Microbe-Mediated Activation of Toll-like Receptor 2 Drives PDL1 Expression in HNSCC

As immunotherapies targeting the PDL1 checkpoint have become a mainstay of treatment for a subset of head and neck squamous cell carcinoma (HNSCC) patients, a detailed understanding of the mechanisms underlying PDL1-mediated immune evasion is needed. To elucidate factors regulating expression of PDL1 in HNSCC cells, a genome-wide CRISPR profiling approach was implemented to identify genes and pathways conferring altered PDL1 expression in an HNSCC cell line model. Our screen nominated several candidate PDL1 drivers, including Toll-like Receptor 2 (TLR2). Depletion of TLR2 blocks interferon-γ-induced PDL1 expression, and stimulation of TLR2 with either Staphylococcus aureus or a bacterial lipopeptide mimetic, Pam3CSK4, enhanced PDL1 expression in multiple models. The data herein demonstrate a role for TLR2 in modulating the expression of PDL1 in HNSCC models and suggest that microbiota may directly modulate immunosuppression in cancer cells. Our study represents a step toward disentangling the diverse pathways and stimuli regulating PDL1 expression in HNSCC and underscores a need for future work to characterize the complex microbiome in HNSCC patients treated with immunotherapy.

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A Genome-Wide Screen Identifies Common Variants Accounting For Inter-Individual Differences In Toll-Like Receptor 2 Signaling

10.1164/ajrccm-conference.2012.185.1_meetingabstracts.a4891 ◽

2012 ◽

Author(s):

Carmen Mikacenic ◽

Alexander P. Reiner ◽

Tarah Holden ◽

Deborah Nickerson ◽

Mark M. Wurfel

Keyword(s):

Individual Differences ◽

Toll Like Receptor ◽

Common Variants ◽

Genome Wide ◽

A Genome ◽

Toll Like Receptor 2

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Integrative oncogene-dependency mapping identifies RIT1 vulnerabilities and synergies in lung cancer

Nature Communications ◽

10.1038/s41467-021-24841-y ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Athea Vichas ◽

Amanda K. Riley ◽

Naomi T. Nkinsi ◽

Shriya Kamlapurkar ◽

Phoebe C. R. Parrish ◽

...

Keyword(s):

Lung Cancer ◽

Spindle Assembly Checkpoint ◽

Spindle Assembly ◽

Genetic Data ◽

Multiple Models ◽

Ras Pathway ◽

Functional Interactions ◽

Genome Wide ◽

A Genome ◽

Mutant Cells

AbstractCRISPR-based cancer dependency maps are accelerating advances in cancer precision medicine, but adequate functional maps are limited to the most common oncogenes. To identify opportunities for therapeutic intervention in other rarer subsets of cancer, we investigate the oncogene-specific dependencies conferred by the lung cancer oncogene, RIT1. Here, genome-wide CRISPR screening in KRAS, EGFR, and RIT1-mutant isogenic lung cancer cells identifies shared and unique vulnerabilities of each oncogene. Combining this genetic data with small-molecule sensitivity profiling, we identify a unique vulnerability of RIT1-mutant cells to loss of spindle assembly checkpoint regulators. Oncogenic RIT1M90I weakens the spindle assembly checkpoint and perturbs mitotic timing, resulting in sensitivity to Aurora A inhibition. In addition, we observe synergy between mutant RIT1 and activation of YAP1 in multiple models and frequent nuclear overexpression of YAP1 in human primary RIT1-mutant lung tumors. These results provide a genome-wide atlas of oncogenic RIT1 functional interactions and identify components of the RAS pathway, spindle assembly checkpoint, and Hippo/YAP1 network as candidate therapeutic targets in RIT1-mutant lung cancer.

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