Abstract IA23: How does the immune system contend with intratumoral heterogeneity in ovarian cancer?

The presence of tumor-infiltrating T cells and B cells is associated with markedly prolonged survival in high-grade serous ovarian cancer (HGSC), yet we have only a rudimentary understanding of how the immune system contends with the continually evolving tumor genome. HGSC exhibits extensive spatial heterogeneity at diagnosis, and tumors undergo dramatic changes in response to treatment. In long-term survivors, the immune system presumably deploys mechanisms that successfully respond to these changes. With better understanding, it may be possible to exploit these mechanisms to create more effective immunotherapies. We have shown that the most prognostically favorable immune responses involve both cytolytic and antibody-based mechanisms, suggesting important cooperative interactions between the T cell and B cell branches of the immune system. By studying serial tumor samples, we have uncovered extensive temporal dynamics of the antitumor immune response. We found that neoadjuvant chemotherapy can enhance preexisting immune responses yet generally fails to initiate responses in tumors that lack immune infiltrates at baseline. Indeed, with better understanding, these immunologically inert or “cold” tumors may represent an attractive therapeutic opportunity, as they can express high levels of tumor-specific antigens with corresponding systemic T-cell and antibody responses. Currently, we are looking at the issue of spatial heterogeneity by subjecting tumor samples collected from different anatomical locations to comprehensive genomic and immunologic analyses, including mutational profiling, RNA-seq, TCR/BCR-seq, and multi-plexed immunohistochemistry. This work is providing novel insights into the relationship between the clonal architecture of tumors and antitumor immunity. Our findings to date indicate that tumor deposits with a high degree of clonal heterogeneity generally have low densities of immune infiltrates, suggesting a means by which tumor evolutionary processes are insulated from immunologic attack. Furthermore, TCR-seq experiments are providing early evidence that T-cell clones track with individual tumor clones across space, suggesting that the immune system contends with intratumoral heterogeneity by battling each tumor clone individually. The presentation will address the implications of these findings on the design of more effective immunotherapies for HGSC and related cancers. Citation Format: Brad H. Nelson. How does the immune system contend with intratumoral heterogeneity in ovarian cancer? [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr IA23.