Abstract
The endogenous anti-tumor responses are limited in part by the absence of tumor-reactive T cells, an inevitable consequence of thymic central tolerance mechanisms ensuring prevention of autoimmunity. Here we show that tumor rejection induced by immune checkpoint blockade is significantly enhanced in Aire-deficient mice, the epitome of central tolerance breakdown. The observed synergy in tumor rejection extended to different tumor models, was accompanied by increased numbers of activated T cells expressing high levels of Gzma, Gzmb, Perforin, Cxcr3, and increased intratumoural levels of Cxcl9 and Cxcl10 compared to wild-type mice. Consistent with Aire’s central role in T cell repertoire selection, single cell TCR sequencing unveiled expansion of several clones with high tumor reactivity. The data suggest that breakdown in central tolerance synergizes with immune checkpoint blockade in enhancing anti-tumor immunity and may serve as a model to unmask novel anti-tumor therapies including anti-tumor TCRs, normally purged during central tolerance.
Highlights
The endogenous anti-tumor responses are limited in part by the absence of tumor-reactive T cells, an inevitable consequence of thymic central tolerance mechanisms ensuring prevention of autoimmunity
The observed increase was restricted to the tumors, as we did not observe any marked differences in the levels of splenic CD8+ or CD4+ T cells suggesting the response is driven by specific tumor antigens in the tumors from Autoimmune regulator (Aire)−/− (Supplementary Fig. 1d–f)
Using the colorectal tumor model MC38 and melanoma B16.F10, we showed that Aire−/− mice treated with anti-PD1 or anti-CTLA4 controlled tumor growth significantly better than the wild-type mice (Figs. 1b, 3a, b) and was accompanied by an increased infiltration of activated CD8+ T cells into the tumors
Summary
The endogenous anti-tumor responses are limited in part by the absence of tumor-reactive T cells, an inevitable consequence of thymic central tolerance mechanisms ensuring prevention of autoimmunity. The immune system has evolved in response to the threat of pathogenic microorganisms by carefully regulating these responses to clear the pathogen and to prevent immunity from damaging the host The latter is primarily achieved by establishing immune tolerance, a two-pronged endeavor consisting of central and peripheral tolerance, ensuring that “self-reactive” lymphocytes are either eliminated or subjected to regulatory programs to limit any negative impact to the host. Advances made over the last two decades in the field of oncology have greatly enhanced the survival rates of cancer patients These advances include immunotherapies such as antibodies blocking the cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and the programmed cell death 1 (PD-1), and the development of chimeric antigen receptor-modified T cells[3,4]. Prior studies have indicated that deficiency in Aire promotes the clearance of melanomas, due to the presence of self-reactive
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