Exploiting Radiation-Induced Immune Recognition of Renal Cell Carcinoma
Abstract
Kidney cancer is a deadly disease and one-third of patients will present with tumors that have spread to distant organs. For these patients, 5-year overall survival rates are less than 15%. Service members are particularly affected with higher rates of developing kidney cancer compared to the general population. Although therapies based on enhancing a patient s immune system (immunotherapy) have improved outcomes in aggressive disease, most patients still do not respond to treatment. Patient outcomes following immunotherapy rely on existing immune responses within the tumor microenvironment that are boosted by treatment with the goal of improving survival. While radiation has been proposed to kill tumors by damaging cells that are dividing, recent studies in mice have shown radiation also increases sensitivity of the remaining live tumor cells to immune-mediated attack. As antitumor immune responses initiated by radiation become more appreciated, trials that combine radiation with immunotherapy are opening for kidney cancer without a basic understanding of the contributions of radiation toward immune-mediated killing of human tumors. Importantly, translation of murine findings to human cancer is limited by large differences in sensitivity of mouse tumors and tumor types to radiation. These limitations along with very restricted access to patient tumors following radiation have resulted in fundamental gaps in our understanding of the overall impact of radiation on antitumor immune responses in human kidney cancer. Therefore, the objective of this proposal will be to determine if radiation sensitizes human kidney cancer to tumor-specific immune responses. This study builds off our recent findings in a first-of-its-kind clinical trial in advanced kidney cancer patients that combined high-dose radiation delivered to the kidney tumor followed by surgical resection of the tumor. With these unique patient tumor samples, we found kidney cancer patient tumors treated with radiation have higher levels of targets of the immune system, termed antigens, compared to patient tumors that were only treated with surgical resection. We further utilized state-of-the-art technology to examine the frequency of immune cells (T cells) specific for particular antigen targets within tumors and peripheral blood. Our preliminary findings show for the first time in any human malignancy, including kidney cancer, that radiation increases the frequency of T cells that have the same specificity/target as those found within tumors. These results suggest that a systemic immune response has been activated against tumor antigens following radiation that can be further amplified through combination approaches with immunotherapy. This project will address multiple KCRP Areas of Emphasis including the microenvironment and immunology, as well as the mechanism of response and resistance, to test the hypothesis that radiation can enhance immune recognition of human tumors and boost responses against kidney tumors. Our current studies will also utilize kidney tumors that have been surgically removed in an innovative model using fresh human tumors to determine how the radiation dose and treatment schedule impacts immune responses. Our work will further evaluate the frequency of T cells specific for a given antigen in tumors and peripheral blood in patients treated with different doses of radiation. Since radiation and immunotherapy are approved for kidney cancer, translational findings from this study can provide immediate rationale for new treatment combinations and clinical trials in kidney cancer for Veterans, their families, and the general public. Additionally, due to widespread usage of radiation as a relatively low-cost technology, findings from this study can be quickly adapted into clinical protocols to improve outcomes and potentially reduce the financial stress of patients who have limited treatment options. Moreover, the information le
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010720
Entities
People
- Jason B Muhitch
Organizations
- United States Army