Mutant p53 drives an immune cold tumor immune microenvironment in oral squamous cell carcinoma

Oral squamous cell carcinoma models are presented with defined Trp53 mutations associated with immune checkpoint inhibitor responsiveness, e.g. T122N amino acid change of Tp53 promotes a cold TME enriched with immunosuppressive M2 macrophages resistant to ICI therapy. The critical role of the tumor immune microenvironment (TIME) in determining response to immune checkpoint inhibitor (ICI) therapy underscores the importance of understanding cancer cell-intrinsic mechanisms driving immune-excluded (cold) TIMEs. One such cold tumor is oral cavity squamous cell carcinoma (OSCC), a tobacco-associated cancer with mutations in the TP53 gene which responds poorly to ICI therapy. Because altered TP53 function promotes tumor progression and plays a potential role in TIME modulation, here we developed a syngeneic OSCC models with defined Trp53 (p53) mutations and characterized their TIMEs and degree of ICI responsiveness. We observed that a carcinogen-induced p53 mutation promoted a cold TIME enriched with immunosuppressive M2 macrophages highly resistant to ICI therapy. p53-mutated cold tumors failed to respond to combination ICI treatment; however, the combination of a programmed cell death protein 1 (PD-1) inhibitor and stimulator of interferon genes (STING) agonist restored responsiveness. These syngeneic OSCC models can be used to gain insights into tumor cell-intrinsic drivers of immune resistance and to develop effective immunotherapeutic approaches for OSCC and other ICI-resistant solid tumors.

Automated summary

Oral squamous cell carcinoma models with defined Trp53 mutations associated with immune checkpoint inhibitor responsiveness were developed. The T122N amino acid change of Tp53 promotes a cold tumor microenvironment enriched with immunosuppressive M2 macrophages resistant to ICI therapy. These models can provide insights into tumor cell-intrinsic drivers of immune resistance and aid in the development of effective immunotherapeutic approaches for OSCC and other ICI-resistant solid tumors.