Project 172482

It has recently been shown that many ovarian cancer patients mount immune responses against their tumor. This is reflected in the fact that many ovarian tumors are densely packed with "T cells", a type of white blood cell that fights viral and bacterial infections, as well as cancer. Importantly, patients with large numbers of T cells in their tumor live longer after chemotherapy compared to patients with fewer T cells in their tumor. However, we do not know which features of the tumor are being recognized by T cells. Recent work has shown that chemotherapy induces mutations in cancer cells, and some of these mutations make the cancer cells resistant to chemotherapy. It is likely that some tumor mutations may be recognized as "foreign" by the immune system. Based on these considerations, we hypothesize that chemotherapy generates new tumor mutations that are recognized by patients' T cells, which in turn help prevent tumor recurrence by killing remaining tumor cells. We propose to use two innovative methods to identify new tumor mutations and T cell responses in ovarian cancer, focusing on patients who show a favorable response to chemotherapy. Aim 1. To identify tumor mutations that induce antibody responses in patients. Aim 2. To use state-of-the-art genomic methods to identify tumor mutations caused by chemotherapy. Aim 3. To determine whether chemotherapy-induced tumor mutations are recognized by T cells. Aim 4. To determine whether recurrent ovarian tumors contain T cells triggered by chemotherapy. This will be the first study to investigate whether chemotherapy generates new mutations that stimulate T cell responses in patients with ovarian cancer. With a better understanding of how chemotherapy affects the immune system, we believe it will be possible in future to improve clinical outcomes further by enhancing immune responses using drugs, vaccines or T cell infusions.