1. Dendritic cell effector mechanisms and tumor immune microenvironment infiltration define TLR8 modulation and PD-1 blockade.
- Author
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Ruiz-Torres DA, Wise J, Zhao BY, Oliveira-Costa JP, Cavallaro S, Sadow P, Fang J, Yilmaz O, Patel A, Loosbroock C, Sade-Feldman M, Faden DL, and Stott SL
- Abstract
The potent immunostimulatory effects of toll-like receptor 8 (TLR8) agonism in combination with PD-1 blockade have resulted in various preclinical investigations, yet the mechanism of action in humans remains unknown. To decipher the combinatory mode of action of TLR8 agonism and PD-1 blockade, we employed a unique, open-label, phase 1b pre-operative window of opportunity clinical trial (NCT03906526) in head and neck squamous cell carcinoma (HNSCC) patients. Matched pre- and post-treatment tumor biopsies from the same lesion were obtained. We used single-cell RNA sequencing and custom multiplex staining to leverage the unique advantage of same-lesion longitudinal sampling. Patients receiving dual TLR8 agonism and anti-PD-1 blockade exhibited marked upregulation of innate immune effector genes and cytokines, highlighted by increased CLEC9A+ dendritic cell and CLEC7A/SYK expression. This was revealed via comparison with a previous cohort from an anti-PD-1 blockade monotherapy single-cell RNA sequencing study. Furthermore, in dual therapy patients, post-treatment mature dendritic cells increased in adjacency to CD8
+ T-cells. Increased tumoral cytotoxic T-lymphocyte densities and expanded CXCL13+ CD8+ T-cell populations were observed in responders, with increased tertiary lymphoid structures (TLSs) across all three patients. This study provides key insights into the mode of action of TLR8 agonism and anti-PD-1 blockade immune targeting in HNSCC patients., Competing Interests: Conflict of Interest and Funding This work was funded by Bristol Myers Squibb and NIH 5K23DE029811. Bristol Myers Squibb was involved in the study design and sample collection, but was not involved in data collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication. Shannon L. Stott receives research funding from NIH: 5R01CA226871–05, U18TR003793–02, V Foundation: T2020–004, American Cancer Society: 132030-RSG-18–108-01-TBG and MGH Research Scholars Program. Daniel L. Faden receives research funding from Calico Life Sciences, in-kind funding from Boston Gene, Predicine and NeoGenomics, receives consulting fees from Merck, and Chrysalis Biomedical Advisors, and receives salary support from NIH 5K23DE029811, R03DE030550, 5R21CA267152. Moshe Sade-Feldman receives funding from Calico Life Sciences, Bristol-Myers Squibb, and Istari Oncology and served as a consultant for Galvanize Therapeutics.- Published
- 2024
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