Immunosurveillance of Chromophobe Renal Cell Carcinoma by Tumor-Resident Cytotoxic Innate Lymphocytes
Abstract
Cancer treatments that use the power of the immune system to attack tumors--known as immunotherapies--have shown exceptional promise. Among these, immune checkpoint inhibitors allow cancer cells to be recognized and destroyed by a patient s own immune system via T cells, with fewer side effects than conventional chemotherapy or radiation. These new drugs can shrink or even eliminate tumors and keep them from coming back. Immune checkpoint inhibitors are now considered standard treatment for very advanced kidney cancers, as large clinical trials showed them to be effective. Nevertheless, many patients do not respond to these therapies. The objective of our proposed research project is to identify additional immunological mechanisms other than those mediated by T cells that suppress cancer progression in patients with renal cell carcinoma (RCC). Within that broad objective, we will focus our research on a class of tumor-resident innate lymphocytes that are present in high numbers in chromophobe RCC (chRCC) patients, a rare RCC type that is largely resistant to immune checkpoint inhibitor therapies. We have two specific goals. First, we will determine how those tumor-resident innate lymphocytes are generated, with an emphasis on a newly described innate lymphocyte production pathway, and whether the extent of their induction is intrinsically modulated in chRCC and clear cell RCC (ccRCC), two RCC subsets with distinct mechanisms of cell transformation and histopathology. Second, we will assess the killing activity of tumor-resident innate lymphocytes on chRCC and ccRCC cells. Our research so far indicates that chRCC and ccRCC exhibit different expressions of molecules that can enhance or inhibit the killing ability of innate lymphocytes. We will additionally identify genes that are selectively expressed in tumor-resident innate lymphocytes and use them to probe the publicly available gene expression database of chRCC patients to further ascertain innate lymphocyte control by cancer cell-expressed molecules and a role of innate lymphocytes in repressing cancer progression. Our work will advance our understanding of why sensitivity to T cell-based immunotherapies varies among patients with kidney cancer and whether the innate lymphocyte-based immune response represents a new antitumor mechanism in chRCC patients, which may lead to development of novel anticancer drugs. If successful, we believe this work will generate new insights to test some of these new drugs in chRCC patients in about two years.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010821
Entities
People
- Ming Li
Organizations
- Sloan-Kettering Institute
- United States Army