Dataset Information

Identification of multiple antigens recognized by tumor-infiltrating lymphocytes from a single patient: tumor escape by antigen loss and loss of MHC expression.

ABSTRACT: The authors describe a patient who experienced recurrence of metastatic melanoma after an initial dramatic response to immunotherapy using peptides derived from gp100, MART-1, and tyrosinase emulsified in incomplete Freund's adjuvant, and present data to support the hypothesis that the progression of disease in this patient was due to in vivo immunoselection for immunoresistant tumor variants. The authors previously demonstrated the existence of T-cell clones in this patient's peripheral blood and tumor-infiltrating lymphocytes (TILs) reactive against multiple antigens, including gp100, the tyrosinase-related protein (TRP)-2, a novel TRP-2 isoform-TRP-2-6b, SOX10, and the melanoma antigen NY-ESO-1. In addition to the multiple HLA-A2 restricted T-cell clones, the authors have now identified additional HLA-B/C-restricted as well as class II (HLA-DP)-restricted anti-melanoma antigen T-cell clones from this patient's TIL. One recurrent tumor showed loss of expression of multiple tumor antigens but retention of HLA class I expression. The other recurrent lesion showed total loss of HLA class I expression even though the tumor cells still expressed many melanoma antigens. This paper thus provides evidence for both the effectiveness of the immune destruction of cancer as well as problems associated with antigen-loss tumor escape mechanisms.

SUBMITTER: Khong HT

PROVIDER: S-EPMC2275330 | biostudies-literature | 2004 May-Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Identification of multiple antigens recognized by tumor-infiltrating lymphocytes from a single patient: tumor escape by antigen loss and loss of MHC expression.

Khong Hung T HT Wang Qiong J QJ Rosenberg Steven A SA

Journal of immunotherapy (Hagerstown, Md. : 1997) 20040501 3

The authors describe a patient who experienced recurrence of metastatic melanoma after an initial dramatic response to immunotherapy using peptides derived from gp100, MART-1, and tyrosinase emulsified in incomplete Freund's adjuvant, and present data to support the hypothesis that the progression of disease in this patient was due to in vivo immunoselection for immunoresistant tumor variants. The authors previously demonstrated the existence of T-cell clones in this patient's peripheral blood a ...[more]

PMID: 15076135

Similar Datasets

Project description:Immunotherapeutic strategies aimed at enhancing tumor cell killing by tumor-specific T cells hold great potential for reducing tumor burden and prolonging survival of cancer patients. Although many potential tumor antigens have been described, identifying relevant targets when designing anti-cancer vaccines or targeted cell therapies remains a challenge. To identify novel, potentially immunogenic candidate tumor antigens, we performed integrated tumor transcriptomic, seromic, and proteomic analyses of high grade serous ovarian cancer (HGSC) patient tumor samples. We identified tumor neo-antigens and over-expressed antigens using whole exome and RNA sequencing and examined these in relation to patient-matched auto-antibody repertoires. Focusing on MHC class I epitopes recognized by CD8+ T cells, HLA-binding epitopes were identified or predicted from the highly expressed, mutated, or auto-antibody target antigen, or MHC-associated peptides (MAPs). Recognition of candidate antigenic peptides was assessed within the tumor-infiltrating T lymphocyte (TIL) population expanded from each patient. Known tumor-associated antigens (TAA) and cancer/testis antigens (CTA) were commonly found in the auto-antibody and MAP repertoires and CD8+ TILs recognizing epitopes from these antigens were detected, although neither expression level nor the presence of auto-antibodies correlated with TIL recognition. Auto-antibodies against tumor-mutated antigens were found in most patients, however, no TIL recognition of the highest predicted affinity neo-epitopes was detected. Using high expression level, auto-antibody recognition, and epitope prediction algorithms, we identified epitopes in 5 novel antigens (MOB1A, SOCS3, TUBB, PRKAR1A, CCDC6) recognized by HGSC patient TILs. Furthermore, selection of epitopes from the MAP repertoire identified 5 additional targets commonly recognized by multiple patient TILs. We find that the repertoire of TIL specificities includes recognition of highly expressed and immunogenic self-antigens that are processed and presented by tumors. These results indicate an ongoing autoimmune response against a range of self-antigens targeted by HGSC TILs.

Project description:Osteosarcoma (OST) is the most common type of high-grade primary bone tumor, which mainly affects young adults. The current standard of care for OST combines surgical resection with chemotherapy. The clinical outcomes and the current options to treat OST patients are unsatisfactory and novel treatment strategies are needed. The crosstalk between tumor cells and immune cells is essential to the OST microenvironment. Despite the efforts that have been made to address the importance of immune-related factors in OST, there is still a lot to understand. The purpose of the current study was to evaluate the tumor-infiltrating lymphocytes (TIL), the expression of proteins involved in tumor biology, and their impact on the clinical outcome of OST patients. We studied 93 samples of OST patients using immunohistochemistry and histomorphometry. We looked for the infiltration of CD3+, CD4+, CD8+, TIA1+ and CD20+ cells and for the expression of CD44 standard (CD44s) and variant 6 (CD44v6), CD95/Fas, Fas-L, p53 and p-glycoprotein. All the parameters were analyzed for the influence on the occurrence of death and metastasis, plus patient overall survival (OS) and progression-free survival (PFS). The effect of sex, age, tumor location (distal femur or proximal tibia) and the combination with neoadjuvant chemotherapy was also assessed. Our results suggest that the presence of tumor-infiltrating CD4+ cells provides protection to OST patients, and that CD8+ cells have a significant impact on the patient's overall survival (OS) and progression-free survival (PFS), which is more evident in male patients. In addition, a strong association between tumor-infiltrating CD4+ cells and the presence of CD44s expression in tumor samples was observed. Analysis of TIL and tumor markers related to tumor biology could be useful to stratify patients and monitor the response to therapy, as well as to assist with the development of immunotherapy strategies to improve the effects of cytotoxic TIL to eradicate the tumor cells.

Dataset Information

Identification of multiple antigens recognized by tumor-infiltrating lymphocytes from a single patient: tumor escape by antigen loss and loss of MHC expression.

Publications

Identification of multiple antigens recognized by tumor-infiltrating lymphocytes from a single patient: tumor escape by antigen loss and loss of MHC expression.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets