Roles of programmed death ligand-1 (pdl-1) and antigen-presenting natural killer (ap-nk) cells in promoting immunosuppressive tumor microenvironment (tme) in oral cancer (oc)

Background Response rate for immune checkpoint blockade (ICB) targeting PD-1/PDL-1 in OC is only 15% to 20%. AP-NK cells coexpressing CD8αα and HLA-DR may contribute to immunosuppression by selectively killing effector T cells. Objective To analyze the PDL-1 expression, tumor-infiltrating lymphocytes (TILs), and AP-NK cell densities within the TME of OC and its precursors. Immunohistochemical stains for PD-L1 (clone 22C3) and CD3 and CD8/HLA-DR double staining for AP-NK cells were performed on tissue microarrays of OC (n = 64) and tissue sections of oral epithelial dysplasias (OEDs; n = 14), proliferative verrucous leukoplakia (PVL; n = 6) that subsequently progressed to OC, and oral lichen planus (OLP; n = 5). Results PDL-1 on TILs showed significant correlation with tumor site, nodal status, and survival. The TME of OC showed 39% were TIL−/PDL-1−, 34% were TIL+/PDL-1−, 14% were TIL+/PDL-1+ (ICB responders), and 13% were TIL−/PDL-1+. CD3+ T cells were significantly lower (P = .0075) in OED and PVL that subsequently progressed to OC compared with conventional OLP. There was a trend for a higher number of AP-NK cells and percentage of AP-NK/CD3 cells in OED (56.7 ± 10.1; 2%) and PVL (64.5 ± 24.2; 7%) than in OLP (30.5 ± 7.4; 0.7%). There was no statistically significant correlation between tumor cell PDL-1 expression and age, gender, smoking status, tumor site, histologic grade, tumor stage, nodal status, survival, and TIL density. Conclusions The PD1/PDL-1 pathway is not an exclusive mediator of immunosuppressive TME in OC. AP-NK cells offer an alternative mechanism for the failure of antitumor immune response in OC.