Beyond PD-L1—Identification of Further Potential Therapeutic Targets in Oral Cancer

Abstract

Background: The involvement of immune cell infiltration and immune regulation in the progression of oral squamous cell carcinoma (OSCC) is shown. Anti-PD-1 therapy is approved for the treatment of advanced OSCC cases, but not all patients respond to immune checkpoint inhibitors. Hence, further targets for therapeutic approaches are needed. The number of identified cellular receptors with immune checkpoint function is constantly increasing. This study aimed to perform a comparative analysis of a large number of immune checkpoints in OSCC in order to identify possible targets for therapeutic application. Materials and Methods: A NanoString mRNA analysis was performed to assess the expression levels of 21 immune regulatory checkpoint molecules in OSCC tissue (n = 98) and healthy oral mucosa (NOM; n = 41). The expression rates were compared between the two groups, and their association with prognostic parameters was determined. Additionally, relevant correlations between the expression levels of different checkpoints were examined. Results: In OSCC tissue, significantly increased expression of CD115, CD163, CD68, CD86, CD96, GITRL, CD28 and PD-L1 was detected. Additionally, a marginally significant increase in CD8 expression was observed. BTLA and PD-1 levels were substantially increased, but the differential expression was not statistically significant. The expression of CD137L was significantly downregulated in OSCC compared to NOM. Correlations between immune checkpoint expression levels were demonstrated, and some occurred specifically in OSCC tissue. Conclusions: The upregulation of inhibitory receptors and ligands and the downregulation of activators could contribute to reduced effector T-cell function and could induce local immunosuppression in OSCC. Increased expression of activating actors of the immune system could be explained by the increased infiltration of myeloid cells and T-cells in OSCC tissue. The analysis contributes to the understanding of immune escape in OSCC and reveals potential targets for oral cancer immunotherapy.

The Concordant Disruption of B7/CD28 Immune Regulators Predicts the Prognosis of Oral Carcinomas

“…This study also identified, for the first time, that the expression of B7/CD28 family members is correlated, except for CD276 and VTCN1. Correlations between the upregulation of CD80, CD86, and CD28 have been found in OSCC [ 3 ], and the lack of change in CD28 and PD-1 transcripts in our tumor samples, which might have been associated with the complexity in CTLA4 abundancy [ 9 , 10 ], requires further stratification. Since a correlation in the expression of multiple immune regulators has also been found in OSCC, targeting only one molecule may have limited therapeutic efficacy [ 24 ].…”

“…Although we found that PD-L1 and PD-L2 cannot be used for prognostic prediction for HNSCC or OSCC, the findings were similar to other studies [ 2 ]. Anti-PD-L1 therapy has been approved for neoadjuvant therapy of HNSCC and can improve the treatment outcomes, albeit with limited effects [ 3 ]. PD-L2 seems to be superior to PD-L1 in PD-1 binding [ 12 ], and it has been shown to be a prognostic factor of HNSCC in studies [ 26 , 27 ].…”

“…The B7 immune checkpoint superfamily includes B7-1 (CD80), B7-2 (CD86), B7-H1 (PD-L1, CD274), PD-L2 (PDCD1LG2), B7-H3 (CD276), B7-H4 (B7-x, VTCN1), and the inducible costimulator ligand (L-ICOS, CD275), which act as ligands on the surface of tumor cells or antigen-presenting cells [ 3 , 4 ]. They couple with CD28 family members, including CD28, CTLA4, PD-1 (PDCD1), and ICOS (inducible costimulator CD278), or other receptors, to drive immune inhibition or stimulation [ 5 , 6 ].…”

“…They couple with CD28 family members, including CD28, CTLA4, PD-1 (PDCD1), and ICOS (inducible costimulator CD278), or other receptors, to drive immune inhibition or stimulation [ 5 , 6 ]. CD28 and CTLA4 expressed on T lymphocytes share identical ligands, CD80 and CD86, on tumor cells or antigen-presenting cells [ 3 , 7 ]. CTLA4 upregulation is an important immunoinhibitory mechanism in HNSCC [ 8 ].…”

“…Antitumor immune responses are an emerging strategy in HNSCC therapy [ 2 ]. Reports have shown that approximately 15% of patients with metastatic HNSCC exhibit responses to anti-PD-1 therapy [ 3 , 24 ]. Moreover, neoadjuvant anti-PD-1/PD-L1 immunotherapy may have advantages in operable HNSCC according to histopathological evaluation [ 25 ].…”