Project 467141

Immunotherapy is becoming a forerunner in cancer treatment as it enhances the patient's immune system to eliminate cancer cells. Immune checkpoint molecules expressed on T cells regulate the immune system by preventing the hyperactivation of immune responses. However, these molecules can be overexpressed in cancer patients and decrease their ability to eliminate cancer cells. Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) is an immune checkpoint molecule highly expressed on regulatory T cells (Tregs) that suppress the function of pro-inflammatory T cells responsible for eliminating cancer cells. Immune checkpoint inhibitors (ICIs) such as anti-CTLA-4, release the "brakes" off the immune system to promote anti-tumor immune responses. However, only ~30% of cancer patients respond to anti-CTLA-4 and the degree of response is variable. Pre-existing infiltration of pro-inflammatory cells in tumors is positively correlated with response to ICIs. Patients bearing tumors with defects in the DNA mismatch repair (MMR) pathway are more responsive to ICIs than those with a proficient MMR pathway. Defects in the MMR pathway increase DNA mutations in the tumor that promote immune cell infiltration. We have shown that response to anti-CTLA-4 can be enhanced in tumors with a low mutation load such as neuroblastoma by inhibiting the MMR pathway. This study will explore the mechanisms of anti-CTLA-4 in neuroblastoma tumors with a defective MMR pathway in mice. I hypothesize that tumors with a defective MMR pathway enable anti-CTLA-4 to deplete Tregs in the tumor and thereby increase the infiltration and function of pro-inflammatory T cells. The results of my study will further our understanding of host-tumor interactions and justify a method to improve patient response to ICIs.