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

Jacqueline E Mann; Megan L Ludwig; Aditi Kulkarni; Erin B Scheftz; Isabel R Murray; Jingyi Zhai; Elizabeth Gensterblum-Miller; Hui Jiang; J Chad Brenner

doi:10.3390/cancers13194782

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

Cancers (Basel). 2021 Sep 24;13(19):4782. doi: 10.3390/cancers13194782.

Authors

Jacqueline E Mann^{1

2}, Megan L Ludwig^{1

3}, Aditi Kulkarni¹, Erin B Scheftz¹, Isabel R Murray¹, Jingyi Zhai⁴, Elizabeth Gensterblum-Miller^{1

3}, Hui Jiang^{4

5}, J Chad Brenner^{1

3

5

6}

Affiliations

¹ Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, MI 48109, USA.
² Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
³ Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, MI 48109, USA.
⁴ Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA.
⁵ Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
⁶ Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA.

Abstract

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.

Keywords: CRISPR; HNSCC; PDL1; TLR2; microbiome.

Abstract

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