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Differences in TCR-V? repertoire and effector phenotype between tumor infiltrating lymphocytes and peripheral blood lymphocytes increase with age.

ABSTRACT: Tumor infiltrating lymphocytes (TIL) reflect the host's anti-tumor immune response, and can be a valuable predictor of prognosis. However, many properties of TIL are not fully understood. In the present study, TCR-V? repertoires of cancer patients were primarily analyzed by flow cytometry. Abnormally expressed TCR-V? subfamilies were generally found in both TIL and peripheral blood lymphocytes (PBL) of each patient. Of note, increased patient age was associated with increasingly biased TCR-V? repertoire in TIL but not in PBL, and the dispersion degree of the differences of TCR-V? subfamilies between TIL and PBL correlated positively with age (P?=?0.007). Utilizing immunoscope analysis, we identified the age-related reduction in TCR-V? diversity, but polyclonal pattern was predominant in significantly expanded TCR-V? subfamilies. In addition, we found that older patients possessed a decreased ratio of CD8+CD62L+ non-effector cells in TIL compared to PBL, implying age-related increase of CD8+CD62L- effector cells in TIL. The colocalization analysis of CD8 and CD3, however, suggested the suppressed activity of these effector cells in tumor microenvironment. These findings further elucidate the properties of TIL, showing an increasing difference between TIL and PBL with age, which may provide insight for the development of effective immunotherapies for cancer patients of different ages.

SUBMITTER: Shao H

PROVIDER: S-EPMC4096599 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Differences in TCR-Vβ repertoire and effector phenotype between tumor infiltrating lymphocytes and peripheral blood lymphocytes increase with age.

Shao Hongwei H Ou Yusheng Y Wang Teng T Shen Han H Wu Fenglin F Zhang Wenfeng W Tao Changli C Yuan Yin Y Bo Huaben H Wang Hui H Huang Shulin S

PloS one 20140714 7

Tumor infiltrating lymphocytes (TIL) reflect the host's anti-tumor immune response, and can be a valuable predictor of prognosis. However, many properties of TIL are not fully understood. In the present study, TCR-Vβ repertoires of cancer patients were primarily analyzed by flow cytometry. Abnormally expressed TCR-Vβ subfamilies were generally found in both TIL and peripheral blood lymphocytes (PBL) of each patient. Of note, increased patient age was associated with increasingly biased TCR-Vβ re ...[more]

PMID: 25019226

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Project description:High levels of tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment (TME) are associated with a survival benefit in various cancer types and the targeted (re)activation of TILs is an attractive therapeutic anti-cancer approach that yields curative responses. However, current T cell targeting strategies directed at known immune checkpoints have not increased objective response rates for all cancer types, including for epithelial ovarian cancer (EOC). For this reason, the identification of new immune checkpoints that regulate T cell immunity remains of great interest. One yet largely uninvestigated checkpoint of potential interest is the G protein-coupled receptor 56 (GPR56), which belongs to the adhesion GPCR family. GPR56 was originally reported to function in cerebral cortical development and in anti-depressant response, but also in cancer. Recently, GPR56 was identified as an inhibitory receptor expressed on human NK cells that by cis-interaction with the tetraspanin CD81 attenuated the cytotoxic activity of NK cells. This NK cell checkpoint could be blocked by an GPR56 antibody, leading to increased cytotoxicity. Interestingly, GPR56 expression has also been reported on cytokine producing memory CD8 T lymphocytes and may thus represent a T cell checkpoint as well. Here, GPR56 mRNA expression was characterized in the context of TILs, with GPR56 expression being detected predominantly in tumor infiltrating CD8 T cells with a cytotoxic and (pre-)exhausted phenotype. In accordance with this mRNA profile, TILs from ovarian cancer patients expressed GPR56 primarily within the effector memory and central memory T cell subsets. On T cells from healthy donors the expression was limited to effector memory and terminally differentiated T cells. Notably, GPR56 expression further increased on TILs upon T cell receptor (TCR)-mediated stimulation in co-cultures with cancer cells, whereas GPR56 expression on healthy primary human T cells did not. Further, the ectopic expression of GPR56 significantly reduced the migration of GPR56-positive T cells. Taken together, GPR56 is a potential immune-checkpoint in EOC found on (pre-)exhausted CD8 TILs that may regulate migratory behavior.

Dataset Information

Differences in TCR-V? repertoire and effector phenotype between tumor infiltrating lymphocytes and peripheral blood lymphocytes increase with age.

Publications

Differences in TCR-Vβ repertoire and effector phenotype between tumor infiltrating lymphocytes and peripheral blood lymphocytes increase with age.

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