Identification of immunogenic peptide neoantigens expressed in sarcomas and their therapeutic potential

Abstract

Abstract T cells recognize tumor neoantigens (TNag) in the context of MHC and eliminate cells which express these antigens, leaving those lacking immunodominant epitopes. Central to investigating tumor immunoediting is the ability to define immunogenic TNag. Differential aggretope index (DAI) is a measure of the difference in MHC binding affinity between mutated and unmutated peptides and has emerged as a highly efficient way of identifying immunogenic TNag. Our previous studies have demonstrated that in mice, TNag with a DAI >8 are considered immunogenic and elicit T cells that lead to the tumor elimination. Thus, tumors expressing TNag of DAI >8 are only found in immunodeficient mice. Given these observations, we investigated the mutational burden and immune phenotype of bone proximal tumors in 122 patients. Tumors included are of bone, surrounding tissue and distal metastases, and were analyzed by flow cytometry, whole exome and TCR-Vβ sequencing. We hypothesized that tumors with high DAI TNag would be immunoedited in patients with robust T cell responses as measured by T cell clonality. Similar to observations in mice, this correlation was only observed in TNag with DAI >8. In contrast, there was no correlation between DAI and frequency of CD8 TILs indicating that the repertoire of TILs is a better indicator of immune reactivity than their frequency. Among tumor types analyzed, osteosarcomas were the least immunoedited, suggesting greatest potential for immunotherapy. We confirmed this potential in a mouse model of osteosarcoma, where we show that therapeutic HSP-mediated responses, augmented by PD-1 blockade, conferred the best survival. These studies provide compelling rationale for novel immunotherapies in patients with osteosarcoma. Supported by NIH R01 CA233803 and an HCC UPMC Developmental Award