361MO - Characterizing the role of NSD family of histone methyltransferases in the head and neck squamous cell carcinoma tumor immune microenvironment

Background

Head neck squamous cell carcinomas (HNSCC) are aggressive tumors, with biologic and genetic diversity contributing to pathogenesis, disease course, and responses to treatment. While loss of function mutations in NSD1 and NSD2 associate with immune cold microenvironment, NSD1, NSD2 and NSD3 enzymes have been shown to positively regulate the disease progression. Here, we characterized the association of NSD1, NSD2, and NSD3 with HNSCC immune signatures.

Methods

2,292 HNSCC samples were analyzed by NGS (592, NextSeq; WES, NovaSeq), WTS (NovaSeq) (Caris Life Sciences). HPV status inferred by staining of p16 by IHC. Tumor mutational burden (TMB) totaled somatic mutations per tumor (high>10 mt/MB). Immune cell fractions were calculated by deconvolution of WTS: Quantiseq. HNSCC with NSD1/NSD2/NSD3-high(H) and -low(L) expressions were classified by top and bottom quartile, respectively. Statistical significance was determined by chi-square and Mann-Whitney U (p<0.05) and adjusted for multiple comparisons (q<0.05).

Results

NSD1/NSD2/NSD3-H HNSCC had increased infiltration of M2 MΦ (3.9% vs 2.7%, 3.6% vs 2.9%, 4% vs 2.6%), DC (2% vs 0.6%, 2% vs 0.4%, 1.9% vs 0.3%), NK cells (3.1% vs 1.9%, 3.2% vs 1.9%, 3% vs 1.9%) and decreased M1 MΦ (3.4% vs 4.4%, 3.4% vs 5%, 3.2% vs 5.3%) (all q<0.05). NSD1/NSD2-H HNSCC and increased Tregs (2.8% vs 2.2%, 2.7% vs 2.3%) (all q<0.05). NSD1/NSD2/NSD3-H HPV+ HNSCC had increased M2 MΦ (3.9% vs 2.7%, 3.8% vs 2.6%, 3.9% vs 2.7%) while NSD2-H tumors had decreased M1 MΦ (3.2% vs 3.9%, q<0.05). NSD1/NSD2/NSD3-H HNSCC had a high T cell inflamed signature (63.3%, 56.8%, 55.6% vs 6.4%, 10.1%, 10.9% respectively, all p<0.05). NSD1/NSD2/NSD3-H HNSCC and HPV+ HNSCC had higher expression of immunoinhibitory genes (CD274, PDCD1, CTLA4, FOXP3, HAVCR2, PDCD1LG2, FC: 1.9-4.7, q<0.05).

Conclusions

Our data suggest a strong association between NSD expression and increased M2 MΦ, Tregs, T cell inflamed score and immune regulatory genes. A better understanding of these differences will provide a rationale for tailored therapeutic approaches for NSD-expressing HNSCC.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The author.

Funding

Caris Life Sciences.

Disclosure

The author has declared no conflicts of interest.