Tumor Neoantigens and a Novel Hapten Vaccine Promote Immune Targeting of Wild-Type Tumor Lineage Antigens and Improve Response to Immune Checkpoint Blockade

Abstract

The renaissance of immunotherapy, spurred on by the discovery of immune checkpoint inhibitors, has dramatically altered treatment of many different cancer types. Despite the ever-expanding clinical scope of immune checkpoint blockade, a majority of cancer patients still do not benefit from immunotherapy. Unraveling the mechanisms of response to immunotherapy and translating that understanding into new or improved therapies will be crucial steps toward extending the promise of immunotherapy to more patients. One major factor correlated with positive response to immunotherapy is tumor neoantigen load. Additionally, in metastatic melanoma patients, the development of vitiligo is also associated with favorable response to immunotherapy. In chapter 2 of this thesis, we test the hypothesis that in melanoma patients treated with immune checkpoint blockade, a direct link exists between tumor neoantigens and vitiligo. Using carefully controlled murine models of melanoma, we demonstrate that in the context of immune checkpoint inhibition, tumor neoantigens promote epitope spreading and generate an autoimmune response against wild-type tumor lineage antigens. Leveraging the knowledge gained in chapter 2, we developed a new therapeutic strategy using haptens to exogenously introduce “neo”-epitopes in tumors lacking neoantigens in order to improve response to immune checkpoint blockade in low neoantigen tumors. In chapter 3 of this thesis, we optimize a novel hapten vaccine that improves response to immune checkpoint blockade in mice with low neoantigen tumors. Furthermore, we show that the hapten vaccine recapitulates the epitope spreading and immune targeting of normal tumor lineage antigens induced by tumor neoantigens. Over the course of testing various topical treatments for cancer immunotherapy, we identified a surprising hair-related phenotype. In chapter 4 of this thesis, we identify the treatment responsible for the phenotype and characterize the hair follicle biology underlying the phenotype. In addition, we connect the mechanism to recruitment of an immune cell population and explore novel topical treatment options.