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.
Sudipto Ganguly, PhD, joined the Johns Hopkins University School of Medicine faculty in June, 2019 as an Assistant Professor in the Cancer Immunology Program (Department of Oncology). He received his B.S. (Honors in Botany) and M.S. (Genetics and Plant Breeding) degrees from the University of Calcutta in India. He received his Ph.D. in Biochemistry from the University of Calcutta, where he was supervised by Professor Mitali Chatterjee, MD, PhD. His doctoral research investigated the role of systemic and intra-lesional cytokines in the immune-pathology of post-Kala-azar dermal leishmaniasis (PKDL). During his post-doctoral training in the laboratory of Professor Leo Luznik, MD, at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Dr. Ganguly showed the efficacy of post-transplant cyclophosphamide against Graft-versus-Host-Disease (GVHD) was dependent on induction, maintenance and expansion of thymic-derived T regulatory cells. His lab is studying novel, in silico-predicted, immune checkpoint targets by expression analysis in clinical samples as well as in syngeneic tumor models in both global and conditional gene-knockout mice. His group have recently characterized PVRIG (Poliovirus Related Immunoglobulin Domain Containing) as a novel cancer-specific immune checkpoint in both mice and humans. He has further shown that PVRL2, the principal ligand of PVRIG, is expressed copiously by infiltrating myeloid cells in the tumor micro-environment, particularly in high-grade serous ovarian cancer, making the PVRIG-PVRL2 axis a target of interest for immunotherapy. He is a recipient of the NCI Ovarian Cancer SPORE CEP award.