962P - Immunotherapeutic implications of mucin 1/16 expression in head and neck squamous cell carcinoma (HNSCC)

Background

The density of tumor-infiltrating lymphocytes (TILs) in ITF is increasingly recognized as important biomarker for immunotherapy response. We sought to identify gene expression signatures that predict high T cells infiltration (“inflamed status”) in the invasive tumor front of HNSCCs.

Methods

We assessed the gene expression and immune profile of biopsy specimens from 31 treatment-naïve HNSCC using RNA-seq and immunohistochemical staining (IHC) respectively. Mutational profile and tumor mutation burden (TMB) were also analyzed by targeted next generation sequencing (NGS) for 523 known cancer drivers. Median value of CD8+ TIL density in the invasive front was used as cutoff point to divide the patients into CD8+^highand CD8+^lowgroups. RNA-seq data were analyzed to identify differentially expressed genes (DEGs) between groups. Validation was performed using HNSCC RNA data from the Cancer Genome Atlas (TCGA), and Z-scores for CD8A⁺, IDO1, CXCL10 and CD274 were used to investigate whether highly infiltrative HNSCC clusters were associated with gene expression signatures.

Results

Integrated analysis of transcriptome and IHC data of our cohort, revealed that expression of MUC1 and MUC16 is associated with high levels of ITF CD8+ density. In cancer, Ras-driven aberrant overexpression of MUC 1 and 16, alteration on their glycosylation pattern (Tn antigens) and loss of their polarized localization has been associated with immune escape. MUC16 mutations may be associated with higher tumor mutation load (TML), better survival outcomesand immune response in bladder cancer. Interestingly, the ITF CD8+^highgroup of tumors in our cohort was also enriched for activating mutations on RAS pathway and displayed higher HRAS and mucin glycotransferases mRNA levels, compared to ITF CD8+^lowgroup. TCGA data confirmed that HNSCC clusters with MUC1/16 overexpression are highly infiltrated and characterized by RAS alterations.

Conclusions

Our study demonstrates that MUC1/16 overexpressing HNSCC are “inflamed”. Moreover, HRAS overexpression and RAS oncogenic mutations are associated with MUC1/16 overexpression. In this context, Ras-targeted therapeutic approaches may sensitize this cluster of tumors to immunotherapy.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Kura Oncology.

Disclosure

All authors have declared no conflicts of interest.