Immunotherapy in Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma: biological landscape and prognostic biomarkers to improve patients' stratification

Serafini, Mara Serena (2023). Immunotherapy in Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma: biological landscape and prognostic biomarkers to improve patients' stratification. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.000155e5

Abstract

Head and neck squamous cell carcinoma (HNSCC) is the eight most frequent cancer in the world, and approximately 2/3 of the patients are diagnosed at locally advanced stages (stage III or IV). Despite improvements in HNSCC management and the aggressiveness of first-line curative treatment, 65% of treated patients experience local recurrence or distant metastasis. Moreover, patients diagnosed with recurrence or distant metastasis have a poor prognosis (from 6 to 12 months) and 5-years survival less than 50%. From 2016 the clinical practice was revolutionized by the introduction of immuno-checkpoint inhibitors, approved for the treatment of recurrent/metastatic HNSCC patients. Nevertheless, only a small subset of patients respond to this therapy and currently predictive biomarkers are still under investigation. Herein, we investigated the tumor biology of R/M HNSCC patients, platinum-refractory, enrolled in the phase IIIb clinical trial Nivactor (EudraCT Number: 2017-000562-30), in which patients were treated with nivolumab. Across the study of single biomarkers and the extensive profiling through genomic and transcriptomic analyses, we aimed to characterize the tumor molecular peculiarity of patients that experienced response or those with the longer survival. While the prognostic/predictive role of Programmed Cell Death Ligand-1 (PD-L1; studied by IHC), Tumor mutational burden (TMB) and microsatellite instability (MSI) appeared to be relatively limited for R/M HNSCC patients, 8 expression signatures (retrieved from literature) showed up significant association with survival and contributed to highlight and extricate the extreme complexity of the tumor microenvironment of HNSCC, which appeared to be strongly immunosuppressive (suggesting and corroborating the activation of several mechanisms of immune evasion). Nevertheless, the testing of previously identified six HNSCC subtypes (De Cecco et al.) with specific biological and prognostic characteristics, indicated for two of them a strong prognostic role and a significant correlation with response. In conclusion, the current study demonstrated the strong relevance of gene expression signatures in HNSCC context (over the mere study of somatic mutations) to identify the biological features associated with benefits from immunotherapy. However, additional analyses for the validation of their significance are required.

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