Neutrophil Antigen Presentation Reprograms the Tumor Microenvironment and Elicits Durable and Broad Antitumor Immunity.

[UNLABELLED] Immunotherapy often fails in solid tumors due to an immunosuppressive tumor microenvironment, driven in part by dysfunctional dendritic cells (DC) impairing antigen presentation and suppressive neutrophils. Recent studies revealed a noncanonical role for neutrophils in antigen presentation (nAPC), whose frequency in tumors correlates with improved prognosis in several human cancers. Here, we show that an intravenously delivered antibody-antigen-conjugate (AAC) targeting neutrophil FcγRIIIB reprograms neutrophils into nAPCs that drive robust CD8+ T-cell activation. This response requires neutrophils and their expression of major histocompatibility complex class I and occurs independently of conventional type 1 DCs (cDC1), demonstrating that nAPCs can compensate for cDC1 deficiencies. In a mouse melanoma model, AAC therapy promotes durable immunity, limiting metastases of Ova-negative tumors in the lung and contralateral skin, with tumor burden inversely correlating with intratumoral nAPC frequency. AAC treatment efficacy is attributed to tumor infiltration by antigen-specific CD8+ T cells, NK cells, and stem cell-like and tissue-resident memory T cells recognizing both the target antigen and melanocyte-lineage antigens, consistent with effective epitope spreading, which could overcome tumor heterogeneity and antigen loss. Mechanistically, the spleen is required for T-cell priming and tumor infiltration, suggesting AAC engages a cancer-spleen axis that bypasses dysfunctional tumor-draining lymph nodes. Both CD8+ T cells and NK cells are essential for tumor control. Anti-PD-1 co-treatment enhances tumor regression and metastasis control, while anti-PD-1 monotherapy is ineffective. In summary, AAC therapy reprograms neutrophils to initiate potent T-cell immunity, offering a novel strategy to break immune exclusion in solid tumors.

[SIGNIFICANCE] A novel mechanism of neutrophil reprogramming, utilizing an AAC that initiates antigen presentation in the absence of conventional cDCs, offers a translational strategy to overcome immune exclusion in solid tumors.