NK cells in renal cell carcinoma : toward biomarker discovery and improved immunotherapeutic strategies

Abstract

Renal cell carcinoma (RCC) represents a significant clinical challenge due to its resistance to conventional therapies and its complex tumor microenvironment (TME). RCC's immunogenic nature, characterized by the infiltration of immune cells, highlights the potential of immunotherapeutic strategies. Among these immune cells, natural killer (NK) cells play a crucial role in the body's defense against tumors, including RCC. However, the functionality of NK cells is often impaired within the RCC TME due to various suppressive factors, leading to decreased tumor infiltration and cytotoxic activity. This thesis delves into the intricate interactions between NK cells and the RCC TME. It aims to uncover biomarkers for disease progression and devise strategies to enhance the efficacy of NK cell-based therapies.

In Paper I, we conduct a comprehensive immune profiling to dissect the immune landscape of RCC, focusing on the secretome and phenotypes of NK cells and other immune populations in both the blood and tumors of RCC patients. Our analysis reveals significant alterations in cellular and soluble factors, pointing to potential biomarkers for disease progression, including CXCL8 levels, which correlate with aggressive tumor behavior and patient relapse. Papers II through IV investigate specific suppressive factors within the RCC TME that hinder NK cell infiltration and function. Paper II focuses on the role of the tumor poliovirus receptor (PVR) and its interaction with the activating receptor DNAM-1 on NK cells. We demonstrate that PVR-positive tumors downregulate DNAM-1, impairing NK cell-mediated cytotoxicity and highlighting PVR/DNAM-1 axis as a target to enhance NK cell function in RCC. Paper III examines the impact of regulatory T cells (Tregs) on NK cells. Our findings suggest that IL-15 primed NK cells, expressing higher levels of CD25, can better withstand Treg-mediated suppression. This points to the potential of IL-15 stimulation and CD25 expression as strategies to empower NK cells within the TME. Lastly, Paper IV addresses the effect of hypoxia, a hallmark of RCC due to VHL mutation, on NK cell activity. We show that hypoxia-inducible factors (HIFs), stabilized in the absence of VHL, create an immunosuppressive environment that reduces NK cell infiltration and activity. Restoration of VHL in RCC models enhances NK cell infiltration and antitumor activity, proposing a novel approach to combat hypoxia-induced NK cell dysfunction.

Together, these studies provide a comprehensive understanding of the factors that limit NK cell efficacy in RCC and propose novel biomarkers and therapeutic strategies to harness NK cells' potential in combating this challenging disease. This thesis lays the groundwork for future research into optimizing NK cell-based immunotherapies for RCC, aiming to improve patient outcomes through targeted modulation of TME.