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Tumor-infiltrating CD8⁺ T cell antitumor efficacy and exhaustion: molecular insights.

ABSTRACT: Host immunity has an essential role in the clinical management of cancers. Therefore, it is advantageous to choose therapies that can promote tumor cell death and concurrently boost host immunity. The dynamic tumor microenvironment (TME) determines whether an antineoplastic drug will elicit favorable or disparaging immune responses from tumor-infiltrating lymphocytes (TILs). CD8⁺ T cells are one of the primary tumor-infiltrating immune cells that deliver antitumor responses. Here, we review the influence of various factors in the TME on CD8⁺ T cell exhaustion and survival, and possible strategies for restoring CD8⁺ T cell effector function through immunotherapy.

SUBMITTER: Kumar S

PROVIDER: S-EPMC8131230 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Tumor-infiltrating CD8<sup>+</sup> T cell antitumor efficacy and exhaustion: molecular insights.

Kumar Sandeep S Singh Sunil Kumar SK Rana Basabi B Rana Ajay A

Drug discovery today 20210112 4

Host immunity has an essential role in the clinical management of cancers. Therefore, it is advantageous to choose therapies that can promote tumor cell death and concurrently boost host immunity. The dynamic tumor microenvironment (TME) determines whether an antineoplastic drug will elicit favorable or disparaging immune responses from tumor-infiltrating lymphocytes (TILs). CD8<sup>+</sup> T cells are one of the primary tumor-infiltrating immune cells that deliver antitumor responses. Here, we ...[more]

PMID: 33450394

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Project description:BackgroundImmunotherapy is now an integral aspect of cancer therapy. Strategies employing adoptive cell therapy (ACT) have seen the establishment of chimeric antigen receptor (CAR)-T cells using peripheral blood lymphocytes as well as tumor-infiltrating lymphocytes (TILs) with significant clinical results. The bone marrow (BM) is an immunological niche housing T cells with specificity for previously encountered antigens, including tumor-associated antigens from certain solid cancers. This study sought to improve our understanding of tumor-specific BM T cells in the context of solid tumors by comparing them with TILs, and to assess whether there is a rationale for using the BM as a source of T cells for ACT against solid malignancies.MethodsWe used the murine B16 melanoma model examining both the endogenous OVA-specific T cell response using an OVA-specific tetramer or examining the OVA-specific response with OVA-specific transgenic CD8+ (OT-1) T cells. Specifically, we compared baseline intrinsic properties of TILs or BM T cells from tumor-bearing mice and their changes following adoptive transfer in the tumor and bone marrow (as well as other compartments when indicated).ResultsIn tumor-bearing mice, endogenous tumor-specific T cells could be detected in the BM early in the course of tumor progression and possessed a more stem-cell-like and memory phenotype in an unsupervised cluster analysis compared with TILs which appeared more exhausted. The BM and tumor microenvironments significantly impact the fate of T cells. Naïve OT-1 transferred T cells acquired an exhausted phenotype in the tumor but maintained a more memory-like phenotype in the BM with tumor progression. Importantly, in a competitive transfer experiment, BM T cells infiltrated the tumor more efficiently than TILs, displayed a higher polyfunctionality with interleukin-2, interferon-γ, tumor necrosis factor-α production and showed greater persistence compared with TILs.ConclusionsT cells from the BM appear superior to TILs as a source of cells for cellular therapy. They possess a memory-enriched phenotype and exhibit improved effector function, greater persistence within a tumor-bearing host, and the capacity for increased tumor infiltration. These data provide a foundation for further exploring the BM as a source of tumor-specific T cells for ACT in solid malignancies.

Dataset Information

Tumor-infiltrating CD8⁺ T cell antitumor efficacy and exhaustion: molecular insights.

Publications

Tumor-infiltrating CD8<sup>+</sup> T cell antitumor efficacy and exhaustion: molecular insights.

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Dataset Information

Tumor-infiltrating CD8+ T cell antitumor efficacy and exhaustion: molecular insights.

Publications

Tumor-infiltrating CD8<sup>+</sup> T cell antitumor efficacy and exhaustion: molecular insights.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Tumor-infiltrating CD8⁺ T cell antitumor efficacy and exhaustion: molecular insights.