Cell reports · 2026
Potentiating dendritic cell immunotherapy by interrupting the Semaphorin 4D-induced immune-suppressive barrier.
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Garg Saurabh K, Snyder Colin, Ramamoorthi Ganesan, Kodumudi Krithika N, Evans Elizabeth E, Lok Vincent, Bussler Holm, Nguyen Jonathan V, Yao Jiqiang, Basu Amrita, Gautam Namrata, Vazquez Martinez Julio A, Chang Darwin C, Aldrich Amy L, Wiener Doris, Rodriguez Paulo C, Zauderer Maurice, Koski Gary K, Czerniecki Brian J
Аннотация
Immune suppression within the tumor microenvironment (TME) remains a significant barrier to effective cancer immunotherapy, including dendritic cell (DC)-based approaches. We address this by targeting Semaphorin 4D (SEMA4D), a pro-tumorigenic mediator expressed by leading-edge tumor cells and host immune cells, particularly in HER2-positive (HER2pos) breast cancer (BC). Antibody blockade of SEMA4D enhances the efficacy of adoptively transferred tumor-specific conventional type 1 DCs (cDC1s) across multiple HER2pos BC models. Tumor-cell-specific ablation of SEMA4D activity amplifies cDC1-driven anti-tumor immunity, highlighting its role in immune evasion. SEMA4D blockade synergizes with cDC1s to increase CD4+ Th1 and other effector cell infiltration into the TME, along with reciprocal elimination of myeloid-derived suppressor cells, fostering robust systemic immune responses that eradicated both local and distant tumors. Given its favorable safety profile, this strategy represents a promising immunotherapy for malignancies, including HER2pos BC that express high levels of SEMA4D in both tumor and stromal compartments.