The concept that tumors express antigens that could render them immunogenic with the provision of adequate immunostimulation was supported by W. Coley in the 1890s, showing the potential for exogenously administered components to stimulate the immune response to achieve tumor regression. Indeed, encouraging results of therapies that enhance antitumor T-cell responses, such as immune-checkpoint inhibitors and adoptive T-cell therapy, emphasize the importance of T cells’ anti-cancer capacity. Although the response in both therapeutic modalities is remarkable, they are not universal and are not always durable. This limitation can be addressed by combining immune-checkpoint inhibitors with the priming of patient T-cells towards tumor Neoantigens. These Neoantigens are unique to the cancerous tissue and constitute an ideal class of anti-cancer targets, as they mount the majority of anti-tumor reactivity. We combined a neo-antigen prediction-pipeline and human-leukocyte-antigen (HLA)-peptidomics to identify tumor-associated-antigens and neo-antigens in over 20 melanoma tumors, and characterize their interactions with their tumor infiltrating lymphocytes. Our investigation of the antigenic and T-cell landscapes encompassing the tumor associate antigens and neo-antigen signatures, their immune reactivity, and their corresponding T-cell identities provides the first comprehensive analysis of cancer cell T-cell co-signatures. As neo-antigen targeting is becoming more established as a powerful therapeutic approach, investigating these molecules has taken center stage. In our investigation we show that a limited set of neo-antigen-specific T-cells mediates tumor rejection, suggesting that identifying just a few antigens and their corresponding T-cell clones could guide personalized immunotherapy.
Our findings further indicate that combining HLA-peptidomics with neo-antigen predictions allows robust identification of targetable neo-antigens, which could successfully guide personalized cancer-immunotherapies.
