Abstract IA07: Hitting the target: T-cell receptors, cross-reactivity, and tumors

Abstract

Abstract Cancer arises due to an accumulation of genetic alterations, which can lead to the production of mutant proteins that are not expressed by normal cells. Some of these mutant proteins can be processed into short peptides and presented on the cell surface by major histocompatibility complex molecules as neoepitopes and CD8+ T cells can effectively recognize and mount responses against these neoepitopes across various cancer types. However, tumor-specific lymphocytes are generally characterized by an exhausted phenotype, which can in some circumstances be reversed with checkpoint blockade therapies that restore antitumor activity, with those cancer types and individual tumors that bear relatively high mutation burdens showing more robust responses. Using predictive algorithms to identify putative endogenous antitumor T-cell responses across solid tumor types has resulted in an average 2% of predicted neoepitopes associated with a detectable response. This has led to the assumption that low mutation burden tumors, which include many pediatric tumors, are poorly immunogenic. Here, we report that pediatric patients with acute lymphocytic leukemia (ALL) possess broad pools of tumor-associated neoepitope-specific CD8+ T cells, responding to 86% of tested neoantigens and recognizing 68% of the tested neoepitopes. We characterized phenotypic and transcriptional profiles of these epitope-specific antitumor CD8+ T cells at the single-cell level and found a heterogeneous population that included many highly functional effector cells. Moreover, we observed immunodominance hierarchies among the neoepitope-specific CD8+ TILs, whereby a majority of tetramer-bound CD8+ T cells were restricted to one or two putative neoepitopes. Our results indicate that robust antitumor immune responses are induced in these pediatric ALL tumors despite their low mutation burdens and emphasize the importance of immunodominance in shaping cellular immune responses. These data suggest that pediatric cancers may be amenable to immunotherapies aimed at enhancing immune recognition of tumor-specific neoantigens. Citation Format: Paul G. Thomas. Hitting the target: T-cell receptors, cross-reactivity, and tumors [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr IA07.