Age and Mutations as Predictors of the Response to Immunotherapy in Head and Neck Squamous Cell Cancer

Abstract

The immunosuppressive tumor microenvironment plays an essential role in the treatment of head and neck squamous cell carcinoma (HNSC). Compared to traditional chemoradiotherapy, immune checkpoint inhibitors (ICIs) have become increasingly important in HNSC therapy. Prior studies linked the efficacy of ICIs to PD-L1, microsatellite instability (MSI), HPV infection, tumor mutation burden (TMB), and tumor lymphocyte infiltration in patients with HNSC, but further verification is needed. Additional predictors are needed to recognize HNSC patients with a good response to ICIs. We collected the clinical information and mutation data of HNSC patients from Memorial Sloan Kettering Cancer Center (MSKCC) and The Cancer Genome Atlas (TCGA) databases to generate two clinical cohorts. The MSKCC cohort was used to recognize predictors related to the efficacy of ICIs, and the TCGA cohort was used to further examine the immune microenvironment features and signaling pathways that are significantly enriched in the subgroups of predictors. Multivariate Cox regression analysis indicated that age (HR = 0.50, p = 0.014) and ARID1A (HR = 0.13, p = 0.048), PIK3CA (HR = 0.45, p = 0.021), and TP53 (HR = 1.82, p = 0.035) mutations were potential predictors for ICI efficacy in HNSC patients. Age > 65 years and ARID1A or PIK3CA mutations correlated with good overall survival (OS). TP53 mutant-type (MT) patients experienced a worse prognosis than TP53 wild-type (WT) patients. The subgroups associated with a good prognosis (age > 65 years, ARID1A-MT, and PIK3CA-MT) universally had a high TMB and increased expression of immune checkpoint molecules. Although TP53-MT was associated with a high TMB, the expression of most immune checkpoint molecules and immune-related genes was lower in TP53-MT patients than TP53-WT patients, which may reflect low immunogenicity. Pathways related to the immunosuppressive tumor microenvironment were mostly enriched in the subgroups associated with a poor prognosis (age ≤ 65 years, low TMB, ARID1A-WT, PIK3CA-WT, and TP53-MT). In conclusion, the factors age > 65 years, PIK3CA-MT, and ARID1A-MT predicted favorable efficacy for ICI treatment in HNSC patients, and TP53 mutation was a negative predictor.

The Effect of Smoking on the Immune Microenvironment and Immunogenicity and Its Relationship With the Prognosis of Immune Checkpoint Inhibitors in Non-small Cell Lung Cancer

“…Among them, TP53 is a gene that is mutated considerably in the smoking group in both the discovery and validation sets. Our previous research also repeatedly confirmed that TP53 mutations are associated with the better efficacy and prognosis of treating various tumors with ICIs ( Lyu et al, 2020 ; Zhang Y. et al, 2020 ).…”

Multiomics analysis of tumor mutational burden across cancer types

“…In some tumors, TMB has a predictive effect on the efficacy of immunotherapy and the prognosis of cancer patients [7] , [17] , it is related to the clinical characteristics [18] , gene expression [53] , DNA methylation [54] , enrichment of signaling pathway [53] , immune cell infiltration [20] , gene mutations and the expression of MMRs [22] , [23] . To date, few studies have been conducted to enable a comprehensive pan-cancer analysis of TMB.…”

“…TMB is also regarded as a prognostic biomarker [16] , [17] . Studies have shown that TMB is related to clinical characteristics [18] , [19] and immune cell infiltration [20] , [21] in some tumor patients. TMB is also affected by gene mutations and the expression of mismatch repair genes (MMRs) [22] , [23] .…”

Tumor-Infiltrating Immune-Related Long Non-Coding RNAs Indicate Prognoses and Response to PD-1 Blockade in Head and Neck Squamous Cell Carcinoma

“…In addition to its significant associations with shortened survival time and resistance to radiotherapy and chemotherapy ( 47 ), TP53 mutation has been recently reported by Zhang et al. to be indicative of poor response to immunotherapy in HNSCC ( 48 ), which supports the signature as a potential predictor for prognoses and immunotherapy response. Immunosuppressive TME is characterized by enriched CAFs, TAMs, T regulatory cells, myeloid-derived suppressor cells, and hypoxia, leading to tumor progression and reduced responses to pembrolizumab and nivolumab ( 49 ).…”