The Tumor Microenvironment and Immunotherapy of Oropharyngeal Squamous Cell Carcinoma

Abstract

Oropharyngeal squamous cell carcinoma (OPSCC) develops as a consequence of several mutations in the tumor suppressor pathways or after a progressive infection with high risk human papillomavirus (HPV). The dismal side effects of the current standard of care and the clear involvement of the immune system has led to a surge in clinical trials that aim to reinforce the tumor-specific immune response as a new treatment option. In this review, we have focused on the most recent literature to discuss the new findings and insights on the role of different immune cells in the context of OPSCC and its etiology. We then applied this knowledge to describe potential biomarkers and analyzed the rationale and outcomes of earlier and ongoing immunotherapy trials. Finally, we describe new developments that are still at the preclinical phase and provide an outlook on what the near future may bring, now that several new and exciting techniques to study the immune system at the single cell level are being exploited.

Prognostic Markers and Driver Genes and Options for Targeted Therapy in Human-Papillomavirus-Positive Tonsillar and Base-of-Tongue Squamous Cell Carcinoma

“…Immunological and stem cell markers have been examined extensively, and are still being examined, by IHC and by other means in HPV + and HPV − OPSCC, TSCC, and BOTSCC [ 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 45 , 46 , 48 , 50 ]. Moreover, recently, an extensive review on the OPSCC tumor microenvironment with regard to options for immunotherapy presented a detailed overview of immune cells present in the microenvironment and their potential role in the promotion of active or suppressive immune responses in OPSCC [ 90 ]. Most reports agree that the numbers of CD8 + lymphocytes infiltrating or surrounding the tumor are generally higher in HPV + TSCC, BOTSCC, and OPSCC than in respective HPV − tumors and that having high numbers of CD8 + cells is correlated with a better outcome irrespective of the HPV status [ 23 , 38 , 39 , 40 , 41 , 47 , 90 ].…”

“…Moreover, recently, an extensive review on the OPSCC tumor microenvironment with regard to options for immunotherapy presented a detailed overview of immune cells present in the microenvironment and their potential role in the promotion of active or suppressive immune responses in OPSCC [ 90 ]. Most reports agree that the numbers of CD8 + lymphocytes infiltrating or surrounding the tumor are generally higher in HPV + TSCC, BOTSCC, and OPSCC than in respective HPV − tumors and that having high numbers of CD8 + cells is correlated with a better outcome irrespective of the HPV status [ 23 , 38 , 39 , 40 , 41 , 47 , 90 ]. The prognostic value of CD4 + and FoxP3 + lymphocytes has also been examined, but in two studies, neither correlated alone with the outcome.…”

“…However, independent of the HPV status, having a low CD4 + /CD8 + ratio or a high CD8 + /FoxP3 + ratio is associated with improved survival [ 38 , 39 ]. In another study, however, it was shown that a high frequency of Tbet+ Tregs is associated with prolonged disease-specific survival and this was most likely because their presence showed a high numbers of effector T-cells [ 90 , 91 ]. The role of macrophages was also discussed extensively in the same review [ 90 ].…”

“…In another study, however, it was shown that a high frequency of Tbet+ Tregs is associated with prolonged disease-specific survival and this was most likely because their presence showed a high numbers of effector T-cells [ 90 , 91 ]. The role of macrophages was also discussed extensively in the same review [ 90 ]. CD68 + CD163 + M2 macrophages were often observed in OPSCC, and a high infiltration of these macrophages was correlated with poor prognosis in two studies on HNSCC, with most or all cases being OPSCC [ 92 , 93 , 94 ].…”

Oropharyngeal Squamous Cell Carcinoma Treatment in the Era of Immune Checkpoint Inhibitors

“…It is sobering to consider that a fundamental re-evaluation of the influence of radiation and chemical treatment protocols on both local and systemic functional immunity should really be reconsidered in the context of the deployment of immunotherapies aimed at either recovery of an existing immune response or the induction of novel anti-tumour activity [121][122][123]. The ongoing clinical studies of checkpoint inhibitors in HNSCC have recently been reviewed by the van der Burg group [46] and can be comprehensively accessed at Clinicaltrials.gov [124]. The extent and diversity of approaches reveals a somewhat scatter-gun approach which may luck out but could also just consume resources for a minimal gain.…”