Targeting the Shedding of Transmembrane PD-L1 to Enhance Therapeutic Efficacy of Immune Checkpoint Inhibitors
Abstract
Renal cell carcinoma (RCC) is among the top ten most common cancers in the United States. Metastatic recurrent RCC has poor prognosis and there is an urgent need to develop more effective targeted therapies to significantly improve the efficacy of currently available therapeutic agents. RCC has a high mutation load and is immunogenic and therefore is a good candidate for immunotherapy. Cancers escape from the host immune system attack by inhibiting T cell activation through the interactions of a group of proteins called the immune checkpoint proteins (ICPs) including the programmed cell death protein 1 (PD-1) and their ligands such as the PD ligand 1 (PD-L1). Immune checkpoint inhibitors (ICIs) such as anti-PD-1/PD-L1 antibodies that block the interactions of the ICPs and their ligands have been approved by the U.S. Food and Drug Administration for treatment of locally advanced and metastatic renal cell carcinoma. However, most of the ICI response rates are less than 25% in the RCC patients. Serious and sometimes life-threatening autoimmune responses have also been observed, all of which urges better understanding of the regulatory mechanisms that are essential for sensitizing the response of RCC patients to lower and safer dose of ICIs. PD-L1 is a transmembrane ligand. High levels of soluble/secreted PD-L1 (sPD-L1) in blood samples of cancer patients, including RCC patients, predict poor prognosis. Previous studies have established that many cell surface receptor ligands with the transmembrane domains, such as the EGFR family ligands, must be proteolytically cleaved mainly by members of the ADAM (A Disintegrin And Metalloproteinase) family to release soluble ligands to be fully activated. Our preliminary analyses indicated that ADAM19 is amplified in approximately 14% of renal clear cell carcinoma patients (TCGA) and up-regulated in RCC tissues and that higher ADAM19 levels are significantly associated with the poor RCC prognosis (p<0.001, Human Protein Atlas). We hypothesize that, compared to the transmembrane PD-L1, sPD-L1 generated via its ectodomain cleavage more potently activates PD-1 receptor expressed by tumor infiltrated T cells to more effectively inhibit T cell activities/functions and inhibit the host anti-RCC immunity, leading to more effective immuno-suppression and promotion of RCC growth and metastasis. We further hypothesize that ADAM19 plays a key role in shedding/activating PD-L1 and releasing sPD-L1 and that inhibition of ADAM19 reduces the PD-L1 shedding/activation, sensitizing the RCC response to the anti-PD-1 antibody. Two specific aims are proposed to test the hypotheses. Aim 1 is to establish that sPD-L1 displays more potent activity than transmembrane PD-L1 in inhibiting T cell proliferation/activation and the anti-RCC immunity, and in promoting the RCC progression. Aim 2 is to establish that ADAM19 plays a key role in shedding/releasing/activating PD-L1 and that ADAM19 inhibition sensitizes the RCC response to the ICIs. This proposal is based on innovative and well-reasoned and supported ideas that sPD-L1 generated via its shedding by ADAM19 displays more potent immunosuppressive activity than the transmembrane PD-L1. Successfully accomplishing this proposal will establish that sPD-L1 is a more potent immunosuppressor and that ADAM19 plays a role in the PD-L1 shedding and is a novel regulator of anti-RCC immunity. Furthermore, we will establish that ADAM19 is a novel target for sensitizing the RCC responses to the ICIs (short-term impact) and that the combined inhibition of ADAM19 and PD-1 constitutes a novel, more efficacious, and less toxic strategy against advanced and metastatic RCC (long-term impact). Therefore, this proposal is of high biologic and clinical relevance and high therapeutic potentials and impact.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110191
Entities
People
- Qin Yu
Organizations
- Icahn School of Medicine at Mount Sinai
- United States Army