Density of immunogenic antigens does not explain presence or absence of the T cell-inflamed tumor microenvironment in metastatic melanoma

Abstract

3002 Background: Patients with melanoma can be categorized based on the presence or absence of a T cell-inflamed tumor microenvironment. The presence of baseline CD8+T cells is associated with clinical benefit to immunotherapies, including anti-PD1 and anti-CTLA4. The molecular mechanism explaining lack of a T-cell infiltrate in a major subset are poorly understood, but differential expression of immunogenic antigens has been proposed as one explanation. Methods: Using the TCGA data set for malignant melanoma, the T cell-inflamed gene expression signature was used to segregate patients by immune phenotype. Three categories of antigens were examined: cancer-testis (CT) antigens, differentiation antigens, and somatic mutational antigens. Results: By transcriptional profiling, no difference was observed in levels of CT antigens or differentiation antigens. Using exome sequencing of tumor versus germline, a range of 18 to 3001 of non-synonymous mutations was observed in both cohorts. Using the syfpeithi algorithm for HLA-A*0201 patients, a median of 123 mutations having a high immunogenicity score were found in the T cell-inflamed cohort versus 176 in the non-T cell inflamed. To confirm actual immunogenicity, several synthesized peptides show positive HLA-A*0201 binding and can be recognized by human CD8+T cells in vitro. Conclusions: Both the T cell-inflamed and non-T cell-inflamed subsets of melanoma show comparable expression of CT, differentiation, and mutational antigens. Lack of spontaneous immune infiltration in a major subset of tumors is unlikely to be due to lack of antigens. Strategies that improve spontaneous T-cell infiltration into tumors therefore could, in principle, render these patients response to immunotherapies once these antigens become recognized.