Tissue-Resident Memory B cells Mediate Local and Metastatic anti-Cancer Immunity 2310347

Abstract Introduction Tissue-resident memory B cells (BRM) have been identified in barrier tissues such as the lung, where they provide durable protection against microbial infection. Whether analogous tissue-resident B-cell populations can be established in peripheral tissues and actively contribute to anti-cancer immunity has remained unknown. Methods Here, we define the dynamics and functional role of BRM in cancer using a localized extracellular vesicle (EV)—based vaccination strategy to deliver DEL or HEL together with OVA antigens directly to the skin. This approach selectively seeded antigen-specific BRM within defined cutaneous niches, arising either endogenously from HEL- or OVA-specific B cells or following adoptive transfer of Hy10 (DEL-specific) B cells with cognate OTII (OVA-specific) T-cell help. Results Phenotypic profiling revealed sustained expression of CD69, CXCR3, and CCR6, consistent with a long-lived tissue-resident memory program. Functionally, the presence of BRM conferred robust, localized protection against antigen-matched MOC2 squamous cell carcinoma expressing DEL/OVA or HEL alone, establishing a direct causal role for skin BRM in suppressing local tumor growth. Extending beyond primary tumors, we further demonstrate that lung BRM contribute to protection in metastatic settings, revealing a role for lung-resident BRM in limiting tumor spread. Ongoing single-cell transcriptomic and mechanistic studies in murine and human tumors are defining the molecular programs and effector pathways that underpin BRM-mediated tumor control. Conclusion Collectively, this work establishes tissue-resident memory B cells as an active and previously unrecognized component of anti-cancer immune surveillance for the first time, demonstrates that BRM can be intentionally programmed by local vaccination, and identifies BRM as a promising target for tissue-directed B cell—based cancer immunotherapies. Funding Source Melanoma Research Alliance, 1253470; Elsa U. Pardee Foundation; Knight Cancer Institute, OHSU Topic Categories Vaccines and Immunotherapy (VAC)