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CD4+ T-cell-induced inflammatory killing controls immune evasive tumors

ABSTRACT: Most clinically applied cancer immunotherapies rely on the ability of CD8+ cytolytic T-cells to directly recognise and kill tumor cells. These strategies are limited by the emergence of MHC-deficient tumor cells and the development of an immunosuppressive tumor microenvironment. The ability of CD4+ effector cells to contribute to anti-tumor immunity independently of CD8+ T-cells is increasingly recognised, but strategies to unleash their full potential remain to be identified. Here, we describe a mechanism through which a small number of CD4+ T-cells is sufficient to eradicate MHC-deficient tumors that escape direct CD8+ T-cell targeting. The CD4+ effector T-cells preferentially cluster at tumor invasive margins where they interact with MHC-II+CD11c+ antigen-presenting cells. We show that Th1-directed CD4+ T-cells and innate immune stimulation reprogram the tumor-associated myeloid cell network towards IFN-activated antigen-presenting and iNOS-expressing tumoricidal effector phenotypes. Together, CD4+ T-cells and tumoricidal myeloid cells orchestrate a remote inflammatory cell death process that indirectly eradicates IFN-unresponsive and MHC-deficient tumors. These results warrant to clinically exploit the ability of CD4+ T-cells and innate immune stimulators as a strategy to complement the direct cytolytic activity of CD8+ T- and NK-cells and advance cancer immunotherapies.

ORGANISM(S): Mus musculus

PROVIDER: GSE230427 | GEO | 2023/05/24

REPOSITORIES: GEO

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Project description:Though T cell expansion and effector differentiation are triggered and, perhaps, maintained by antigen, the proliferative behaviors of CD4+ and CD8+ T cells responding to timed antigen presentation have rarely been compared side by side. Proliferation and effector differentiation of TCR transgenic and polyclonal T cells were analyzed following transient and continuous TCR signals. We found CD4+ T cell proliferation to be dependent on prolonged antigen presence, whereas CD8+ T cells were able to divide and differentiate into effector cells in the absence of it. We excluded CD4+ T cell proliferation to be abrogated by coinhibitory signals or the lack of inflammatory stimuli and found that autonomous proliferation of CD8* T cells was independent of any MHC class I signals. Gene expression analyses illustrated differences in global gene transcription between the two subsets following stimulation periods of different lengths. These T cell data reflect the MHC class difference in that class II but not class I molecules were stabilized on activated DCs in vivo, suggesting a coevolution of MHC molecules and their respective T cell subsets. Samples 1-12: Analysis on day 2. Purified CD4+ AND-TCR transgenic cells andÂ CD8+ OT1-TCR transgenic cells were separately stimulated with anti-CD3 and anti-CD28 antibodies. 48 hours later, the cells were sorted again to a purity of >99 %. Extracted total RNA was amplified twice and hybridized on Affymetrix Mouse 430A2 microarrays. First, we analysed the changes of the CD4+ and CD8+ T cells after stimulation. Second, we compared the differences of the changes between the two cell types after stimulation. For each of the four groups (CD4+ and CD8+, stimulated and unstimulated), we analysed three independent biological replicates. Samples 13-28: Analysis on day 5. AND and OT1 TCR-transgenic T cells were prepared as described before, but transferred into mice that do not or do present their respective antigens. 72 hours later, the cells were FACS-sorted twice to >99 % purity, directly into Trizol. For each of the six groups (CD4+ and CD8+, unstimulated, transient (2 days) and continuous (5 days) stimulation), three independent biological replicates were analyzed, except for CD4+ unstimulated and CD4+ transient, with two replicates each.

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CD4+ T-cell-induced inflammatory killing controls immune evasive tumors

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