Antibody Blockade of Semaphorin 4D Promotes Immune Infiltration into Tumor and Enhances Response to Other Immunomodulatory Therapies

Elizabeth E. Evans, Alan S. Jonason, Holm Bussler, Sebold Torno, Janaki Veeraraghavan, Christine Reilly, Michael A. Doherty, Jennifer Seils, Laurie A. Winter, Crystal Mallow, Renee Kirk, Alan Howell, Susan Giralico, Maria Scrivens, Katya Klimatcheva, Terrence L. Fisher, William J. Bowers, Mark Paris, Ernest S. Smith, Maurice Zauderer

Semaphorin 4D (SEMA4D, CD100) and its receptor plexin-B1 are broadly expressed in murine and human tumors, and their expression has been shown to correlate with invasive disease in several human tumors. SEMA4D normally functions to regulate the motility and differentiation of multiple cell types, including those of the immune, vascular, and nervous systems. In the setting of cancer, SEMA4D/PLXNB1 interactions have been reported to affect vascular stabilization and transactivation of ERBB2, but effects on immune cell trafficking in the tumor microenvironment have not been previously investigated. We describe a novel immunomodulatory function of SEMA4D, whereby strong expression of SEMA4D at the invasive margins of actively growing tumors influences the infiltration and distribution of leukocytes in the tumor microenvironment (TME). Antibody neutralization of SEMA4D disrupts this gradient of expression, enhances recruitment of activated monocytes and lymphocytes into the tumor, and shifts the balance of cells and cytokines toward a pro-inflammatory and anti-tumor milieu within the TME. This orchestrated change in the tumor architecture was associated with durable tumor rejection in murine Colon26 and ERBB2+ mammary carcinoma models. The immunomodulatory activity of anti-SEMA4D antibody can be enhanced by combination with other immunotherapies, including immune checkpoint inhibition and chemotherapy. Strikingly, the combination of anti-SEMA4D antibody with antibody to CTLA-4 acts synergistically to promote complete tumor rejection and survival. Inhibition of SEMA4D represents a novel mechanism and therapeutic strategy to promote functional immune infiltration into the TME and inhibit tumor progression.