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Programme of self-reactive innate-like T cell-mediated cancer immunity.

ABSTRACT: Cellular transformation induces phenotypically diverse populations of tumour-infiltrating T cells^1-5, and immune checkpoint blockade therapies preferentially target T cells that recognize cancer cell neoantigens^6,7. Yet, how other classes of tumour-infiltrating T cells contribute to cancer immunosurveillance remains elusive. Here, in a survey of T cells in mouse and human malignancies, we identified a population of αβ T cell receptor (TCR)-positive FCER1G-expressing innate-like T cells with high cytotoxic potential⁸ (ILTCKs). These cells were broadly reactive to unmutated self-antigens, arose from distinct thymic progenitors following early encounter with cognate antigens, and were continuously replenished by thymic progenitors during tumour progression. Notably, expansion and effector differentiation of intratumoural ILTCKs depended on interleukin-15 (IL-15) expression in cancer cells, and inducible activation of IL-15 signalling in adoptively transferred ILTCK progenitors suppressed tumour growth. Thus, the antigen receptor self-reactivity, unique ontogeny, and distinct cancer cell-sensing mechanism distinguish ILTCKs from conventional cytotoxic T cells, and define a new class of tumour-elicited immune response.

SUBMITTER: Chou C

PROVIDER: S-EPMC9250102 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Programme of self-reactive innate-like T cell-mediated cancer immunity.

Chou Chun C Zhang Xian X Krishna Chirag C Nixon Briana G BG Dadi Saida S Capistrano Kristelle J KJ Kansler Emily R ER Steele Miranda M Han Jian J Shyu Amy A Zhang Jing J Stamatiades Efstathios G EG Liu Ming M Li Shun S Do Mytrang H MH Edwards Chaucie C Kang Davina S DS Chen Chin-Tung CT Wei Iris H IH Pappou Emmanouil P EP Weiser Martin R MR Garcia-Aguilar J J Smith J Joshua JJ Leslie Christina S CS Li Ming O MO

Nature 20220420 7908

Cellular transformation induces phenotypically diverse populations of tumour-infiltrating T cells<sup>1-5</sup>, and immune checkpoint blockade therapies preferentially target T cells that recognize cancer cell neoantigens<sup>6,7</sup>. Yet, how other classes of tumour-infiltrating T cells contribute to cancer immunosurveillance remains elusive. Here, in a survey of T cells in mouse and human malignancies, we identified a population of αβ T cell receptor (TCR)-positive FCER1G-expressing innate- ...[more]

PMID: 35444279

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Project description:The concept of cancer immunosurveillance ascribes a role of cellular immunity in eliminating transformed cells with cytotoxic CD8+ T cells being a primary mediator. Cancer cells can express neoantigens to prime conventional CD8+ T cells which nonetheless transition to a dysfunctional state of exhaustion characterized by high expression of the immune checkpoint co-inhibitory receptor PD-1. Despite the clinical success of anti-PD-1 to revive cancer immunity, many patients do not respond to checkpoint blockade therapies. Of note, recent studies have revealed an incredible heterogeneity among tumor-infiltrating CD8+ T cells with the PD-1+ population being only a fraction, and yet, beside the PD-1+ subset, the identity of other populations of CD8+ T cells remains largely unknown. Here, in an unbiased survey of CD8+ T cells present in murine and human malignancies, we rediscovered a population of FCER1G+ innate-like T cells that we have previously shown to possess high cytotoxic potential and are resistant to exhaustion, hereon termed ‘killer innate-like T cells’, or ILTCks. While tumor-infiltrating CD8+PD-1+ T cells were oligoclonal, ILTCks were polyclonal with broad reactivity to unmutated tumor-associated antigens. ILTCks were not differentiated from conventional CD8+ T cells, but arose from ILTCk-committed progenitors following early encounter with cognate antigens during thymocyte development. Committed ILTCk thymic progenitors were continuously generated throughout life, and replenished the ILTCk compartment during tumor progression. Notably, expansion and effector differentiation of intratumoral ILTCks depended on high expression of IL-15 in cancer cells, and inducible activation of IL-15 signaling in adoptively transferred ILTCk progenitors suppressed tumor growth. Thus, antigen receptor self-reactivity and unconventional ontogeny distinguish ILTCks from CD8+PD-1+ T cells as a new class of tumor-elicited immune response. Strategies targeting ILTCks may enhance and complement current conventional CD8+ T cell-based cancer immunotherapies, in particular against tumors with low mutation burden or refractory to checkpoint blockade modalities.

Dataset Information

Programme of self-reactive innate-like T cell-mediated cancer immunity.

Publications

Programme of self-reactive innate-like T cell-mediated cancer immunity.

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