Genetic Changes Driving Immunosuppressive Microenvironments in Oral Premalignancy

Abstract

Oral premalignant lesions (OPLs) are the precursors to oral cavity cancers, and have variable rates of progression to invasive disease. As an intermediate state, OPLs have acquired a subset of the genomic alterations while arising in an oral inflammatory environment. These specific genomic changes may facilitate the transition to an immune microenvironment that permits malignant transformation. Here, we will discuss mechanisms by which OPLs develop an immunosuppressive microenvironment that facilitates progression to invasive cancer. We will describe how genomic alterations and immune microenvironmental changes co-evolve and cooperate to promote OSCC progression. Finally, we will describe how these immune microenvironmental changes provide specific and unique evolutionary vulnerabilities for targeted therapies. Therefore, understanding the genomic changes that drive immunosuppressive microenvironments may eventually translate into novel biomarker and/or therapeutic approaches to limit the progression of OPLs to potential lethal oral cancers.

Keywords: CDKN2A; NOTCH1; TP53; head and neck cancer; immunosuppression.

Figure 1

Schema for immune/inflammatory microenvironment evolution during OPL progression. OPL are often strongly infiltrated with CD8⁺ T cells. Early low grade dysplasias also demonstrate tumoricidal and/or M1 TAMs. As dysplastic lesions progress, increased immunosuppressive M2 TAM, Treg, MDSCs and immunosuppressive molecules including PD-1/PD-L1 and A2AR. Created with BioRender.com.

Figure 2

Current OPL progression model. Schematic diagram showing the relative timing of genomic events during OPL progression. The stages are labeled early, middle, and late because the data are not well associated with specific histology. LOH, loss of hetorozygosity; WGS, whole genome sequencing; SNV, single nucleotide variant; CNA, copy number alteration. Modified from Califano and Gerstung. Created with BioRender.com.

Figure 3

Mutational changes that potentially alter the tumor microenvironment. Schematic diagram showing the common mutational changes in OPL can impact the immune microenvironment. TP53 mutants can activate NF-kB or inhibit the STING pathway to alter cytokine expression, increase TAM recruitment, increate Treg recruitment. CDKN2A mutants has been associated with immunogenic cold tumors through currently unknown mechanisms. NOTCH1 mutants was associated with altered MMP expression and decreased TAM infiltrations. Created with BioRender.com.