Neoantigen screening identifies broad TP53 mutant immunogenicity in patients with epithelial cancers

Abstract

The adoptive cell transfer of select tumor-infiltrating lymphocytes (TILs) for personalized immunotherapy can mediate long-term objective tumor regressions in patients with metastatic melanoma, bile duct, cervix, colon, and breast cancers (1–5). These clinical responses are likely mediated by recognition of mutated gene products termed neoantigens because they are absent in normal tissues. Intratumoral T cell responses to mutated neoantigens identified thus far have been unique to the patient, i.e., they are private mutations not identified in other patients’ tumors, except for a neoepitope arising from the KRASG12D driver mutation (1, 3). However, it is largely unknown whether naturally occurring T cells within tumors recognize other shared mutated neoantigens expressed by cancers of unrelated patients. Across all cancer types, TP53 is the most commonly mutated gene, but mutations occur throughout the gene with preference in the DNA binding domain (6, 7). Therapeutic approaches evaluating small-molecule inhibitors and T cells targeting both WT and mutant p53 tumors in mouse models have been described (8–11). Preliminary studies provided some evidence that mutated TP53 could be recognized by peripheral blood T cells after in vitro stimulation and in vivo vaccination (12–14). However, evidence of immune responses to mutated TP53 within human tumors is limited even though most tumors will express a TP53 mutation. We previously reported patient-specific neoantigen screening in 7 patients with metastatic ovarian cancer, 2 of whom had mutated TP53 neoantigens restricted by HLA-DRB3*02:02 (15, 16). Here, we developed a novel strategy to systematically and comprehensively analyze intratumoral T cell responses to defined TP53 hot spot mutations independent of other tumor mutations in 133 new patients with multiple tumor types. The goal was to translate these cells or their TCR genes into broadly applicable adoptive cellular therapies for common epithelial malignancies.