Identification of a Novel Key Regulator of Anti-Renal Cancer Immunotherapy
Abstract
Renal Cell Carcinoma (RCC) is among the top ten most common cancers in the United States and risk of RCC recurrence remains high. Metastatic recurrent RCC has poor prognosis and there is urgent need to develop more effective targeted therapies and novel strategies to significantly improve efficacy of current available therapeutic agents. An increased level of tumor-associated blood vessels is a hallmark of RCC. Inhibitors targeting tumor angiogenesis such as VEGF receptor inhibitors (VEGRIs) sunitinib and axitinib have been approved by the FDA as first-line and adjuvant treatments of adult patients at high risk of recurrent RCC. RCC has a high mutation load and is immunogenic and therefore is a good candidate for immunotherapy. T cells are required for antitumor immunity. T cell functions and antitumor immunity are negatively regulated by immune checkpoint proteins such as PD-1. The immune checkpoint inhibitors that target/inhibit the immune checkpoint proteins and release host immunity against cancers have shown clinical benefit as adjuvant/neoadjuvant and first-line therapeutic agents against locally advanced and metastatic RCC. The FDA has approved pembrolizumab (an anti-PD1 antibody) or avelumab (an anti-PD-1L1 antibody) in combination with a VEGFRI (axitinib/Inlyta) as first-line treatments of patients with advanced RCC, suggesting great potential for combinational treatments using the checkpoint inhibitors and anti-angiogenic agents. Analyses of the immune checkpoint proteins and several known angiogenic factors indicated that in addition to most of the immune checkpoint proteins, VEGFA, C, D, and VEGFR1/2, high levels of angiopoietin-2 (Angpt2), angiopoietin-like protein 2, 4, 5, 6, and 8 (AngptL2, 4, 5, 6, 8) are associated with RCC’s poor prognosis. AngptL2 is a ligand of leukocyte immunoglobulin (Ig)-like receptor B2 (LILRB2) in human and paired immunoglobulin-like receptor B (PIR-B) in mouse. PIR-B is the mouse ortholog of human LILRB2. LILRB2 signals through its intracellular immunoreceptor tyrosine-based inhibitory motifs (ITIMs) via recruiting protein tyrosine phosphatases, which in turn negatively regulates the immune cell activation and immune response. Myeloid-derived suppressor cells (MDSCs) are known to express LILRB2 and tumor-infiltrating MDSCs display immunosuppressive activity. We hypothesize that AngptL2 promotes RCC growth and progression by promoting an immuno-suppressive microenvironment in RCC via recruitment/activation of LILRB2+/PIR-B+ MDSCs, which leads to inhibition of CD4+/CD8+T cell proliferation/functions and expansion of regulatory T cells (Treg). We further hypothesize that inhibition of AngptL2 reverses its immunosuppressive effects and sensitizes the RCC response to the immune checkpoint inhibitors. To test the hypothesis, we will (1) establish that increased AngptL2 promotes RCC growth and progression and promotes recruitment/activation of LILRB2+/PIR-B+ MDSCs, which leads to inhibition of CD4+/CD8+T cell proliferation/functions and expansion of Treg whereas AngptL2 inhibition reverse its effects and enhances the PD-1/PD-L1-inhibitor mediated anti-RCC immunity. We will (2) establish that combinational inhibition of AngptL2 and the immune checkpoint proteins together with or without VEGFRIs constitutes a novel and more efficacious strategy against RCC. This proposal seeks to increase our understanding of the biology of kidney cancer and to identify targets for sensitizing RCC response to the immune checkpoint inhibitors and development of novel and more efficacious combinational treatments against RCC. The hypothesis and experiments outlined are highly innovative and feasible. Successfully accomplishing this proposal will establish a novel role of AngptL2 in negatively regulating anti-RCC immunity, provide a novel target for sensitizing the RCC response to the immune checkpoint inhibitors, and develop the novel and more efficacious combinational treatments by using
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010713
Entities
People
- Qin Yu
Organizations
- Icahn School of Medicine at Mount Sinai
- United States Army