Clavijo et al. found that use of a semaphorin4D (Sema4D)-blocking antibody enhanced the antitumor efficacy of anti-CTLA-4 or anti-PD-1 checkpoint blockade and improved survival in mice bearing MOC1 or LCC tumors. Mechanistically, anti-Sema4D prevented the recruitment of Ly6Ghi MDSCs by inhibiting MAPK-dependent production of CXCL1, 2, and 5 by tumor cells. Anti-Sema4D also decreased the suppressive capacity of MDSCs by blocking Sema4D-driven arginase expression. Together these effects increased tumor infiltration and expansion of CD8+ (and to a lesser extent, CD4+) T cells, which demonstrated an enhanced response to tumor antigen.
Tumor infiltration by immunosuppressive myeloid cells, such as myeloid-derived suppressor cells (MDSCs), causes resistance to immunotherapy. Semaphorin4D, originally characterized for its axonal guidance properties, also contributes to endothelial cell migration and survival and modulates global immune cytokine profiles and myeloid cell polarization within the tumor microenvironment. Here, we show how a therapeutic murine Sema4D mAb improves responses to immune checkpoint blockade in two murine carcinoma models. Treatment of tumor-bearing mice with Sema4D mAb abrogated Ly6Ghi PMN-MDSC recruitment through reducing MAPK-dependent chemokine production by tumor cells in Murine oral cancer-1 (MOC1) tumors. PMN-MDSC suppressive capacity was reduced through inhibition of Sema4D-driven arginase expression. These changes led to enhanced tumor infiltration by CD8+ TIL and activation of tumor draining lymph node T-lymphocytes in response to tumor antigen. Sema4D mAb in combination with either CTLA-4 or PD-1 blockade enhanced rejection of tumors or tumor growth delay, resulting in prolonged survival with either treatment. This function of Sema4D mAb provides a rationale for its evaluation in combination with immune checkpoint blockade to treat tumors with immunosuppressive myeloid infiltration.
Author Info: (1) Head and Neck Surgery Branch, National Institutes of Deafness and Other Communication Disorders, National Institutes of Health. (2) HNSB, National Institute on Deafness and Oth
Author Info: (1) Head and Neck Surgery Branch, National Institutes of Deafness and Other Communication Disorders, National Institutes of Health. (2) HNSB, National Institute on Deafness and Other Communication Disorders, National Institutes of Health. (3) Head and Neck Surgery Branch, National Institutes of Deafness and Other Communication Disorders, National Institutes of Health. (4) Head and Neck Surgery Branch, National Institutes of Deafness and Other Communication Disorders, National Institutes of Health. (5) Research, Vaccinex, Inc. (6) Research, Vaccinex, Inc. (7) Research, Vaccinex Inc. (8) Department of Otolaryngology - Head and Neck Surgery, Johns Hopkins University clint.allen@nih.gov.
