Anti-tumor activity of a novelLAIR1antagonist in combination with anti-PD-1to treat collagen-rich solid tumors (mouse)

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), and thus we hypothesized that LAIR1 and collagen cooperated to suppress therapeutic response. Here, we report 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 monoclonal antibody, elicits myeloid inflammation and allogeneic T cell responses by binding to LAIR1 and blocking collagen engagement. Further, 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. Overall design: The murine lung cancer cell line 344SQ was derived from K-rasLA1/+p53R172H?g/+ mice. 6-8 week old 129/Sv mice were obtained from Charles River Laboratories. For studying the tumor growth in syngeneic immunocompetent models, 344SQ cells (1x106) were implanted subcutaneously into the right flank of male and female mice. When tumors reached an average size of 50-100 mm3 anti-LAIR was dosed 10 mg/kg I.P. twice per week and/or anti-PD-1 (Bioxcell) was dosed 8 mg/kg once per week. Tumor growth was measured with digital calipers once a week, and tumor sizes were calculated using the formula: ½(length × width × width) at indicated time points. At end points, mice were sacrificed to examine the tumor weight and metastatic lung nodules. GEMM (KrasLSL-G12D/p53fl/fl) were generated as previously described (47,49). Mice were infected at 3-4 months of age with 2.5x107 titer pfu adenovirus-cre by intratracheal intubation. Treatment with antibodies were performed at 2 months post-infections when tumors were visualized by micro-CT imaging. All mice were immunocompetent and assessed for health daily by the department of veterinary medicine and surgery at The University of Texas MD Anderson Cancer Center. All animal procedures were reviewed and approved by The University of Texas MD Anderson Cancer Center Animal Care and Use Committee.