Immunological subtyping of salivary gland cancer identifies histological origin-specific tumor immune microenvironment

Abstract

Gene expression analysis enhances proper cancer subtyping, a better understanding of the molecular characteristics of cancer, and strategies for precision medicine. However, salivary gland cancer (SGC) subtyping remains largely unexplored because of its rarity and diverse histopathological and immunological characteristics. This study aimed to determine whether the histological origin and immunological characteristics of SGC subtypes are intrinsic tumor immunity factors. We performed immune profiling of 94 RNA-seq of SGC tissues and found that the SGCs that originated from the excretory duct (ED), such as the salivary duct and mucoepidermoid carcinomas, exhibit higher immunity than those from the intercalated duct (ID), such as the adenoid cystic and myoepithelial carcinomas, based on the computationally predicted immune score (p < 0.001), immune cell enrichment in the tumor immune microenvironment (TIME) (p < 0.001), T-cell receptor diversity (p < 0.001), and expression of signal I (major histocompatibility complex, MHC, p < 0.001) and signal II (co-stimulatory, p < 0.001 and co-inhibitory, p < 0.001) genes. Further analysis revealed that tolerogenic dendritic cell-induced dysfunctional T-cell populations and T-cell exclusion in the TIME are the major immune evasive mechanisms of the ED-and ID-derived SGCs, respectively.

Exploring Immunological Effects and Novel Immune Adjuvants in Immunotherapy for Salivary Gland Cancers

“…Immune checkpoint molecules, including PD-L1, programmed death ligand-2 (PD-L2), T-cell immunoreceptors with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains, and CTLA-4, are abundantly expressed in MECs with immune-hot TME compared to those with immune-cold TME [ 23 ]. Among SGCs, MECs show higher immune cell infiltration in the TME, greater T-cell receptor diversity, and increased expression of HLA class I and II than that of AdCCs [ 24 ]. Given that MEC may represent an immunogenetic tumor type where immunotherapies could be effective ( Figure 1 ), further research is necessary to examine the immunological differences in the TME across different histological grades of MEC.…”

“…RNA-sequencing studies have revealed increased T-cell infiltration and neoantigen expression in SDCs compared to that of myoepithelial carcinoma or AdCC [ 30 ]. In addition to immune cell infiltration, another study has shown that SDCs express high levels of T-cell receptor diversity and HLA class I/II [ 24 ]. However, multiple immunosuppressive mechanisms co-exist in the TME of SDCs.…”