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CD4⁺ T cell exhaustion leads to adoptive transfer therapy failure which can be prevented by immune checkpoint blockade.

ABSTRACT: Cytotoxic CD8⁺ T cell exhaustion is one of the mechanisms underlying the tumor immune escape. The paradigm-shifting immune checkpoint therapy can mitigate CD8⁺ T lymphocyte exhaustion, reinvigorate the anticancer immunity, and achieve durable tumor regression for some patients. Emerging evidence indicates that CD4⁺ T lymphocytes also have a critical role in anticancer immunity, either by directly applying cytotoxicity toward cancer cells or as a helper to augment CD8⁺ T cell cytotoxicity. Whether anticancer CD4⁺ T lymphocytes undergo exhaustion during immunotherapy of solid tumors remains unknown. Here we report that melanoma antigen TRP-1/gp75-specific CD4⁺ T lymphocytes exhibit an exhaustion phenotype after being adoptively transferred into mice bearing large subcutaneous melanoma. Exhaustion of these CD4⁺ T lymphocytes is accompanied with reduced cytokine release and increased expression of inhibitory receptors, resulting in loss of tumor control. Importantly, we demonstrate that PD-L1 immune checkpoint blockade can prevent exhaustion, induce proliferation of the CD4⁺ T lymphocytes, and consequently prevent tumor recurrence. Therefore, when encountering an excessive amount of tumor antigens, tumor-reactive CD4⁺ T lymphocytes also enter the exhaustion state, which can be prevented by immune checkpoint blockade. Our results highlight the importance of tumor-specific CD4⁺ T lymphocytes in antitumor immunity and suggest that the current immune checkpoint blockade therapy may achieve durable anticancer efficacy by rejuvenating both tumor antigen-specific CD8⁺ T lymphocytes and CD4⁺ T lymphocytes.

SUBMITTER: Fu J

PROVIDER: S-EPMC7783768 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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CD4+ T cell exhaustion leads to adoptive transfer therapy failure which can be prevented by immune checkpoint blockade.

Fu Jinfei J Yu Anze A Xiao Xiang X Tang Juyu J Zu Xiongbing X Chen Wenhao W He Bin B

American journal of cancer research 20201201 12

Cytotoxic CD8+ T cell exhaustion is one of the mechanisms underlying the tumor immune escape. The paradigm-shifting immune checkpoint therapy can mitigate CD8+ T lymphocyte exhaustion, reinvigorate the anticancer immunity, and achieve durable tumor regression for some patients. Emerging evidence indicates that CD4+ T lymphocytes also have a critical role in anticancer immunity, either by directly applying cytotoxicity toward cancer cells or as a helper to augment ...[more]

PMID: 33414997

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CD4⁺ T cell exhaustion leads to adoptive transfer therapy failure which can be prevented by immune checkpoint blockade.

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CD4<sup>+</sup> T cell exhaustion leads to adoptive transfer therapy failure which can be prevented by immune checkpoint blockade.

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