W163 - NK-mediated Protection Against Tumor Recurrence in CMV+ Bladder Cancer Patients Upon BCG Treatment

Iyinyeoluwa Okulate – Department of Immunology & Immunotherapy, Lipschultz Precision Immunology Institute;Department of Oncological Sciences, Tisch Cancer Institute – Icahn School of Medicine at Mount Sinai, New York, NY, USA; Dan Fu Ruan – Department of Immunology & Immunotherapy, Lipschultz Precision Immunology Institute; Department of Oncological Sciences, Tisch Cancer Institute – Icahn School of Medicine at Mount Sinai, New york, NY, USA; Trine Strandgaard – Department of Molecular Medicine, Aarhus University Hospital; Department of Clinical Medicine, Aarhus University; – Aarhus University Hospital; Aarhus University, Aarhus, Denmark; Lars Dyrskjøt Andersen – Department of Molecular Medicine, Aarhus University Hospital; Department of Clinical Medicine, Aarhus University – Aarhus University Hospital; Aarhus University, Aarhus, Denmark; Nina Bhardwaj – Department of Medicine, Division of Hematology and Oncology, Tisch Cancer Institute – Icahn School of Medicine at Mount Sinai, New York, NY, USA; Matthew Galsky – Department of Medicine, Division of Hematology and Oncology, Tisch Cancer Institute – Icahn School of Medicine at Mount Sinai, New York, NY, USA; John Sfakianos – Department of Urology, Tisch Cancer Hospital – Icahn School of Medicine at Mount Sinai, New York, NY, USA; Amir Horowitz – Department of Immunology & Immunotherapy, Lipschultz Precision Immunology Institute; Department of Oncological Sciences, Tisch Cancer Institute – Icahn School of Medicine at Mount Sinai, New York, NY, USA

Abstract Text: The intersection of viral infections and solid tumors presents a complex landscape for immunotherapy strategies, where treatments such as intravesical instillation of BCG are standard first-line therapy in non-muscle-invasive bladder cancer (NMIBC), yet its efficacy remains limited with a 32-42% recurrence rate. We found that cytomegalovirus (HCMV) reactivates in response to BCG-therapy and spreads to NMIBC tumors, including infection of monocytes, fibroblasts, and even tumor cells, suggesting a viral influence that extends beyond traditional perspectives on cancer treatment.

Approximately 40-50% of HCMV-seropositive individuals harbor a subset of "adaptive" NK cells, which exhibit enhanced capacity for antibody-mediated immune responses. Adaptive NK cells expand in response to HCMV-reactivation and may hold a key to overcoming treatment resistance.

Using a cohort of NMIBC patients treated at Mount Sinai, we found that HCMV-seropositive NMIBC patients respond better to BCG-therapy than their HCMV-seronegative counterparts and HCMV-seropositive patients with adaptive NK cells had a perfect response. Further, we profiled urine-derived CD45+ cells and bladder biopsies of patients during BCG-therapy and observed that adaptive NK cells infiltrate and establish residency in bladder tissues and colocalize with HCMV-infected cells within the bladder. Additionally, we observed significant elevation in plasma IgG1/IgG3 after exposure to BCG and unique to HCMV-seropositive NMIBC patients, suggesting a role for antibody-dependent cellular cytotoxicity (ADCC) mediated by adaptive NK cells.

HCMV's role in cancers has been understudied, especially its impact on the immune landscape of solid tumors. Our results provide critical evidence for targeting HCMV and adaptive NK cells for improving immunotherapies for solid tumors.