Abstract B03: Integrin agonists reduce infiltration of tumor-associated macrophages to promote T-cell mediated anti-tumor immunity

Tumors associated macrophages (TAMs) mediate neovascularization and promote tumor growth. Integrin CD11b/CD18 is highly expressed on cells of myeloid and granulocytic lineage and mediates their adhesion, migration and tissue recruitment functions. CD11b+ TAMs are present at high numbers in several types of human cancers, including breast and non-small cell lung cancer, and are associated with reduced T-cell mediated anti-tumor immunity. This suggests that reducing infiltration of CD11b+ TAMs could have a therapeutic benefit. Recently, we have developed a novel small molecule CD11b agonist termed leukadherin-1 (LA1) that binds to and allosterically activates integrin CD11b on leukocytes. We also reported that CD11b activation is a more effective strategy for reducing CD11b+ cell tissue infiltration, as compared to integrin antagonists. LA1 binding transiently increases leukocyte adhesion to the vascular endothelium and reduces their transmigration in vivo. Here, we show that LA1 mediated CD11b activation reduced the number of CD11b+ TAMs in two different murine tumor models that was accompanied with diminished primary tumor growth. LA1 treated animals also had significantly reduced tumor angiogenesis and prolonged survival. These improved aspects were accompanied with reduction in vessel density as indicated by reduced intratumoral expression levels of CD31 and αSMA and increased numbers of CD8+ T cells indicating an anti-tumor immune profile response fostering tumor suppression. Our data provide a rationale for using allosteric CD11b agonists to target TAMs as a novel therapeutic approach for treating cancer. Citation Format: Samia Q. Khan, Mohd. H. Faridi, Shehryar J. Khaliqdina, Antonio J. Barbosa, Judith A. Varner, Vineet Gupta. Integrin agonists reduce infiltration of tumor-associated macrophages to promote T-cell mediated anti-tumor immunity. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr B03.