PD-1 Expression in Head and Neck Squamous Cell Carcinomas Derives Primarily from Functionally Anergic CD4+ TILs in the Presence of PD-L1+ TAMs

Abstract

Oral tongue squamous cell carcinoma (OTSCC) is the most common oral cavity tumor. In this study, we examined the basis for the activity of PD-1-based immune checkpoint therapy that is being explored widely in head and neck cancers. Using multispectral imaging, we systematically investigated the OTSCC tumor microenvironment (TME) by evaluating the frequency of PD-1 expression in CD8+, CD4+ and FoxP3+ tumor-infiltrating lymphocytes (TIL). We also defined the cellular sources of PD-L1 to evaluate the utility of PD-1:PD-L1 blocking antibody therapy in this patient population. PD-L1 was expressed in 79% of the OTSCC specimens examined within the TME. Expression of PD-L1 was associated with moderate to high levels of CD4+ and CD8+ TIL. We found that CD4+ TIL were present in equal or greater frequencies than CD8+ TIL in 94% of OTSCC, and that CD4+ FOXP3neg TIL were co-localized with PD-1/PD-L1/CD68 more frequently than CD8+ TIL. However, both CD4+PD1+ and CD8+PD1+ TIL were anergic in the setting of PD-L1 expression. Overall, our results highlight the importance of CD4+ TIL as pivotal regulators of PD-L1 levels and in determining the responsiveness of OTSCC to PD1-based immune checkpoint therapy.

Immune checkpoints indoleamine 2,3‐dioxygenase 1 and programmed death‐ligand 1 in oral mucosal dysplasia

“…In contrast to the expression of PD‐L1 in cancer cells of oral squamous cell carcinoma, in our study, PD‐L1 was negative in the oral epithelium of both healthy control and dysplasia samples. In the lamina propria, PD‐L1 was expressed mainly in dysplastic samples and only rarely in controls.…”

“…On the other hand, IDO1 expression in the lamina propria was enhanced with increase in dysplasia grade, which may be caused by associated inflammation and the production of pro-inflammatory cytokines. 24 In contrast to the expression of PD-L1 in cancer cells of oral squamous cell carcinoma, [25][26][27] in our study, PD-L1 was negative in the oral epithelium of both healthy control and dysplasia samples. In the lamina propria, PD-L1 was expressed mainly in dysplastic samples and only rarely in controls.…”

Tissue-infiltrating immune cells as prognostic markers in oral squamous cell carcinoma: a systematic review and meta-analysis

“…Thirteen different studies assessed various subsets of T cells 23,28,29,34,40,[44][45][46][47][48][49][50][51] (Table 3). High numbers of tumourinfiltrating CD3+ T cells (pan T cell marker), CD4+ T cells (T helper (Th) cell marker) or CD8+ T cells (T cytotoxic (Tcyt) marker) were usually associated with somewhat longer survival, whereas high numbers of forkhead box P3 (FOXP3)+ T-regulatory cells showed significant association with decreased survival in two of the five studies addressing this cell type.…”

An update of knowledge on PD‐L1 in head and neck cancers: Physiologic, prognostic and therapeutic perspectives

“…Similarly, Chen et al found that patients with both tumour necrosis and PD‐L1 overexpression had a worse OS (Chen, Wu, et al, ). However, six studies failed to find a relationship between OS or tumour‐associated death and PD‐L1 positivity (Cho et al, ; Kouketsu et al, ; Lin et al, ; Mattox et al, ; Satgunaseelan et al, ; Troeltzsch et al, ). Furthermore, Ahn et al found a better prognosis in OSCC with both PD‐L1 overexpression and high miR‐197 levels (Ahn et al, ).…”