Using colorectal (MC38) and melanoma (B16F10) tumor models, Benitez et al. showed that mice lacking Aire demonstrate enhanced antitumor immune responses when combined with anti-PD-1 or anti-CTLA-4. Aire-/- mice demonstrated increased infiltration of CD8+ T cell expressing higher levels of cytolytic molecules (Gzma, Gzmb, and Perforin), type-I interferon stimulated genes, and markers of tissue residency. Tumors from Aire-/- mice treated with anti-PD-1 showed an increase in NK cells, a decrease in macrophages with an increase in the M1 phenotype, and an increase in tumor-reactive CD8+ TILs with expanded clonal diversity.
Contributed by Shishir Pant
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.
Author Info: (1) Regeneron Pharmaceuticals, Inc. 777 Old Saw Mill River Road, Tarrytown, NY, 10591, USA. (2) Regeneron Pharmaceuticals, Inc. 777 Old Saw Mill River Road, Tarrytown, NY, 10591, U
Author Info: (1) Regeneron Pharmaceuticals, Inc. 777 Old Saw Mill River Road, Tarrytown, NY, 10591, USA. (2) Regeneron Pharmaceuticals, Inc. 777 Old Saw Mill River Road, Tarrytown, NY, 10591, USA. (3) Regeneron Pharmaceuticals, Inc. 777 Old Saw Mill River Road, Tarrytown, NY, 10591, USA. (4) Regeneron Pharmaceuticals, Inc. 777 Old Saw Mill River Road, Tarrytown, NY, 10591, USA. (5) Regeneron Pharmaceuticals, Inc. 777 Old Saw Mill River Road, Tarrytown, NY, 10591, USA. (6) Regeneron Pharmaceuticals, Inc. 777 Old Saw Mill River Road, Tarrytown, NY, 10591, USA. (7) Regeneron Pharmaceuticals, Inc. 777 Old Saw Mill River Road, Tarrytown, NY, 10591, USA. (8) Regeneron Pharmaceuticals, Inc. 777 Old Saw Mill River Road, Tarrytown, NY, 10591, USA. (9) Regeneron Pharmaceuticals, Inc. 777 Old Saw Mill River Road, Tarrytown, NY, 10591, USA. sokol.haxhinasto@regeneron.com.
