]
Abstract
Numerous developments have been achieved in the study and treatment of cancer throughout the decades that it has been common. After decades of research, about 100 different kinds of cancer have been found, each with unique subgroups within certain organs. This has significantly expanded our understanding of the illness. A mix of genetic, environmental, and behavioral variables contribute to the complicated and diverse process of cancer formation. Mutations, or changes in the DNA sequence, are crucial to the development of cancer. These mutations have the ability to downregulate the expression and function of Major Histocompatibility Complex class I (MHC I) and MHCII receptors, as well as activate oncogenes and inactivate tumor suppressor genes. Cancer cells use this tactic to avoid being recognized by cytotoxic CD8+T lymphocytes, which causes issues with antigen presentation and processing. This review goes into great length into the PI3K pathway, changes to MHC I, and positive impacts of tsMHC-II on disease-free survival and overall survival and the involvement of dendritic cells (DCs) in different tumor microenvironments. The vital functions that the PI3K pathway and its link to the mTOR pathway are highlighted and difficulties in developing effective cancer targeted therapies and feedback systems has also been mentioned, where resistance mechanisms include RAS-mediated oncogenic changes and active PI3K signalling.
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Affiliation(s)
- Sohom Naskar
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu 603203, India
| | - Nawaneetan Sriraman
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu 603203, India
| | - Ankita Sarkar
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu 603203, India
| | - Nitika Mahajan
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu 603203, India
| | - Koustav Sarkar
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu 603203, India.
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Wen M, Li Y, Qin X, Qin B, Wang Q. Insight into Cancer Immunity: MHCs, Immune Cells and Commensal Microbiota. Cells 2023; 12:1882. [PMID: 37508545 PMCID: PMC10378520 DOI: 10.3390/cells12141882] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 06/16/2023] [Accepted: 07/05/2023] [Indexed: 07/30/2023] Open
Abstract
Cancer cells circumvent immune surveillance via diverse strategies. In accordance, a large number of complex studies of the immune system focusing on tumor cell recognition have revealed new insights and strategies developed, largely through major histocompatibility complexes (MHCs). As one of them, tumor-specific MHC-II expression (tsMHC-II) can facilitate immune surveillance to detect tumor antigens, and thereby has been used in immunotherapy, including superior cancer prognosis, clinical sensitivity to immune checkpoint inhibition (ICI) therapy and tumor-bearing rejection in mice. NK cells play a unique role in enhancing innate immune responses, accounting for part of the response including immunosurveillance and immunoregulation. NK cells are also capable of initiating the response of the adaptive immune system to cancer immunotherapy independent of cytotoxic T cells, clearly demonstrating a link between NK cell function and the efficacy of cancer immunotherapies. Eosinophils were shown to feature pleiotropic activities against a variety of solid tumor types, including direct interactions with tumor cells, and accessorily affect immunotherapeutic response through intricating cross-talk with lymphocytes. Additionally, microbial sequencing and reconstitution revealed that commensal microbiota might be involved in the modulation of cancer progression, including positive and negative regulatory bacteria. They may play functional roles in not only mucosal modulation, but also systemic immune responses. Here, we present a panorama of the cancer immune network mediated by MHCI/II molecules, immune cells and commensal microbiota and a discussion of prospective relevant intervening mechanisms involved in cancer immunotherapies.
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Affiliation(s)
- Minting Wen
- School of Life Science, Guangzhou University, Guangzhou 510006, China
| | - Yingjing Li
- School of Life Science, Guangzhou University, Guangzhou 510006, China
| | - Xiaonan Qin
- School of Life Science, Guangzhou University, Guangzhou 510006, China
| | - Bing Qin
- School of Life Science, Guangzhou University, Guangzhou 510006, China
| | - Qiong Wang
- School of Life Science, Guangzhou University, Guangzhou 510006, China
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Shukla A, Cano-Mejia J, Andricovich J, Burga RA, Sweeney EE, Fernandes R. An Engineered Prussian Blue Nanoparticles-based Nanoimmunotherapy Elicits Robust and Persistent Immunological Memory in a TH-MYCN Neuroblastoma Model. ADVANCED NANOBIOMED RESEARCH 2021; 1. [PMID: 34435194 DOI: 10.1002/anbr.202100021] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
A combination therapy using Prussian blue nanoparticles (PBNP) as photothermal therapy (PTT) agents coated with CpG oligodeoxynucleotides, an immunologic adjuvant, as a nanoimmunotherapy (CpG-PBNP-PTT) for neuroblastoma (NB) is described. NB driven by MYCN amplification confers high risk and correlates with a dismal prognosis, accounting for the majority of NB-related mortality. The efficacy of the CpG-PBNP-PTT nanoimmunotherapy in a clinically relevant, TH-MYCN murine NB model (9464D) overexpressing MYCN is tested. When administered to 9464D NB cells in vitro, CpG-PBNP-PTT triggers thermal dose-dependent immunogenic cell death and tumor cell priming for immune recognition in vitro, measured by the expression of specific costimulatory and antigen-presenting molecules. In vivo, intratumorally administered CpG-PBNP-PTT generates complete tumor regression and significantly higher long-term survival compared to controls. Furthermore, CpG-PBNP-PTT-treated mice reject tumor rechallenge. Ex vivo studies confirm these therapeutic responses result from the generation of robust T cell-mediated immunological memory. Consequently, in a synchronous 9464D tumor model, CpG-PBNP-PTT induces complete tumor regression on the treated flank and significantly slows tumor progression on the untreated flank, improving animal survival. These findings demonstrate that localized administration of the CpG-PBNP-PTT nanoimmunotherapy drives potent systemic T cell responses in solid tumors such as NB and therefore has therapeutic implications for NB.
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Affiliation(s)
- Anshi Shukla
- The George Washington Cancer Center, The George Washington University, 800 22nd St NW, Science and Engineering Hall 8 Floor, Washington, DC 20052, USA
| | - Juliana Cano-Mejia
- The George Washington Cancer Center, The George Washington University, 800 22nd St NW, Science and Engineering Hall 8 Floor, Washington, DC 20052, USA
| | - Jaclyn Andricovich
- The George Washington Cancer Center, The George Washington University, 800 22nd St NW, Science and Engineering Hall 8 Floor, Washington, DC 20052, USA.,The Institute for Biomedical Sciences, The George Washington University,2300 Eye Street NW, Ross Hall Room 561, Washington, DC 20037, USA
| | - Rachel A Burga
- The George Washington Cancer Center, The George Washington University, 800 22nd St NW, Science and Engineering Hall 8 Floor, Washington, DC 20052, USA.,The Institute for Biomedical Sciences, The George Washington University,2300 Eye Street NW, Ross Hall Room 561, Washington, DC 20037, USA
| | - Elizabeth E Sweeney
- The George Washington Cancer Center, The George Washington University, 800 22nd St NW, Science and Engineering Hall 8 Floor, Washington, DC 20052, USA
| | - Rohan Fernandes
- The George Washington Cancer Center, The George Washington University, 800 22nd St NW, Science and Engineering Hall 8 Floor, Washington, DC 20052, USA
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Balhorn R, Balhorn MC. Therapeutic applications of the selective high affinity ligand drug SH7139 extend beyond non-Hodgkin's lymphoma to many other types of solid cancers. Oncotarget 2020; 11:3315-3349. [PMID: 32934776 PMCID: PMC7476732 DOI: 10.18632/oncotarget.27709] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Accepted: 07/27/2020] [Indexed: 01/04/2023] Open
Abstract
SH7139, the first of a series of selective high affinity ligand (SHAL) oncology drug candidates designed to target and bind to the HLA-DR proteins overexpressed by B-cell lymphomas, has demonstrated exceptional efficacy in the treatment of Burkitt lymphoma xenografts in mice and a safety profile that may prove to be unprecedented for an oncology drug. The aim of this study was to determine how frequently the HLA-DRs targeted by SH7139 are expressed by different subtypes of non-Hodgkin’s lymphoma and by other solid cancers that have been reported to express HLA-DR. Binding studies conducted with SH7129, a biotinylated analog of SH7139, reveal that more than half of the biopsy sections obtained from patients with different types of non-Hodgkin’s lymphoma express the HLA-DRs targeted by SH7139. Similar analyses of tumor biopsy tissue obtained from patients diagnosed with eighteen other solid cancers show the majority of these tumors also express the HLA-DRs targeted by SH7139. Cervical, ovarian, colorectal and prostate cancers expressed the most HLA-DR. Only a few esophageal and head and neck tumors bound the diagnostic. Within an individual’s tumor, cell to cell differences in HLA-DR target expression varied by only 2 to 3-fold while the expression levels in tumors obtained from different patients varied as much as 10 to 100-fold. The high frequency with which SH7129 was observed to bind to these cancers suggests that many patients diagnosed with B-cell lymphomas, myelomas, and other non-hematological cancers should be considered potential candidates for new therapies such as SH7139 that target HLA-DR-expressing tumors.
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Affiliation(s)
- Rod Balhorn
- SHAL Technologies Inc., Livermore, CA 94550, USA
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Balhorn R, Balhorn MC, Balakrishnan K, Rebhun RB. The small molecule antibody mimic SH7139 targets a family of HLA-DRs expressed by B-cell lymphomas and other solid cancers. J Drug Target 2020; 28:1124-1136. [PMID: 32588667 DOI: 10.1080/1061186x.2020.1787418] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Selective high-affinity ligands (SHALs) belong to a novel class of small-molecule cancer therapeutics that function as targeted prodrugs. SH7139, the most advanced of the SHAL drugs designed to bind to a unique β-subunit structural epitope located on HLA-DR10, has exhibited exceptional preclinical efficacy and safety profiles. A comparison of SH7139 and SH7129, a biotin derivative of the drug developed for use as a diagnostic, showed the incorporation of a biotin tag did not alter the SHALs ability to target or kill HLA-DR10 expressing Raji cells. The use of SH7129 in an immuno-histochemical type assay to stain peripheral blood mononuclear cells (PBMCs) obtained from individuals expressing specific HLA-DRB1 alleles has also revealed that in addition to HLA-DR10, seven other more commonly expressed HLA-DRs are targeted by the drug. Computational dockings of the SHAL's recognition ligands to a number of HLA-DR structures explain, in part, why the targeting domains of SH7129 and SH7139 bind to some HLA-DRs but not others. The results also substantiate the selectivity of SH7129 and suggest it may prove useful as a companion diagnostic for pre-screening biopsy samples to identify those patients whose tumours should respond to SH7139 therapy.
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Affiliation(s)
| | | | - Karuppiah Balakrishnan
- Department of Immunology, School of Biological Sciences, Madurai Kamaraj University, Madurai, India
| | - Robert B Rebhun
- The Comparative Cancer Center, University of California, Davis, Davis, CA, USA
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Axelrod ML, Cook RS, Johnson DB, Balko JM. Biological Consequences of MHC-II Expression by Tumor Cells in Cancer. Clin Cancer Res 2019; 25:2392-2402. [PMID: 30463850 PMCID: PMC6467754 DOI: 10.1158/1078-0432.ccr-18-3200] [Citation(s) in RCA: 324] [Impact Index Per Article: 54.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Revised: 10/02/2018] [Accepted: 11/16/2018] [Indexed: 12/20/2022]
Abstract
Immunotherapy has emerged as a key pillar of cancer treatment. To build upon the recent successes of immunotherapy, intense research efforts are aimed at a molecular understanding of antitumor immune responses, identification of biomarkers of immunotherapy response and resistance, and novel strategies to circumvent resistance. These studies are revealing new insight into the intricacies of tumor cell recognition by the immune system, in large part through MHCs. Although tumor cells widely express MHC-I, a subset of tumors originating from a variety of tissues also express MHC-II, an antigen-presenting complex traditionally associated with professional antigen-presenting cells. MHC-II is critical for antigen presentation to CD4+ T lymphocytes, whose role in antitumor immunity is becoming increasingly appreciated. Accumulating evidence demonstrates that tumor-specific MHC-II associates with favorable outcomes in patients with cancer, including those treated with immunotherapies, and with tumor rejection in murine models. Herein, we will review current research regarding tumor-enriched MHC-II expression and regulation in a range of human tumors and murine models, and the possible therapeutic applications of tumor-specific MHC-II.
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Affiliation(s)
- Margaret L Axelrod
- Department of Medicine, Vanderbilt University Medical Center, Vanderbilt University, Nashville, Tennessee
- Cancer Biology Graduate Program, Vanderbilt University, Nashville, Tennessee
| | - Rebecca S Cook
- Cancer Biology Graduate Program, Vanderbilt University, Nashville, Tennessee
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee
- Vanderbilt-Ingram Cancer Center, Nashville, Tennessee
| | - Douglas B Johnson
- Department of Medicine, Vanderbilt University Medical Center, Vanderbilt University, Nashville, Tennessee
- Vanderbilt-Ingram Cancer Center, Nashville, Tennessee
| | - Justin M Balko
- Department of Medicine, Vanderbilt University Medical Center, Vanderbilt University, Nashville, Tennessee.
- Cancer Biology Graduate Program, Vanderbilt University, Nashville, Tennessee
- Vanderbilt-Ingram Cancer Center, Nashville, Tennessee
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7
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Ssadh HA, Abdulmonem WA. Immunophenotyping of the cluster of differentiation 74, migration inhibitory factor, and cluster of differentiation 44 expression on human breast cancer-derived cell lines. Int J Health Sci (Qassim) 2019; 13:17-24. [PMID: 30983941 PMCID: PMC6436447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
OBJECTIVE Cluster of differentiation (CD) 74, CD44, and macrophage migration inhibitory factor (MIF) are well known for their immunological functions; however, it has been shown that recently, CD74, CD44, and MIF have a role in tumor and tumor progression. This study was undertaken to investigate the expression of CD74, MIF, and CD44 in breast cancer cells. MATERIALS AND METHODS The expression of CD74, MIF, and CD44 molecules on the breast cancer-derived cell lines CAMA-1, 3,4-methylenedioxyamphetamine (MDA)-MB-231, and MDA-MB-43 was determined by flow cytometry, western immunoblotting, and confocal microscope. To validate the study the studying expression of CD74, MIF, and CD44 on the normal breast cell line 266LDM, whole cell lysate obtained from adult normal breast tissue and normal breast tissue. RESULTS The results show that all breast cancer cells overexpress CD74 isoforms, MIF, and CD44, in contrast to the normal cell lines and normal breast tissues, which express only CD44 and MIF in low levels. The expression of CD74, MIF, and CD44 was studied in the immortalized normal breast luminal cell line 226LDM, normal breast tissues, and lysate to validate the study. CONCLUSION The data show, in this study, the evidence that breast cancer cell lines expressing three different isoforms of CD74. The results of the present study indicate a crucial role of CD74 in breast cancer cells along with MIF and CD44. The results also suggest that CAMA-1, MDA-MB-231, and MDA-MB-435 cells are poorly immunogenic, expressing low levels of HLA-A, B, and C and HLA-DR.
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Affiliation(s)
- Hussain Al Ssadh
- Department of Molecular Medicine, School of Biological Sciences, University of Essex, Colchester, United Kingdom,Clinical Laboratory Science, Inaya Medical College, Riyadh, Saudi Arabia
| | - Waleed Al Abdulmonem
- Department of Pathology, College of Medicine, Qassim University, Qassim, Saudi Arabia,Address for correspondence: Waleed Al Abdulmonem, Department of Pathology, College of Medicine, Qassim University, Qassim, Saudi Arabia. E-mail:
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Tamiolakis D, Venizelos I, Lambropoulou M, Jivannakis T, Seliniotaki E, Tsikouras P, Limberis V, Tsalkidis A, Papadopoulos N. Gains and Losses of HLA Class II (DR) and CD4 in Atypical Hyperplasia, Carcinoma in situ and Infiltrating Ductal Carcinoma of the Breast. ACTA MEDICA (HRADEC KRÁLOVÉ) 2018. [DOI: 10.14712/18059694.2018.101] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Aim: Breast cancer is a frequent cause of death among women with gynaecologic malignancies despite the introduction of combination chemotherapy. There is therefore a need for new therapeutic strategies for patients with breast cancer, such as cellular immunotherapy. In this immunohistochemical study we analyzed the epithelial expression of major histocompatibility complex (MHC) class II (HLA-DR) on atypical and malignant primary mammary epithelial cells, as well as the magnitude of the stromal T lymphocytes (T4 subset) at the tumor site. Experimental design: The study was carried out retrospectively in tumor tissue from 82 patients with mammary lesions (31 cases of atypical ductal hyperplasia -ADH-, 12 cases of ductal carcinoma in situ –DCIS- and 39 cases of infiltrating ductal carcinoma not otherwise specified -IDC-NOS). Medullary carcinomas were not included in our investigation. Material used had been formalin fixed and paraffin embedded. Results: HLA class II (DR) was expressed in 20 of 31 ADHs (64.5%), in 4 of 12 DCISs (33.3%), and in 10 of 39 IDC-NOSs (25.6%). CD4 was expressed in 9 of 31 ADHs (29%), in 5 of 12 DCISs (42%), and in 26 of 39 IDCNOSs (67%). Conclusions: The results showed decreased epithelial expression of HLA class II (DR) and increased stromal expression of CD4, as the lesion progressed to malignancy. Gradual loss of epithelial HLA class II expression might be a manifestation of cellular differentiation from the atypical form versus the malignant one, signaling simultaneously a selective effect on the response capacity of the immune system.
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Diagnostic significance of intratumoral CD8+ tumor-infiltrating lymphocytes in medullary carcinoma. Hum Pathol 2017; 70:129-138. [PMID: 29122657 DOI: 10.1016/j.humpath.2017.10.020] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2017] [Revised: 10/10/2017] [Accepted: 10/18/2017] [Indexed: 01/30/2023]
Abstract
Invasive ductal carcinomas of breast with marked stromal lymphocytic infiltration have come to be classified as lymphocyte-predominant breast cancer (LPBC) because it obtains high pathological complete response rates with neoadjuvant chemotherapy. Medullary carcinoma (MC), which is independent from LPBC, is a rare histological subtype of invasive breast carcinoma accompanied by abundant lymphoplasmacytic infiltration as LPBC. Although MC shows marked cellular and structural atypia, it usually has a favorable outcome. It is occasionally difficult to distinguish MC from LPBC because both subtypes have nonspecific morphological features according to the present diagnostic criteria. Herein, we adopted multiplexed fluorescent immunohistochemistry to perform quantitative and simultaneous analyses of tumor-infiltrating lymphocytes (TILs) considering their spatial distribution and examined focal immune reaction differences between MC and LPBC. We found that CD8+ TILs are predominant in the intratumoral region, whereas CD4+ TILs are less common in MC. In non-luminal-type cancers, the numbers of stromal and intratumoral CD8+ TILs were significantly higher in MC than in LPBC. Stratified analyses by CD4+ TIL subsets showed robust infiltration of intratumoral CD8+ TILs in non-luminal-type MC even in suppressive environments, such a low T helper 1-to-regulatory T cell ratio. Our results suggest that extensive intratumoral CD8+ TIL infiltration might well be a promising biomarker for distinguishing MC from LPBC, especially in non-luminal-type cancers. Intratumoral CD8+ TILs and nonluminal intrinsic subtypes may serve as diagnostic characteristics allowing reliable histological criteria to be established for reproducibly diagnosing MC.
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Park IA, Hwang SH, Song IH, Heo SH, Kim YA, Bang WS, Park HS, Lee M, Gong G, Lee HJ. Expression of the MHC class II in triple-negative breast cancer is associated with tumor-infiltrating lymphocytes and interferon signaling. PLoS One 2017; 12:e0182786. [PMID: 28817603 PMCID: PMC5560630 DOI: 10.1371/journal.pone.0182786] [Citation(s) in RCA: 80] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2017] [Accepted: 07/24/2017] [Indexed: 12/30/2022] Open
Abstract
Tumor-infiltrating lymphocytes (TILs) have been known for their strong prognostic and predictive significance in triple-negative breast cancer (TNBC). Several mechanisms for TIL influx in TNBC have been elucidated. Major histocompatibility complex class II (MHC-II) is an essential component of the adaptive immune system and is generally restricted to the surface of antigen-presenting cells. However, it has been reported that interferon-gamma signaling may induce MHC-II in almost all cell types, including those derived from cancer. We aimed to examine the relationship between MHC-II expression in tumor cells and the amount of TILs in 681 patients with TNBC. Further, the prognostic significance of MHC-II and the association of MHC-II with a couple of molecules involved in the interferon signaling pathway were investigated using immunohistochemical staining. Higher MHC-II expression in tumor cells was associated with the absence of lymphovascular invasion (p = 0.042); larger amounts of TILs (p < 0.001); frequent formations of tertiary lymphoid structures (p < 0.001); higher expression of myxovirus resistance gene A, one of the main mediators of the interferon signaling pathway (p < 0.001); and higher expression of double-stranded RNA-activated protein kinase, which can be induced by interferons (p = 0.008). Moreover, tumors that showed high MHC class I expression and any positivity for MHC-II had larger amounts of CD4- and CD8-positive T lymphocytes (p < 0.001). Positive MHC-II expression in tumor cells was associated with better disease-free survival in patients who had lymph node metastasis (p = 0.009). In conclusion, MHC-II expression in tumor cells was closely associated with an increase in TIL number and interferon signaling in TNBC. Further studies are warranted to improve our understanding regarding TIL influx, as well as patients’ responses to immunotherapy.
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Affiliation(s)
- In Ah Park
- Departments of Pathology, Asan Medical Center, Seoul, Korea
| | - Seong-Hye Hwang
- Departments of Pathology, Asan Medical Center, Seoul, Korea
- Asan Center for Cancer Genome Discovery, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - In Hye Song
- Departments of Pathology, Asan Medical Center, Seoul, Korea
| | - Sun-Hee Heo
- Departments of Pathology, Asan Medical Center, Seoul, Korea
- Asan Center for Cancer Genome Discovery, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Young-Ae Kim
- Departments of Pathology, Asan Medical Center, Seoul, Korea
- Asan Center for Cancer Genome Discovery, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Won Seon Bang
- Departments of Pathology, Asan Medical Center, Seoul, Korea
- Asan Center for Cancer Genome Discovery, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Hye Seon Park
- Departments of Pathology, Asan Medical Center, Seoul, Korea
- Asan Center for Cancer Genome Discovery, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Miseon Lee
- Departments of Pathology, Asan Medical Center, Seoul, Korea
| | - Gyungyub Gong
- Departments of Pathology, Asan Medical Center, Seoul, Korea
| | - Hee Jin Lee
- Departments of Pathology, Asan Medical Center, Seoul, Korea
- * E-mail:
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11
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The Immunophenotype of Nodular Variant of Medullary Carcinoma of the Breast. Appl Immunohistochem Mol Morphol 2015; 23:624-7. [PMID: 25710588 DOI: 10.1097/pai.0000000000000161] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
The histologic and immunohistochemical profile of typical medullary carcinomas (TMC) of the breast are well established. Among the strict histologic criteria for the diagnosis of TMC is complete circumscription of tumor with pushing borders. Those tumors that do not fulfill all morphologic requirements of TMC are designated as atypical medullary carcinomas (AMC). We herewith describe the histology and immunophenotype of a heretofore undescribed variant of TMC composed of multiple distinctly separate nodules that otherwise meet all other histologic and immunohistochemical phenotypes of TMC. Among 2952 cases of infiltrating mammary carcinomas, 111 (3.8%) met the strict criteria for TMC, including positivity for HLA-DR. Nine of these tumors were composed of multiple separate noncoalescing nodules. Immunohistochemical stains for ER, PR, HER2, and HLA-DR, as well as for p53 and Ki-67 were repeated on these nodular forms. Staining for p63 was used to identify possible intraductal components of these tumors. The age of patients ranged from 34 to 53 years. All 9 patients had negative sentinel lymph nodes. Tumors ranged in the overall size from 2.2 to 3.9 cm and were composed of 3 to 6 distinct nodules ranging in size from 0.2 to 1.1 cm surrounding a larger main tumor nodule. The nodules were composed of syncytial groups of large cells with atypical nuclei and prominent nucleoli. A lymphoplasmacytic infiltrate was present within and around each satellite nodule. Serial sections did not show coalescing of the nodules into a single tumor mass. Similarly, staining for p63 failed to support the possibility of nodules representing intraductal components of main tumor. All tumors were negative for ER, PR, and HER2, but positive for HLA-DR. Eight of 9 tumors were diffusely positive for p53 and all 9 showed a high proliferation index in >70% of tumor cells with Ki-67. We conclude that the nodular variants of medullary carcinomas (nTMC) of the breast are uncommon forms of TMC. They occur in relatively younger women and share the same immunophenotype with TMCs; they are triple negative, express HLA-DR and p53, and show a high proliferative index. As the diagnosis of TMC carries major clinical and prognostic implications, the recognition of its nodular variant becomes equally important.
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Gun FD, Ozturk OG, Polat A, Polat G. HLA class-II allele frequencies in Turkish breast cancer patients. Med Oncol 2011; 29:466-71. [DOI: 10.1007/s12032-011-9873-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2011] [Accepted: 02/17/2011] [Indexed: 10/18/2022]
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13
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Baccar Harrath A, Yacoubi Loueslati B, Troudi W, Hmida S, Sedkaoui S, Dridi A, Jridi A, Ben Ayed F, Ben Rhomdhane K, Ben Ammar Elgaaied A. HLA class II polymorphism: protective or risk factors to breast cancer in Tunisia? Pathol Oncol Res 2006; 12:79-81. [PMID: 16799707 DOI: 10.1007/bf02893448] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2005] [Accepted: 03/18/2006] [Indexed: 01/18/2023]
Abstract
HLA system plays a key role in the tumor cells' escape from immune surveillance. Herein is the first report on the correlation of the susceptibility to breast cancer with HLA class II markers in Tunisia. Molecular typing of HLA-DRB1 and -DQB1 loci was undertaken for 70 Tunisian female patients. Comparison of allele and haplotype distribution between patients and 70 female control subjects reveals a negative association between HLADRB1* 07-DQB1*02 and the incidence of breast cancer in the Tunisian population.
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Affiliation(s)
- Amal Baccar Harrath
- Laboratory of Molecular Genetics, Immunology and Biotechnology, Faculty of Sciences of Tunis, ElManar University, Tunis, 1060, Tunisia.
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Huang H, Hara A, Homma T, Yonekawa Y, Ohgaki H. Altered Expression of Immune Defense Genes in Pilocytic Astrocytomas. J Neuropathol Exp Neurol 2005; 64:891-901. [PMID: 16215461 DOI: 10.1097/01.jnen.0000183345.19447.8e] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Pilocytic astrocytoma (WHO grade I) is a circumscribed, slowly growing, benign astrocytoma that most frequently develops in the cerebellar hemispheres and in midline structures and occurs predominantly in childhood and adolescence. In contrast to diffusely infiltrating gliomas in adults (e.g. grade II astrocytomas, oligodendrogliomas), survival of patients with pilocytic astrocytoma is excellent after surgical intervention. To search for potential molecular mechanisms underlying its benign biologic behavior, we compared gene expression profiles of pilocytic astrocytomas (8 cases) with those of normal cerebellum (4 cases), low-grade astrocytomas (WHO grade II; 15 cases), and oligodendrogliomas (WHO grade II; 17 cases) by cDNA array analysis. A number of immune system-related genes such as HLA-DRalpha, HLA-DPB1, HLA-DQB1, IgG3, IgGK, FCER1G, A2M, FCRN, IFI-56K, and DAP12 were upregulated in pilocytic astrocytomas relative to normal cerebellum, grade II astrocytomas, and oligodendrogliomas. Genes expressed at higher levels in pilocytic astrocytomas than in grade II astrocytomas and oligodendrogliomas include HLA-DRalpha, HLA-DPA1, HLA-DPB1, HLA-DQB1, A2M, TIMP1, TIMP2, CDKN1A, and SOCS3 and those expressed at lower levels include EGFR and PDGFRA. Hierarchical clustering analysis using the entire set of 1176 genes distinguished pilocytic astrocytomas from grade II astrocytomas and oligodendrogliomas. Clustering analysis using selected subgroups of genes based on their molecular functions revealed that immune system-related genes (75 genes) or cell adhesion, migration, and angiogenesis-related genes (69 genes) showed similar power to the entire gene set for separation of pilocytic astrocytomas from diffusely infiltrating low-grade gliomas. Immunohistochemistry revealed that HLA-DRalpha is expressed diffusely in neoplastic cells in pilocytic astrocytomas, whereas in oligodendrogliomas, expression was limited to scattered reactive astrocytes. These results suggest that gene expression profiles of pilocytic astrocytomas differ significantly from those of diffusely infiltrating low-grade gliomas and that their benign biologic behavior may be related to upregulation of immune defense-associated genes.
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Affiliation(s)
- Hervé Huang
- International Agency for Research on Cancer, Lyon, France, and Department of Neurosurgery, University of Zurich, Zurich, Switzerland
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15
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Darom A, Gomatos IP, Leandros E, Xatziyiannis E, Fotiadis C, Konstadoulakis MM. HLA-DR Antigen and Bax Protein Expression in Patients with Primary Non-Hodgkin's Gastric Lymphoma. ACTA ACUST UNITED AC 2004; 23:87-92. [PMID: 15165481 DOI: 10.1089/hyb.2004.23.87] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Primary gastric lymphoma represents a rare gastrointestinal malignancy with an unclear prognosis. The aim of this study was to determine the prognostic significance of HLA-DR antigen and bax expression in patients with primary non-Hodgkin's gastric lymphoma. We immunohistochemically studied bax protein and HLA-DR antigen expression in 36 B-cell, MALT-type primary gastric lymphoma patients diagnosed and treated in our department from 1990 to 1995. Ten non-malignant gastric tissue specimens were used as benign controls. Clinicopathological and survival data were correlated with the staining results. HLA-DR antigen expression was observed in 33 gastric lymphoma patients (91.7%). Positive bax staining was found in 24 gastric lymphomas (66.7%) and in none of the benign cases studied. In the univariate analysis, those gastric lymphoma patients who expressed HLA-DR antigen in more than 15% of their tumor cells, presented a significantly improved 5-year survival rate (75% vs. 37.5%, p = 0.04). Furthermore, gastric lymphoma patients who were bax(+)/HLA-DR(+) had a statistically better overall survival compared to those who were bax(-)/HLA-DR(-) (82.4% vs. 25%, p = 0.01). HLA-DR antigen expression was associated with a favorable clinical outcome. Its expression improved the predictive value of bax protein expression in non-Hodgkin's gastric lymphoma patients. The combined use of these markers permits the identification of a high-risk group of patients that may benefit from a more aggressive therapeutic approach.
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Affiliation(s)
- A Darom
- Laboratory of Surgical Research, First Department of Propaedeutic Surgery, Hippokration Hospital, Athens Medical School, Athens, Greece
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16
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McDermott RS, Beuvon F, Pauly M, Pallud C, Vincent-Salomon A, Mosseri V, Pouillart P, Scholl SM. Tumor antigens and antigen-presenting capacity in breast cancer. Pathobiology 2004; 70:324-32. [PMID: 12865628 DOI: 10.1159/000071272] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2002] [Accepted: 01/08/2003] [Indexed: 11/19/2022] Open
Abstract
AIMS Cancer cells frequently express antigens capable of being recognized by the host immune system; however, any resultant immune response is often ineffective. This may be related in part to tumor-induced defects in antigen presentation. We screened for dendritic cell infiltration, tumor MHC II expression and associated lymphocytic reaction in the context of three established breast tumor antigens. METHODS Forty primary breast tumors were evaluated by immunohistochemical techniques for expression of her2/neu, p53, and MUC1 and MHC class II molecules. Twenty-five samples were further analyzed for p53 mutations by PCR-SSCP analysis and DNA sequencing. The phenotype of tumor-infiltrating inflammatory cells was evaluated using the following markers: CD1a, MHC Class II, CD3, CD45, and CD45RO. RESULTS Tumors with p53 mutations and overexpression, but not her2/neu or MUC1 overexpressing tumors, more frequently harbored marked CD1a+ dendritic cell infiltrates. An overall correlation between CD1a+ cell infiltrates and HLA class II expression on tumor cells (p = 0.0008) was also observed and these tumors had greater CD45RO+ lymphocytic infiltrates. CONCLUSIONS In breast cancer, p53 mutations may present a more visible signal to the immune system and hence provide a better target for immunotherapy. Infiltrating CD1a positive cells are associated with a more dense tumor lymphocytic infiltrate and tumor cell expression of MHC II molecules.
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17
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Altomonte M, Fonsatti E, Visintin A, Maio M. Targeted therapy of solid malignancies via HLA class II antigens: a new biotherapeutic approach? Oncogene 2003; 22:6564-9. [PMID: 14528281 DOI: 10.1038/sj.onc.1206960] [Citation(s) in RCA: 40] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Intracellular signals, delivered in professional antigen-presenting cells following the engagement of major histocompatibility complex (MHC) class II molecules, activate a variety of cellular functions that also contribute to efficient antigen presentation. As far as human malignancies, the signaling ability of human leukocyte antigens (HLA) class II molecules is a rather well-characterized event in hematologic tumors; in contrast, very limited evidences are available in solid neoplasias of different histotypes that may constitutively express HLA class II antigens. Among solid malignancies, a significant proportion of human cutaneous melanomas have been shown to express HLA class II molecules, and cutaneous melanoma undoubtedly represents a 'model disease' to investigate tumor immunobiology, to unveil the molecular basis underlying the interactions between neoplastic cells and host's immune system, and ultimately to set up new bio-immunotherapeutic approaches. Upcoming preclinical evidences unveil a signaling potential of HLA-DR antigens expressed on melanoma cells, and suggest for the clinical implication of HLA class II molecules as novel therapeutic targets. Therefore, in this review, we will focus on the emerging role of HLA class II antigens as intracellular signal transducing elements in neoplastic cells of the melanocytic lineage, emphasizing their foreseeable role in targeted therapy of human melanoma and potentially of HLA class II antigens-positive tumors of different histology.
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Affiliation(s)
- Maresa Altomonte
- Cancer Bioimmunotherapy Unit, Department of Medical Oncology, Centro di Riferimento Oncologico, Istituto di Ricovero e Cura a Carattere Scientifico, via Pedemontana Occ. le, 12, Aviano 33081, Italy.
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18
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Xu R, Feiner H, Li P, Yee H, Inghirami G, Delgado Y, Perle MA. Differential amplification and overexpression of HER-2/neu, p53, MIB1, and estrogen receptor/progesterone receptor among medullary carcinoma, atypical medullary carcinoma, and high-grade invasive ductal carcinoma of breast. Arch Pathol Lab Med 2003; 127:1458-64. [PMID: 14567723 DOI: 10.5858/2003-127-1458-daaoon] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
CONTEXT Medullary carcinoma (MC) is a special type of breast cancer that has a better prognosis than atypical medullary carcinoma (AMC) and high-grade invasive ductal carcinoma (HGIDC) with prominent lymphocytic infiltrates. What accounts for the different clinical courses of these carcinomas, despite their similar histology, is unknown. To address this issue, we performed a comparative study of amplification and overexpression of HER-2/neu and expression of several other important biochemical markers (p53, MIB1, and estrogen receptor [ER]/progesterone receptor [PR]) in these 3 cancer groups. OBJECTIVE To evaluate HER-2/neu, p53, MIB1, and ER/PR as markers in the differential diagnosis of MC, AMC, and HGIDC.Design.-Nine cases of MC, 13 cases of AMC, and 16 cases of HGIDC with prominent lymphocytic infiltrates were identified according to strict histologic criteria. All tests were performed on formalin-fixed, paraffin-embedded archival tissues. HER-2/neu gene amplification was examined by fluorescence in situ hybridization using PathVysion HER-2 DNA probes. Expression of HER-2/neu, p53, MIB1, and ER/PR was detected by immunohistochemistry. chi2 and Student t tests were applied for statistical analyses. RESULTS None of 9 cases of MC examined had either amplification or overexpression of HER-2/neu (0%). In contrast, HER-2/neu amplification was observed in AMC (46%, P <.025) and HGIDC (56%, P <.005). All 3 categories of tumors had similar percentages of expression of p53 (78% of MC, 77% of AMC, and 69% of HGIDC) and MIB1 (89% of MC, 92% of AMC, and 94% of HGIDC). Immunostaining for ER/PR was rarely positive in either MC or AMC, and there were no significant differences of expression of ER/PR between these 2 lesions (P >.05). However, the expression rate of ER/PR (31%/44%) in HGIDC is higher than in both MC (P =.05) and AMC (P =.01). CONCLUSIONS Medullary carcinoma of breast is distinct from AMC and HGIDC with prominent lymphocytic infiltrates in amplification and overexpression of HER-2/neu. This difference may account for its different clinical and biological behavior, and may potentially aid in diagnosis and management of these groups of patients.
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MESH Headings
- Adult
- Aged
- Aged, 80 and over
- Biomarkers, Tumor
- Breast Neoplasms/genetics
- Carcinoma, Ductal, Breast/genetics
- Carcinoma, Medullary/genetics
- Diagnosis, Differential
- Gene Amplification/genetics
- Gene Expression Regulation, Neoplastic/genetics
- Genes, erbB-2
- Genes, p53
- Humans
- Ki-67 Antigen/biosynthesis
- Ki-67 Antigen/genetics
- Lymphocytes, Tumor-Infiltrating/pathology
- Middle Aged
- Receptor, ErbB-2/biosynthesis
- Receptor, ErbB-2/genetics
- Receptors, Estrogen/biosynthesis
- Receptors, Estrogen/genetics
- Receptors, Progesterone/biosynthesis
- Receptors, Progesterone/genetics
- Tumor Suppressor Protein p53/biosynthesis
- Tumor Suppressor Protein p53/genetics
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Affiliation(s)
- Ruliang Xu
- Department of Pathology, Mount Sinai School of Medicine of New York University, New York, NY, USA
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19
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Jiang YG, Wang YM, Liu TH, Liu J. Association between HLA class II gene and susceptibility or resistance to chronic hepatitis B. World J Gastroenterol 2003; 9:2221-5. [PMID: 14562382 PMCID: PMC4656467 DOI: 10.3748/wjg.v9.i10.2221] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the association between the polymorphism of HLA-DRB1, -DQA1 and -DQB1 alleles and viral hepatitis B.
METHODS: HLA-DRB1, -DQA1 and -DQB1 alleles in 54 patients with chronic hepatitis B, 30 patients with acute hepatitis B and 106 normal control subjects were analyzed by using the polymerase chain reaction/sequence specific primer (PCR/SSP) technique.
RESULTS: The allele frequency of HLA-DRB1*0301 in the chronic hepatitis B group was markedly higher than that in the normal control group (17.31% vs 5.67%), there was a significant correlation between them (χ2 = 12.3068, Pc = 0.0074, RR = 4.15). The allele frequency of HLA-DQA1*0501 in the chronic hepatitis B group was significantly higher than that in the normal control group (25.96% vs 13.68%), there was a significant correlation between them (χ2 = 9.2002, Pc = 0.0157, RR = 2.87). The allele frequency of HLA-DQB1*0301 in the chronic hepatitis B group was notably higher than that in the normal control group (35.58% vs 18.87%), there was a significant correlation between them (χ2 = 15.5938, Pc = 0.0075, RR = 4.07). The allele frequency of HLA-DRB1*1101/1104 in the chronic hepatitis B group was obviously lower than that in the normal control group (0.96% vs 13.33%), there was a significant correlation between them (χ2 = 11.9206, Pc = 0.0145, RR = 18.55). The allele frequency of HLA-DQA1*0301 in the chronic hepatitis B group was remarkably lower than that in the normal control group (14.42% vs 30%), there was a significant correlation between them (χ2 = 8.7396, Pc = 0.0167, RR = 0.35).
CONCLUSION: HLA-DRB1*0301, HLA-DQA1*0501 and HLA-DQB1*0301 are closely related with susceptibility to chronic hepatitis B, and HLA-DRB1*1101/1104 and HLA-DQA1*0301 are closely related with resistance to chronic hepatitis B. These findings suggest that host HLA class II gene is an important factor determining the outcome of HBV infection.
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Affiliation(s)
- Ye-Gui Jiang
- Institute of Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
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20
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Hansen MH, Nielsen HV, Ditzel HJ. Translocation of an intracellular antigen to the surface of medullary breast cancer cells early in apoptosis allows for an antigen-driven antibody response elicited by tumor-infiltrating B cells. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2002; 169:2701-11. [PMID: 12193744 DOI: 10.4049/jimmunol.169.5.2701] [Citation(s) in RCA: 57] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Tumor-infiltrating lymphoplasmacytic cells are a key feature of medullary carcinoma of the breast (MCB), a distinct subtype of human breast cancer that, despite cytologically anaplastic characteristics, has a more favorable prognosis than other types of breast cancer. Since it has been proposed that the improved clinical outcome is due at least in part to the presence of a prominent lymphoplasmacytic cell infiltrate in the tumor stroma, we recently examined the tumor-infiltrating B cell response in MCB and showed that it is oligoclonal and directed against an intracellular protein translocated to the cell surface upon MCB cell apoptosis. Human Abs cloned from MCB lymphoplasmacytic infiltrate-derived phage display libraries and reflecting the dominant part of the response were used to identify the target Ag as actin. Here, we have characterized in detail the cloned human IgG Abs and the translocation process of actin to the cell surface of apoptotic MCB cells. Our analysis shows that the cloned Abs bind specifically and with high affinity to actin, as determined by ELISA and surface plasmon resonance. Sequence analysis revealed that the Abs are highly somatically mutated, with high replacement to silent ratios, indicative of an Ag-driven, affinity-matured response. Interestingly, the tumor-infiltrating B cells in half the MCB patients mainly exhibited an IgG2 response, while IgG1 dominated in the others. To gain insight to the molecular events that may elicit such an Ab response, we examined the translocation of actin to the cell surface of apoptotic MCB cells using flow cytometry and laser scanning cytometry. Our results show that actin becomes exposed on the cell surface of a large proportion of apoptotic MCB cells as an early apoptotic event. We propose that the Ab response against actin produced by tumor-infiltrating B lymphoplasmacytic cells is Ag-driven, affinity-matured, and elicited due to the increased rate of apoptosis occurring within the MCB tumor that facilitates the translocation and proteolytic fragmentation of intracellular proteins.
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Affiliation(s)
- Margit H Hansen
- Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA
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21
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Coronella JA, Spier C, Welch M, Trevor KT, Stopeck AT, Villar H, Hersh EM. Antigen-driven oligoclonal expansion of tumor-infiltrating B cells in infiltrating ductal carcinoma of the breast. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2002; 169:1829-36. [PMID: 12165506 DOI: 10.4049/jimmunol.169.4.1829] [Citation(s) in RCA: 127] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
The objective of this study was to determine whether tumor-infiltrating B cells (TIL-B) of infiltrating ductal carcinoma (IDC) of the breast represent a tumor-specific humoral immune response. Immunohistochemical analysis of three Her-2/neu-negative IDC tumors from geriatric patients showed that TIL-B cluster in structures similar to germinal centers containing CD20(+) B lymphocyte and CD3(+) T lymphocyte zones with interdigitating CD21(+) follicular dendritic cells, suggesting an in situ immune response. A total of 29, 31, and 58 IgG1 H chain clones was sequenced from the three IDC tumors, respectively. Intratumoral oligoclonal expansion of TIL-B was demonstrated by a preponderance (45-68%) of clonal B cells. In contrast, only 7% of tumor-draining lymph node and 0% of healthy donor PBL IgG H chains were clonal, consistent with the larger repertoires of node and peripheral populations. Patterns and levels of TIL-B IgG H chain somatic hypermutation suggested affinity maturation in intratumoral germinal centers. To examine the specificity of TIL-B Ig, a phage-displayed Fab library was generated from the TIL-B of one IDC tumor. Panning with an allogeneic breast cancer cell line enriched Fab binding to breast cancer cells, but not nonmalignant cell lines tested. However, panning with autologous tumor tissue lysate increased binding of Fab to both tumor tissue lysate and healthy breast tissue lysate. These data suggest an in situ Ag-driven oligoclonal B cell response to a variety of tumor- and breast-associated Ags.
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MESH Headings
- Aged
- Aged, 80 and over
- Antigens, Neoplasm/metabolism
- B-Lymphocytes/immunology
- B-Lymphocytes/pathology
- Breast Neoplasms/immunology
- Breast Neoplasms/pathology
- Carcinoma, Ductal, Breast/immunology
- Carcinoma, Ductal, Breast/pathology
- Female
- Genes, Immunoglobulin
- Germinal Center/immunology
- Germinal Center/pathology
- Humans
- Immunoglobulin Fab Fragments/metabolism
- Immunohistochemistry
- Lymphocytes, Tumor-Infiltrating/immunology
- Lymphocytes, Tumor-Infiltrating/pathology
- Mutation
- Peptide Library
- Tumor Cells, Cultured
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Affiliation(s)
- Julia A Coronella
- Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA.
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22
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van der Stoep N, Biesta P, Quinten E, van den Elsen PJ. Lack of IFN-gamma-mediated induction of the class II transactivator (CIITA) through promoter methylation is predominantly found in developmental tumor cell lines. Int J Cancer 2002; 97:501-7. [PMID: 11802213 DOI: 10.1002/ijc.1623] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Downregulation of major histocompatibility complex (MHC) molecules by tumor cells impairs cellular immune recognition and contributes to inefficient cell-mediated tumor eradication. Low or lack of expression of MHC molecules is frequently observed in early developmental or embryonically derived tumor cells. Considering the central role of the class II transactivator (CIITA) in MHC class II- and class I-mediated antigen presentation, we compared the induction of CIITA by interferon-gamma (IFN-gamma) in a diverse panel of developmental and more differentiated tumor cell lines. In contrast to the more differentiated tumor cell lines, none of the developmental tumor cell lines were capable of expressing CIITA after treatment with IFN-gamma. Remarkably, in transient transfection assays, CIITA promoter IV (CIITA-PIV) was found to be induced by IFN-gamma. Southern blot analysis of genomic DNA obtained from the developmental tumor cell lines indicated that the absence of endogenous CIITA induction was due to methylation of the CIITA-PIV region. Exposure to 5-azacytidine restored induction of CIITA and congruent HLA-DRA expression in these cells. The observation that only developmental tumor cell lines, originating from various tissues, employ methylation to silence CIITA expression may reflect the natural status of CIITA expression during early development rather than oncogenic transformation.
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Affiliation(s)
- Nienke van der Stoep
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center (LUMC), Leiden, The Netherlands
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23
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Foulkes WD, Rosenblatt J, Chappuis PO. The contribution of inherited factors to the clinicopathological features and behavior of breast cancer. J Mammary Gland Biol Neoplasia 2001; 6:453-65. [PMID: 12013534 DOI: 10.1023/a:1014791115760] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
This review is focused on genetic factors that may influence the development and/or appearance of breast cancer metastases. Over the last decade there have been significant advances in the understanding of genetic predisposition to breast cancer. The first breast cancer predisposing gene to be identified was TP53, and this was followed over the next 5 years by two more genes, BRCA1 and BRCA2, which from a population perspective are much more important than TP53. Other rarer genes have subsequently been identified, but the role of more common, less penetrant genes in breast cancer susceptibility remains unknown. Recent work has shown that breast cancers occurring in women carrying germ-line BRCA1 mutations tend to have clinicopathological features that are usually associated with a poor prognosis, such as high grade, estrogen receptor negative status and somatic TP53 mutations. On the other hand, they are usually ERBB2 negative. Whether or not such tumors are more or less likely to metastasize, and hence be associated with a poor outcome, is currently uncertain and has been the subject of much debate. Here, we outline some of the clinicopathological features of hereditary breast cancer, discuss the prognostic studies that have been performed, and introduce some possible new research directions.
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Affiliation(s)
- W D Foulkes
- Department of Oncology, McGill University, Montreal, Quebec, Canada.
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24
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Ghaderi A, Talei A, Gharesi-Fard B, Farjadian SH, Amirzargar A, Vasei M. HLA-DBR 1 alleles and the susceptibility of Iranian patients with breast cancer. Pathol Oncol Res 2001; 7:39-41. [PMID: 11349219 DOI: 10.1007/bf03032603] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Breast cancer is considered a major malignancy among women worldwide. The contribution of genetic elements to the onset of familial breast cancer has already been established. The current study investigate the alfele frequency of HLA-DRB 1 in 36 primary operable female breast cancer patients from southern Iran by polymerase chain reaction using sequence specific primers (PCR-SSP). Results were compared with those of 36 female control subjects. Statistical analysis was performed and P values were determined for each character. Our results indicated that the frequency of HLA-DRB 1*12 allele is significantly higher in the patient group (p<0.03) compared to the control group. In addition, HLA-DRB1*11 appeared to be as the most frequent allele in the control group (29.2%) and had approximately the same distribution among the patient group (22.5%).
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Affiliation(s)
- A Ghaderi
- Medical School, Shiraz University of Medical Sciences, Department of Immunology, Shiraz, Iran.
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