Project description:We previously identified stress keratin 17 (K17) as a host factor that contributes to immune evasion in the context of mouse papillomavirus-induced disease. Analyses of head and neck squamous cell carcinoma (HNSCC) patient TCGA and tissue microarray data revealed that K17 can be overexpressed in both HPV+ and HPV- human cancer samples, with a more profound upregulation in HPV- HNSCC samples. In this report, we investigated the role of K17 in regulating immune response in HPV- head and neck cancer. To test whether K17 mediates immune evasion and resistance to immune checkpoint blockade (ICB) therapy in HPV- HNC, we used MOC2, a K17-expressing murine HNC cell line, and knocked out the K17 gene from it using CRISPR/Cas9 (K17KO MOC2 cells). Then we injected K17KO MOC2 cells or parental MOC2 cells into NSG and C57BL/6 mice and monitored tumor growth, immune cell infiltration, and response to ICB treatment in vivo. In NSG mice, the K17KO MOC2 cell lines grew as fast as parental MOC2 tumors. In C57BL/6 mice, K17KO MOC2 tumors grew significantly slower than parental MOC2 tumors, with 50% tumor rejection rate, in a T-cell dependent manner. Flow cytometry of tumor infiltrating T cells and bulk tumor RNA seq analyses show an active anti-tumor microenvironment in the K17KO MOC2 tumors, compared to parental MOC2 tumors. In addition, we observed that 5 out of 5 anti-PD1 + anti-CTLA4 treated K17KO MOC2 tumors completely regressed, while only 1 out of 5 parental MOC2 tumors similarly treated at the same size completely regressed (p<0.05). In exploring the role of chemokine CXCL9 in increased T cell infiltration, we blocked the receptor CXCR3, a receptor often upregulated on activated T cells, and saw a delay in the immune-mediated rejection K17KO MOC2 tumors. Single cell RNA seq analyses revealed a completely different immune landscape including both lymphoid and myeloid populations in K17KO MOC2 tumors. Overall, we demonstrated that K17 expression in HNSCC contributes to immune evasion and resistance to immune checkpoint blockade treatment through modulating the immune landscape in the tumor microenvironment.

			Action	DRS
	SRR29339368_1.fastq.gz	Fastqsanger.gz
	SRR29339368_2.fastq.gz	Fastqsanger.gz
	SRR29339369_1.fastq.gz	Fastqsanger.gz
	SRR29339369_2.fastq.gz	Fastqsanger.gz
	SRR29339370_1.fastq.gz	Fastqsanger.gz

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In vivo CRISPR screens in Head and Neck Cancer reveal that Uchl5 modulates extracellular matrix deposition to promote immune evasion [in vivo]

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