Abstract LB-180: Targeting galectin-1 in combination with radiation and immune checkpoint therapy in head and neck cancers

Head and neck cancers (HNC) development shows significant changes in the immune profile, with lower systemic lymphocyte counts and reduced tumor-infiltrating lymphocytes, which inversely correlate with survival. Galectin-1 (Gal-1) is secreted at high level by cancer cells, including HNC, and contributes to tumor-immune escape and disease progression. Previously, we have shown that both hypoxia and radiotherapy (RT) can stimulate Gal-1 secretion. Immune checkpoint therapies, specifically targeting the PD1 pathway, allows T cells to be effective in shrinking tumors and lengthen survival in patients with metastatic HNC. However, these therapies work only in a small number of patients with tumors showing significant T cell infiltration. Targeting Gal-1 in HNC therefore, could be a useful therapeutic approach, as it may synergize with radiation and immunotherapy. Using the CRISPR/Cas9 deletion approach, we developed an orthotopic model of HNC with/without Gal-1 expression. We found that in both subcutaneous and orthotopic model of oral cancer, Gal-1 KO (knock-out) tumors showed marked decrease in tumor growth and nodal metastases. These differences were attributed to enhanced infiltration of CD4+ and CD8+ T cells, in the absence of Gal-1. Using a series of transendothelial migration assays in vitro and tracking adoptively transferred T cells in vivo, we show that presence of Gal-1 in the tumor microenvironment strongly suppresses T cell infiltration into tumors. We found that Gal-1 secretion led to a systemic immune suppressive response not just intra-tumorally but also in the circulating blood compartment, resulting in reduction of both CD4+ and CD8+ T cells. Concurrently, we detected higher levels of IFN-γ secretion in mice with Gal-1 KO tumors. We also observed a higher expression of PD-L1 and Gal-9 on the endothelium of WT-Gal1 compared to Gal-1 KO tumors, leading to T cell exhaustion and ineffective systemic immune response. In addition, there was noteworthy increase in the PD1+ and Tim3+ T cells in Gal-1 WT tumors compared to Gal-1 KO tumors, suggesting a role of Gal-1 in T cell anergy. Finally, we show that knocking out Gal-1 either genetically or by a blocking antibody, we could convert an anti-PD1 Ab non-responsive tumor into a responsive tumor with a significant decrease in tumor burden. In summary, our study shows Gal-1 in the tumor microenvironment could hamper immune response by impeding transendothelial T cell migration into the tumor, blocking pro-inflammatory cytokine secretions and up-regulating inhibitory immune checkpoints ligands in both tumor endothelial and T cells. Our data suggests that Gal-1 may mediate poor-response or resistance to anti-PD1 therapy and combinatorial approaches of galectin-1 inhibition with PD-1 checkpoint inhibitors may enhance therapeutic efficacy in HNC. (Acknowledgements: BMS for Anti-PD1 and Anti-Gal1 Abs. Dr R. Uppaluri, for MOC-2 oral cancer cells). Citation Format: Dhanya K. Nambiar, Todd Aguilera, Joshua Daniel Bloomstein, Hongbin Cao, Albert Koong, Quynh Thu Le. Targeting galectin-1 in combination with radiation and immune checkpoint therapy in head and neck cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-180. doi:10.1158/1538-7445.AM2017-LB-180