Modulation of fibronectin extracellular matrix enhances anti-tumor efficacy of immune checkpoint blockade
Kabir A. Khan, Maresa Caunt Mitzner, William Cruz‐Muñoz, Grant Li, Patricia Himmels, Ping Xu, H Kuo, Rajiv Jesudason, Alvin Gogineni, Robby M. Weimer, Annabelle Chow, Robert Piskol, Iacovos P. Michael, Weilan Ye, Robert S. Kerbel
Abstract
The success of immune checkpoint inhibitors is limited by multiple factors, including poor T cell infiltration and function within tumors, partly due to a dense extracellular matrix (ECM). Here, we investigate modulating the ECM by targeting integrin α5β1, a major fibronectin-binding and organizing integrin, to improve immunotherapy outcomes. Use of a function-blocking murinized α5β1 antibody reduces fibronectin fibril formation, enhances CD8 + T cell transendothelial migration, increases vascular permeability, and decreases vessel-associated collagen. These changes culminate in improving the effectiveness of PD-L1 blockade, alone or with chemotherapy, in the E0771 breast cancer model. Clinically, high integrin alpha 5 (ITGA5) expression correlates with worse survival in patients treated with atezolizumab as monotherapy or combined with chemotherapy or anti-angiogenic therapies in numerous clinical trials. Overall, our studies suggest that ECM-modulating approaches could be used as a future strategy to increase the proportion of patients who respond to immune checkpoint inhibition and other immunotherapies.