Head and Neck Cancer Immunotherapy beyond the Checkpoint Blockade.

The success of immune checkpoint receptor blockade has brought exciting promises for the treatment of head and neck squamous cell carcinoma (HNSCC). While patients who respond to checkpoint inhibitors tend to develop a durable response, <15% of patients with HNSCC respond to immune checkpoint inhibitors, underscoring the critical need to alleviate cancer resistance to immunotherapy. Major advances have been made to elucidate the intrinsic and adaptive resistance mechanisms to immunotherapy. Central genomic events in HNSCC have been found to possess previously unknown roles in suppressing immune sensing. Such inhibitory function affects both the innate and adaptive arms of tumor-specific immunity. While checkpoint blockade effectively reinvigorates adaptive T-cell responses, additional targeting of the oncogenic inhibitors of innate immune sensing likely informs a novel and potent strategy for immune priming. This review discusses the recent advances on the identification of key HNSCC oncogenes that impair antitumor immunity and emerging immune-priming approaches that sensitize poorly immunogenic HNSCCs to checkpoint blockade. These approaches include but are not limited to cancer vaccine systems utilizing novel type I interferon agonists as immune adjuvants, radiation, DNA damage-inducing agents, and metabolic reprogramming. The goal of these multipronged approaches is to expand tumor-specific effector T-cells, break checkpoint receptor-mediated tolerance, and metabolically support sustained T-cell activation. The translation of therapeutics that reverses oncogenic inhibition of immune sensing requires thorough characterization of the HNSCC regulators of innate immune sensors, development of additional immunocompetent HNSCC mouse models, as well as engineering of more robust immune adjuvant delivery systems. Built on the success of checkpoint blockade, validation of novel immune-priming approaches holds key promises to expand the pool of responders to immunotherapy.

Ret Signaling Is Required for Tooth Pulp Innervation during Organogenesis.

During organogenesis, the timing and patterning of dental pulp innervation require both chemoattractive and chemorepellent cues for precise spatiotemporal regulation. Our understanding of the signaling mechanisms that regulate tooth innervation during development, as well as the basic biology of these sensory neurons, remains rudimentary. In this study, we analyzed the expression and function of glial cell line-derived neurotrophic factor (GDNF) and its receptor tyrosine kinase, Ret, in the regulation of innervation of the mouse tooth pulp by dental pulpal afferent (DPA) neurons of the trigeminal ganglion (TG). Using reporter mouse models, we demonstrate that Ret is highly expressed by a subpopulation of DPA neurons projecting to the tooth pulp at both postnatal day 7 (P7) and in the adult. In the adult tooth, GDNF is highly expressed by many cell types throughout the dental pulp. Using a ubiquitous tamoxifen (TMX)-inducible Cre ( UBC-Cre/ERT2) line crossed to Ret conditional knockout mice ( Retfx/fx), Ret was deleted immediately prior to tooth innervation, and the neural projections into P7 molars were analyzed. TMX treatment was efficient in ablating >95% of Ret protein. We observed that UBC-Cre/ERT2; Retfx/fx mice had a significant reduction in the total number of neurites present within the pulp at P7, with a significant accumulation of aberrant fibers in the dental follicle and periodontium. In agreement with these findings, inhibition of Ret signaling through in vivo administration of a highly specific pharmacologic inhibitor (1NM-PP1) of Ret also caused a substantial reduction in pulpal innervation. Taken together, these findings indicate that Ret signaling regulates the timing and patterning of tooth innervation by dental primary afferent neurons of the TG during organogenesis and provide a rationale to explore whether alterations in the GDNF-Ret pathway contribute to pathophysiological conditions in the adult dentition.

Histologic pattern of invasion and epithelial-mesenchymal phenotype predict prognosis in squamous carcinoma of the head and neck.

INTRODUCTION: Disruption of E-cadherin function and increased expression of vimentin and the transcriptional oncogene, SOX2, are thought to characterize epithelial to mesenchymal transition (EMT) in HNSCC that contributes to invasive and metastatic behavior. To determine if such changes relate to prognosis or host immune response, expression of these markers and correlations with clinical characteristics, histologic worst pattern of invasion (WPOI) and tumor infiltrating lymphocytes (TIL) and survival were assessed. METHODS: Immunohistologic expression of markers was determined in tissue microarrays from 274 previously untreated HNSCC patients. Expression was correlated with levels of TILs in microcores and WPOI in biopsy specimens. Correlations were assessed by Kruskal-Wallis testing and Spearman correlation coefficients where appropriate. Overall and relapse-free survival were analyzed with Cox proportional hazards models. Median follow up was 60.0 months. RESULTS: Loss of E-cadherin expression was significantly associated with low or absent SOX2 expression (R = 0.433, p < 0.0001). SOX2 expression and low grade WPOI were significantly associated with favorable overall (OS) and relapse free (RFS) survival in multivariable analysis. E-cadherin expression did not correlate with TILs, however WPOI score correlated indirectly with CD4, CD8, and FoxP3 levels. When grouped by primary treatment, lower grades (1, 2) of WPOI predicted improved RFS and OS in patients treated with primary surgery but not for patients treated with chemoradiation. CONCLUSION: The findings suggest that SOX2 expression and WPOI are significant prognostic factors and that WPOI correlates with decreased T cell infiltration. The combination of markers and TILs might be useful in selecting patients for primary surgery.