2020 Early Career Investigator Grant Recipient — Sudipto Ganguly, PhD
Project Summary
Advanced stage diagnosis is common in high-grade serous ovarian cancer (HGSOC) primarily due to ineffective screening. Late-stage patients make up 75-80% of all HGSOC cases and are frequently refractory to standard chemotherapy administered after a debulking surgery to remove as much of the tumor as possible. Resistance-mitigating treatment strategies against HGSOC constitute an unmet need. Encouragingly, HGSOC shares immunologic features with other cancers that confer sensitivity to immunotherapy. Immuno-oncology agents include antibodies that block surface inhibitory receptor proteins on tumor-infiltrating T lymphocytes, the sentinels tasked with killing tumor cells. In cancer, these receptors are upregulated, engage with their binding partners (ligands) on specialized immune cells or tumor cells and relay a de-activating signal. However, immune therapies that have been approved for select cancers have been largely ineffective against HGSOC, underlining the necessity of screening novel immunologic agents tailored for late-stage HGSOC. A relatively new ligand-inhibitory receptor pair is the Poliovirus Receptor-Related 2 (PVRL2) – Poliovirus Receptor-Related Immunoglobulin Domain-Containing (PVRIG) axis, which has recently been described both in human cancer and in mouse tumor models. PVRL2 (on tumor cells or myeloid cells) binds PVRIG (on CD8 T cells), resulting in impaired anti-tumor immunity. Expression on immune cells is restricted to cells of the myeloid lineage (e.g. monocytes and macrophages) in both species. Interestingly, both human and murine tumor – infiltrating myeloid cells are strongly positive for surface PVRL2. Our preliminary analyses have shown that surface PVRL2 is elevated on HGSOC tumor-infiltrating myeloid cells and tumor cells. This data is consistent with reports in literature of HGSOC being among the cancer types that are strongly positive for PVRL2 on both tumor cells and intra-tumoral myeloid cells. We hypothesize that surface PVRL2 on tumor-infiltrating myeloid cells is a clinically targetable ligand in HGSOC, and binding of PVRL2 with its receptor, PVRIG, on CD8 T cells in the HGSOC tumor micro-environment impairs anti-tumor immunity. To validate our hypothesis, we propose to study: 1) mouse ovarian tumors in PVRL2-deficient mice to confirm PVRL2 promotes tumor growth; 2) PVRL2-expressing myeloid cells obtained from tumors of HGSOC patients to corroborate an immune-suppressive gene-protein signature; and 3) archived HGSOC tumor tissue, where we will correlate PVRL2 staining (by immunohistochemistry) with clinical outcomes to demonstrate its utility as a prognostic marker. The near-term objectives of our research will be availability of translatable pre-clinical information on the PVRL2-PVRIG checkpoint axis in HGSOC. We anticipate a long-term outcome wherein clinical development of a PVRL2 blocker will be tested in patients with advanced primary and recurrent HGSOC.