Dissecting Mechanisms of Tumor Response and Resistance to Radiation and Immunotherapy

Over half of all cancer patients receive radiation therapy, and it contributes to over 40% of cancer cures. Within the last decade, cancer immunotherapy has become a pillar of cancer therapy, along with surgery, chemotherapy, and radiation therapy. The most commonly used type of immunotherapy is immune checkpoint blockade, which can increase immune cell activity by blocking inhibitory signals. Preclinical studies with transplanted tumors demonstrate high cure rates with either immune checkpoint blockade, radiotherapy, or combination treatment. These studies have led to hundreds of clinical trials testing checkpoint blockade and radiotherapy alone or in combination with other therapies, but emerging results are disappointing. My thesis work seeks to develop novel mouse models of cancer that recapitulate human disease, understand mechanisms of tumor resistance to radiation and immunotherapy, and identify novel immunologic targets that can enhance patient responses to radiation therapy.

Using complex genetically engineered mouse models of cancer, we investigated the contributions of the tumor microenvironment to therapeutic resistance. First, we explored the role of neutrophils in mediating radiation response. We showed that elevated neutrophil levels were associated with poor local control and survival in cervical cancer patients treated with definitive chemoradiation. Furthermore, in a genetically engineered mouse model of sarcoma, we demonstrated that genetic and antibody-mediated depletion of neutrophils increases radiosensitivity and decreases a mitogen-activated protein kinase transcriptional program. These results demonstrate that neutrophils promote tumor resistance to radiotherapy.

In complementary work using novel genetically engineered mouse models of sarcoma, we found that cells with high tumor mutational burden transplanted into syngeneic mice were cured by immune checkpoint blockade and radiation therapy, but the identical treatment failed in autochthonous sarcomas. To understand the mechanisms by which primary tumors were resistant to tumor cure by radiation and immunotherapy, we generated a single cell atlas of tumor-infiltrating immune cells from transplant and primary sarcomas treated with radiation and immunotherapy, which revealed marked differences in their immune landscapes. We found that radiation therapy remodeled myeloid cell phenotypes in primary and transplant sarcomas, but only transplant tumors were enriched for the effector CD8+ T cells that mediate response to combination therapy. In contrast, mice with autochthonous sarcomas demonstrated tumor-specific tolerance. These results indicate that radiation and immunotherapy cooperate to promote immunity within the tumor microenvironment, but identify immune tolerance in autochthonous tumors that must be overcome for this promising combination treatment to cure cancers that co-evolve with the immune system.