Multimodal genomic markers predict immunotherapy response in the head and neck squamous cell carcinoma

Abstract

Immune checkpoint blockade (ICB) therapy has had a major impact on the clinical management of head and neck squamous cell carcinoma (HNSCC). However, clinical responses to ICB are observed in only a fraction of patients. In the present paper, we used multimodal approaches to a) evaluate the utility of existing ICB biomarkers including tumor mutation burden (TMB), microsatellite instability (MSI), and a T-cell specific signature in predicting therapy response in HNSCC using TCGA cohort, and; b) identify a novel molecular signature to predict ICB therapy response using an ICB clinical trial of HNSCC. Our results confirm previous reports showing TMB efficacy as a biomarker and its outcome can be influenced by age, tumor sub-site, and smoking status; and that High-TMB and high-MSI tumors are associated with T-cell signature, and better survival probability in the HNSCC. We go on to demonstrate that High-TMB and high-MSI utilizes cell-cycle/cell proliferation processes for their molecular functionality; and identify a novel Cell Proliferation ICB-therapy Predicting (CPIP) signature capable of predicting ICB therapy response in HNSCC, retrospectively, where traditional biomarkers of ICB response were insufficient. In summary, the present study defines strategies and novel signatures that can be appropriately used for patient selection for ICB therapy that can improve the clinical outcomes of HNSCC patients.

Relationship between Tumor Mutational Burden, PD-L1, Patient Characteristics, and Response to Immune Checkpoint Inhibitors in Head and Neck Squamous Cell Carcinoma

“…In concordance with two other reports on patients with HNSCC [34,44], this study found that TMB was associated with tumor location in a statistically significant way. The proportion of patients with laryngeal tumors was significantly increased, and oropharyngeal cancer decreased, in the TMB-(6+) group when compared to patients with any other throat tumor location.…”

“…Although the split of TMB between groups was based on Foundation Medicine guideline, the groups would be similar for a threshold based on median TMB, with 70 patients in the TMB-(<6) group and 58 patients in the TMB-(6+) group. Similar to the reports in HN-SCC [27,28] and in other malignancies [24,33,34], this study demonstrated that there was no significant relationship between PD-L1 and TMB, reflecting the dynamic interactions between the two variables.…”

“…Similarly, there are conflicting data in the literature concerning the relationship between HPV/p16 and TMB. Some studies have shown that high TMB was associated with HPV negative disease [28,42], and others have demonstrated no significant correlation between the two variables [34]. There was no significant association between HPV and PD-L1 or TMB in this study.…”

“…This TMB finding is further supported by two other recent reports. One such project was dedicated to a population size similar to this study [28] and another analyzed the TCGA-HNSCC [34]. Our study additionally demonstrated an association between alcohol consumption and lower PD-L1 expression.…”

“…A study of The Cancer Genome Atlas (TCGA) HNSCC population did not find any significant correlation between TMB and race or gender but did identify a statistically significant association between high TMB and age above 60 [34]. This finding was confirmed by other reports on the same public TCGA HNSCC database [35] as well as in another study involving 100,000 human cancer genomes in which many malignancies were considered [33].…”