Abstract A41: Absence of central tolerance as a sculpting mechanism of immune-checkpoint therapy

Abstract

Abstract Therapeutic targeting of immune checkpoint pathways, which are exploited by tumors to evade the immune system, can result in increased overall survival for some patients with specific types of cancers. The endogenous antitumor response is limited in part by the absence of tumor-reactive T cells, an inevitable consequence of thymic central tolerance mechanisms ensuring their deletion to protect against autoimmunity. In this study, we show that compared to wild-type mice, 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 and was accompanied by increased numbers of activated T cells expressing high levels of genes such as Gzma, Gzmb, Perforin, and Cxcr3, and tumors contained high levels of the chemokines Cxcl9 and Cxcl10 compared to wild-type mice. Furthermore, there was an enrichment of T cells expressing markers associated with the potent antitumor tissue-resident memory T cells expressing Cd103. Consistent with Aire’s central role in T cells’ repertoire selection, single-cell TCR sequencing unveiled the expansion of several clones with high tumor reactivity. Together, these results show that a break in central tolerance in combination with immune checkpoint blockade can potently enhance antitumor immunity and serve as a model system to unmask novel antitumor therapies. Citation Format: Asiel A. Benitez, Sara Khalil-Aguero, Anjali Nandakumar, Namita Gupta, Wendy Zhang, Gurinder S. Atwal, Andrew J. Murphy, Matthew A. Sleeman, Sokol Haxhinasto. Absence of central tolerance as a sculpting mechanism of immune-checkpoint therapy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A41.