Description

Squamous Cell Carcinomas Escape Immune Surveillance via Inducing Chronic Activation and Exhaustion of CD8⁺ T Cells co-expressing PD-1 and LAG-3 Inhibitory Receptors

Ameet K. Mishra¹, Tanya Kadoishi¹, Xiaoguang Wang¹, Emily Driver², Zhangguo Chen¹, Xiao-Jing Wang², Jing H. Wang^1,*

¹Department of Immunology and Microbiology, ²Department of Pathology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045

*Corresponding author

Squamous cell carcinoma (SCC) is the second commonest type of skin cancer. Moreover, about 90% of head and neck cancers are SCCs. It remains largely unknown how SCCs evade immune recognition. Here, we established a mouse model by injecting tumor cells derived from primary SCCs harboring Kras^G12D mutation and Smad4 deletion into wild-type (wt) or CD8^-/- recipients. We found comparable tumor growth between wt and CD8^-/- recipients, indicating a complete escape of CD8⁺ T cell-mediated anti-tumor responses by these SCCs. Mechanistically, CD8⁺ T cells were not defective in infiltrating tumors given their relatively increased percentage among tumor infiltrating lymphocytes (TILs). CD8⁺ TILs exhibited phenotypes of chronic activation and exhaustion, including overexpression of activation markers, co-expression of programmed death 1 (PD-1) and lymphocyte activation gene-3 (LAG-3), as well as TCRb downregulation. Among CD4⁺ TILs, T regulatory cells (Tregs) were preferentially expanded. Contradictory to prior findings in melanoma, Treg expansion was independent of CD8⁺ T cells in our SCC model. Unexpectedly, CD8⁺ T cells were required for promoting NK cell infiltration within SCCs. Furthermore, we uncovered AKT-dependent lymphocyte-induced PD-L1 upregulation on SCCs, which was contributed greatly by combinatorial effects of CD8⁺ T and NK cells. Lastly, dual blockade of PD-1 and LAG-3 inhibited the tumor growth of SCCs. Thus, our findings identify novel immune evasion mechanisms of SCCs and suggest that immunosuppressive mechanisms operate in a cancer-type specific and context-dependent manner.