Following are public and technical abstracts for the VISTA:VSIG3 project funded by the Department of Defense Kidney Cancer Research Program (KCRP) for 2017.
Principal Investigator: Kathleen Mahoney
Institution: Dana-Farber Cancer Institute
Funding Mechanism: Idea Development Award — Early Career Investigator
Award Amount: $425,000
Public Abstract
Background: For cancers to grow, they must evade destruction by the immune system. Many cancers evade the immune system by expressing molecules that turn off the anti-cancer immune response. Blocking these inhibitory checkpoints, like Programmed cell death-1 (PD-1), has become a standard therapy for treatment of many types of tumors including kidney cancer. Combining immune checkpoint inhibitors has been shown to improve outcomes for patients with kidney cancer. However, many patients fail to respond to currently available immune checkpoint inhibitors. These tumors appear to have a smoldering antitumor immune response that is turned off by expression of other negative immune regulators related to PD-1, such as VISTA. VISTA is an immune checkpoint that is highly expressed across kidney cancers, and a subset of kidney tumors also expresses VISTA’s binding partners: VSIG3 and VSIG8.
Objectives: My primary goal is to determine if targeting receptors of the VISTA pathway, VSIG3 or VSIG8, can overcome PD-1 resistance in a mouse kidney cancer model. This proposal addresses multiple KCRP Areas of Emphasis, including immunotherapies and resistance to standard therapy.
Innovation: By determining if blocking the function of VSIG3 and VSIG8 overcomes the tumor’s ability to evade the immune system in a mouse model, we may be able to develop better therapeutics for blocking this pathway in patients with cancer.
Impact: In addition to investigating VISTA:VSIG3 or VSIG8 as a target for fighting cancer, we will study patients’ tumors to explore biomarkers that would predict whether the therapy is likely to work. This could help to determine which patients will most likely benefit from VISTA pathway inhibitors and facilitate the development of new therapies to treat patients with kidney cancer.
Technical Abstract
Background: Blockade of either Programmed death-ligand 1 (PD-L1) or its T-cell immune checkpoint receptor Programmed cell death-1 (PD-1) has produced clinical benefit in multiple tumor types, including kidney cancer. However, many patients fail to benefit from PD-1/PD-L1 checkpoint blockade. Combining immune checkpoint blockade of PD-1 and CTLA4 has been shown to improve outcomes for patients with kidney cancer, but tumors that do not express PD-L1 do not respond well to this combination. Our preliminary data suggest that renal cell carcinomas (RCC) are an excellent model for studying mechanisms of immune resistance mediated by the tumor microenvironment since kidney tumors are highly infiltrated with lymphoid and myeloid cells. Our transcriptomic analysis of human kidney cancers in The Cancer Genome Atlas indicated that kidney cancers express a broad range of potentially targetable immune checkpoints. VISTA, a B7 family member with homology to PD-L1, is a particularly promising target in kidney cancer, not only because it is highly expressed across kidney cancers, but also because we have found a subset of kidney tumors that expresses the putative receptors for VISTA: VSIG3 and VSIG8.
Areas of Emphasis: This proposal will address multiple KCRP Areas of Emphasis, including immunotherapies and resistance to PD-1 blocking therapy, as well as exploring biomarker development for translating anti-VISTA interventions into patients with kidney cancer in the future.
Hypothesis: The failure of PD-1 blockade in RCC is due to expression of other immune checkpoints, such as VISTA:VSIG3 or VSIG8, which may be targeted for greater therapeutic benefit in cancers refractory to PD-1 pathway blockade, including the mouse kidney tumor RENCA.
Specific Aims: (1) Determine whether blocking the VSIG3 or VSIG8 immune checkpoint pathway improves the response to PD-1 pathway blockade in the RENCA model. (2) Determine which cell types in human RCC express VISTA, VSIG3, and VSIG8.
Study Design: Since VISTA may be expressed on lymphocytes and myeloid cells, I will test the ability of the VSIG3 and VSIG8 antibodies that we are developing to block lymphocyte activation and macrophage activity in vitro. I will test the ability of our panels of human and mouse antibodies to block the VISTA-VSIG3 interaction, and VISTA-VSIG8 interaction. I will test the efficacy of VISTA:VSIG3 blockade alone and in combination with PD-1 blockade in the RENCA model. I will analyze tumor-infiltrating lymphocytes and myeloid cells in these therapeutic preclinical trials to determine the mechanism of immune activation mediated by VISTA pathway blockade. I will compare the RENCA tumor gene and protein expression in vivo with that of human RCC. I expect that this research will be particularly relevant for patients with kidney cancer, given that VISTA is highly expressed across types of RCC.
Innovation: While much data supports the role of VISTA as a negative immune checkpoint, translating mouse blocking antibody therapeutics into functional human therapeutics is difficult without knowledge of the specific receptor:ligands interaction (epitope) to target. I aim to determine whether the VSIG3 and VSIG8 interaction is responsible for lymphocytes inhibition in vitro and in vivo in an immunocompetent mouse kidney cancer model.
Impact: In addition to establishing VSIG3 and VSIG8 as targetable for fighting cancer, we will study patients’ tumors to explore potential biomarkers found in human kidney cancer, which will determine which patients will most likely benefit from VSIG3 and VSIG8 inhibitors and facilitate the development of new immunotherapies for treating patients with kidney cancer.