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

Abstract

Semaphorin 4D (SEMA4D, CD100) and its receptor plexin-B1 (PLXNB1) 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 (TME) have not been 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 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 proinflammatory and antitumor milieu within the TME. This orchestrated change in the tumor architecture was associated with durable tumor rejection in murine Colon26 and ERBB2 þ 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. Cancer Immunol Res; 3(6); 689-701. Ó2015 AACR.

Human Head and Neck Squamous Cell Carcinoma–Associated Semaphorin 4D Induces Expansion of Myeloid-Derived Suppressor Cells

“…They are also in good agreement with a recent report showing that Sema4D modulates the inflammatory cytokine milieu in a murine colon and mammary carcinoma model (48). Several clinical trials showed that advanced cancers can be controlled by immunotherapy.…”

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“…220 In a slightly different approach, Evans et al (from Vaccinex, Inc., Rochester, NY, USA) reported that semaphorin 4D (SEMA4D) expression at the tumor invasive margin facilitates pro-tumorigenic inflammation, and that combining anti-SEMA4D monoclonal antibodies (mAbs) with ICBs or cyclophosphamide promotes immunological rejection in murine colorectal carcinoma models. 221 Finally, Blake et al…”

Osteosarcomagenesis: Biology, Development, Metastasis, and Mechanisms of Pain

“…VX15/2503 (Vaccinex, Inc.) is a highly novel, immunomodulatory monoclonal antibody that speciically targets SEMA4D (CD100), a receptor and soluble protein from the semaphorin family known to be involved in immune modulation [67] and regulation of normal bone formation [68]. Initial interest in this monoclonal antibody was rooted in results indicating that immune cell-dependent interactions were in fact responsible for its antitumor activity [67].…”

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