PlexinB1 inactivation reprograms immune cells in the tumor microenvironment, inhibiting breast cancer growth and metastatic dissemination

Semaphorin–Plexin signaling plays a major role in the tumor microenvironment (TME). In\r\nparticular, Semaphorin 4D (SEMA4D) has been shown to promote tumor growth and metastasis;\r\nhowever, the role of its high-affinity receptor Plexin-B1 (PLXNB1), which is expressed in the\r\nTME, is poorly understood. In this study, we directly targeted PLXNB1 in the TME of triplenegative murine breast carcinoma to elucidate its relevance in cancer progression. We found that\r\nprimary tumor growth, and metastatic dissemination were strongly reduced in PLXNB1-deficient\r\nmice, which showed longer survival. PLXNB1-loss in the TME induced a switch in the polarization\r\nof tumor-associated macrophages (TAMs) towards a pro-inflammatory M1 phenotype and\r\nenhanced the infiltration of CD8+\r\nT lymphocytes both in primary tumors and in distant metastases.\r\nMoreover, PLXNB1-deficiency promoted a shift in the Th1/Th2 balance of the T-cell population\r\nand an antitumor gene signature, with the up-regulation of Icos, Perforin-1, Stat3 and Ccl5 in tumor\r\ninfiltrating lymphocytes (TILs). We thus tested the translational relevance of TME re-programming\r\ndriven by PLXNB1 inactivation for responsiveness to immunotherapy. Indeed, in the absence of\r\nPLXNB1, the efficacy of anti-PD-1 blockade was strongly enhanced, efficiently reducing tumor\r\ngrowth and distant metastasis. Consistent with this, pharmacological PLXNB1 blockade by\r\nsystemic treatment with a specific inhibitor significantly hampered breast cancer growth and\r\nenhanced the antitumor activity of the anti-PD1 treatment in a preclinical model. Altogether, these\r\ndata indicate that PLXNB1 signaling controls the antitumor immune response in the TME and\r\nhighlight this receptor as a promising immune therapeutic target for metastatic breast cancers.