Abstract IA007: Tumor HLA-E expression and cytomegalovirus infection modulate NK cell activity in human bladder cancer

Abstract The intersection of viral infections and cancer therapy presents a complex landscape for immunotherapy strategies, particularly in solid tumors, where treatments such as systemic chemotherapy and targeted radiation are standard. Largely unexplored in solid tumors are the effects of human herpes virus-5 (HHV-5) also known as HCMV that imprints both lifelong effects on natural killer (NK) cells as well progressive effects on T cells with aging. HCMV is an extremely successful virus as it rarely kills the host outside of settings of compromised immunity, e.g. transplantation and advanced HIV-1 infection. HCMV is not considered a comorbidity in patients with solid tumors. Our group has identified reactivated cytomegalovirus (HCMV), found in bladder tissues post treatment, including infection of monocytes, fibroblasts, and even tumor cells, suggesting a viral influence that extends beyond traditional perspectives on cancer treatment resistance and response. We have observed spread of infection in both settings of BCG-treated non-muscle-invasive bladder cancer (NMIBC) as well as MIBC treated with gemcitabine and cisplatin chemotherapy. HCMV infection leads to the development of “adaptive” NK cells that express the activating isoform of NKG2A: NKG2C, which are likely expanded in response to HCMV reactivation and have established functions for controlling virus reactivation. Our central hypothesis is that certain treatments may reactivate HCMV, potentially greatly altering the biology within the tumor microenvironment (TME) and providing a framework to exploit NK cells for immunotherapy strategies. In a cohort of NMIBC patients (N=90) receiving BCG therapy at Mount Sinai, we profiled patients’ serum for HCMV-IgG (N=47 HCMV seropositive; N=43 HCMV seronegative) and observed a significantly improved recurrence-free survival in HCMV seropositive patients (HR=0.58, p=0.03). Further, HCMV-seropositive patients with circulating NKG2C+ adaptive NK cells experienced a near perfect response to BCG therapy (p=0.0002). Strikingly, in situ imaging and RNAscope analyses of patient tumors before and after BCG therapy revealed strong presence of active viremia in tumors. Further, analysis of on-treatment bladder biopsies after tumor resection demonstrated the presence of adaptive NK cells in HCMV+ bladder tissues, but only after exposure to BCG therapy and tissue-derived adaptive NK cells expressed high levels of chemokine receptors, CXCR3 and CXCR4 as well as tissue-residency markers, suggesting a mechanisms for trafficking to the bladder and taking up residence for subsequent antitumor control against recurrence. Impact and Translation: Our findings suggest that adaptive NK cells mediate response to immunotherapies for solid tumors as well as provide preclinical models for adoptive transfer therapies targeting NK cells. Additionally, if HCMV reactivation is widespread across solid tissues in response to systemic therapies, it may prove a critical comorbidity to consider in design of treatment strategies and in clinical trials. Citation Format: Amir Horowitz. Tumor HLA-E expression and cytomegalovirus infection modulate NK cell activity in human bladder cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr IA007.