Antitumor Activity of a Novel LAIR1 Antagonist in Combination with Anti-PD1 to Treat Collagen-Rich Solid Tumors
B. Leticia Rodriguez, Jiawei Huang, Laura Gibson, Jared J. Fradette, Hung-I Harry Chen, Kikuye Koyano, Czrina Cortez, Betty Li, Carmence Ho, Amir M. Ashique, Vicky Y. Lin, Suzanne Crawley, Julie M. Roda, Peirong Chen, Bin Fan, Jeong Kim, James Sissons, Jonathan Sitrin, Daniel D. Kaplan, Don L. Gibbons, Lee B. Rivera
Abstract
We recently reported that resistance to PD-1 blockade in a refractory lung cancer-derived model involved increased collagen deposition and the collagen-binding inhibitory receptor leukocyte-associated immunoglobulin-like receptor 1 (LAIR1). Thus, we hypothesized that LAIR1 and collagen cooperated to suppress therapeutic response. In this study, we report that LAIR1 is associated with tumor stroma and is highly expressed by intratumoral myeloid cells in both human tumors and mouse models of cancer. Stroma-associated myeloid cells exhibit a suppressive phenotype and correlate with LAIR1 expression in human cancer. NGM438, a novel humanized LAIR1 antagonist mAb, elicits myeloid inflammation and allogeneic T-cell responses by binding to LAIR1 and blocking collagen engagement. Furthermore, a mouse-reactive NGM438 surrogate antibody sensitized refractory KP mouse lung tumors to anti-PD-1 therapy and resulted in increased intratumoral CD8+ T-cell content and inflammatory gene expression. These data place LAIR1 at the intersection of stroma and suppressive myeloid cells and support the notion that blockade of the LAIR1/collagen axis can potentially address resistance to checkpoint inhibitor therapy in the clinic.