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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE201722 | GEO | 2022/05/04

REPOSITORIES: GEO

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PBAF loss leads to DNA damage induced inflammatory signalling through defective G2/M checkpoint maintenance

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2022-10-13 | PXD028336 | Pride

Genomic binding of wild-type and mutant Trp53 in mouse breast cancer cell lines

Project description:TP53 is one of the most frequently mutated gene in breast cancer. While p53 mutations often lead to loss of wild-type p53 activity, they can have a wide variety of gain-of-function (GOF) consequences. The impact of these GOF mutations in p53 on the anti-tumor immune response in breast cancer remains elusive. To address this, we have generated mouse mammary tumor models based on orthotopic injection of isogenic cell lines harboring the p53 mutations that most frequently occur in human breast cancer. By comparing the tumor immune landscape of these models and human breast tumors, we have uncovered that specific p53 point mutants consistently induce an immunologically ‘hot’ tumor phenotype, characterized by high infiltration of cytotoxic T cells, while other p53 mutations induce a non-T cell inflamed (‘cold’) microenvironment. In accordance with these high T cell levels, the hotp53 mutant tumors respond better to anti-PD-1immune checkpoint blockade than cold p53 mutant tumors. By comparing the different p53 mutants in terms of proteome profile, chromatin bindingproperties and protein complex formation, we have uncovered that T cell-enriched p53 mutants activate autophagy. Disruption of autophagy in an immunologically hot p53 mutant tumor abrogated the response to anti-PD-1 therapy. This work demonstrates that not all p53 mutations shape the immune microenvironment of mammary tumors in a similar fashion, and that response to immune checkpoint blockade depends on specific mutations in p53. This argues that screening for specific p53 aberrations in breast cancer may help guide immunotherapeutic strategies.

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2016-12-07 | GSE85508 | GEO

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2016-12-07 | GSE85507 | GEO

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2023-02-01 | GSE216762 | GEO

Clonal dynamics of alloreactive T cells in kidney allograft rejection after anti-PD-1 therapy [bulkTCRseq]

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2021-11-16 | GSE153098 | GEO

Inhibition of IL-17A Protects against Thyroid Immune-related Adverse Events while Preserving Checkpoint Inhibitor Anti-tumor Efficacy [RNA-seq (murine)]

Project description:Checkpoint inhibitor (ICI) immunotherapy leverages the body’s own immune system to attack cancer cells but leads to unwanted autoimmune side effects in up to 60% of patients. Such immune related adverse events (IrAE) lead to treatment interruption, permanent organ dysfunction, hospitalization and premature death. Thyroiditis is one of the most common IrAE, but the cause of thyroid IrAE remains unknown. Here we present a novel mouse model in which checkpoint inhibitor therapy leads to multi-organ autoimmune infiltrates and show that activation and infiltration of Type 3 immune cells including IL17A+ RORgt+ CD4+ (T helper 17 or Th17) and gamma delta 17 (gdT17) T cells promote thyroid IrAE development. In parallel, Th17 and gdT17 cells were similarly expanded in cancer patients treated with ICI. Furthermore, antibody-based inhibition of IL-17A, a clinically available therapy, significantly reduced thyroid IrAE development in ICI-treated mice. Finally, combination of IL-17A neutralization with ICI treatment in a mouse tumor model did not reduce ICI anti-tumor efficacy and indeed showed a trend toward enhancement. These studies suggest that targeting Th17 and gd17 function may reduce IrAE without impairing ICI anti-tumor efficacy and may be a generalizable strategy to address IL17-mediated IrAE.

2022-11-21 | GSE176561 | GEO

Inhibition of the IL-17A axis Protects against Immune-related Adverse Events while Supporting Checkpoint Inhibitor Anti-tumor Efficacy [RNA-seq (human)]

Project description:Checkpoint inhibitor (ICI) immunotherapy leverages the body’s own immune system to attack cancer cells but leads to unwanted autoimmune side effects in up to 60% of patients. Such immune related adverse events (IrAE) lead to treatment interruption, permanent organ dysfunction, hospitalization and premature death. Thyroiditis is one of the most common IrAE, but the cause of thyroid IrAE remains unknown. Here we present a novel mouse model in which checkpoint inhibitor therapy leads to multi-organ autoimmune infiltrates and show that activation and infiltration of Type 3 immune cells including IL17A+ RORt+ CD4+ (T helper 17 or Th17) and gamma delta 17 (T17) T cells promote thyroid IrAE development. In parallel, Th17 and T17 cells were similarly expanded in cancer patients treated with ICI. Furthermore, antibody-based inhibition of IL-17A, a clinically available therapy, significantly reduced thyroid IrAE development in ICI-treated mice. Finally, combination of IL-17A neutralization with ICI treatment in a mouse tumor model did not reduce ICI anti-tumor efficacy and indeed showed a trend toward enhancement. These studies suggest that targeting Th17 and 17 function may reduce IrAE without impairing ICI anti-tumor efficacy and may be a generalizable strategy to address IL17-mediated IrAE.

2023-12-31 | GSE192580 | GEO

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