Frontiers in Immunology (Dec 2024)
Dendritic cell effector mechanisms and tumor immune microenvironment infiltration define TLR8 modulation and PD-1 blockade
- Daniel A. Ruiz-Torres,
- Daniel A. Ruiz-Torres,
- Daniel A. Ruiz-Torres,
- Daniel A. Ruiz-Torres,
- Jillian F. Wise,
- Jillian F. Wise,
- Jillian F. Wise,
- Jillian F. Wise,
- Jillian F. Wise,
- Brian Yinge Zhao,
- Joao Paulo Oliveira-Costa,
- Joao Paulo Oliveira-Costa,
- Joao Paulo Oliveira-Costa,
- Sara Cavallaro,
- Sara Cavallaro,
- Sara Cavallaro,
- Peter M. Sadow,
- Peter M. Sadow,
- Jacy Fang,
- Jacy Fang,
- Osman Yilmaz,
- Amar Patel,
- Christopher Loosbroock,
- Moshe Sade-Feldman,
- Moshe Sade-Feldman,
- Moshe Sade-Feldman,
- Daniel L. Faden,
- Daniel L. Faden,
- Daniel L. Faden,
- Shannon L. Stott,
- Shannon L. Stott,
- Shannon L. Stott,
- Shannon L. Stott
Affiliations
- Daniel A. Ruiz-Torres
- Department of Otolaryngology-Head and Neck Surgery, Massachusetts Eye and Ear, Boston, MA, United States
- Daniel A. Ruiz-Torres
- Department of Medicine, Harvard Medical School, Boston, MA, United States
- Daniel A. Ruiz-Torres
- Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Boston, MA, United States
- Daniel A. Ruiz-Torres
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, United States
- Jillian F. Wise
- Department of Medicine, Harvard Medical School, Boston, MA, United States
- Jillian F. Wise
- Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Boston, MA, United States
- Jillian F. Wise
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, United States
- Jillian F. Wise
- Department of Biology and Biomedical Sciences, Salve Regina University, Newport, RI, United States
- Jillian F. Wise
- Department of Pathology, Massachusetts General Hospital, Boston, MA, United States
- Brian Yinge Zhao
- Department of Otolaryngology-Head and Neck Surgery, Massachusetts Eye and Ear, Boston, MA, United States
- Joao Paulo Oliveira-Costa
- Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Boston, MA, United States
- Joao Paulo Oliveira-Costa
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, United States
- Joao Paulo Oliveira-Costa
- Department of Pathology, Massachusetts General Hospital, Boston, MA, United States
- Sara Cavallaro
- Department of Medicine, Harvard Medical School, Boston, MA, United States
- Sara Cavallaro
- Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Boston, MA, United States
- Sara Cavallaro
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, United States
- Peter M. Sadow
- Department of Medicine, Harvard Medical School, Boston, MA, United States
- Peter M. Sadow
- Department of Pathology, Massachusetts General Hospital, Boston, MA, United States
- Jacy Fang
- Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Boston, MA, United States
- Jacy Fang
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, United States
- Osman Yilmaz
- Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, United States
- Amar Patel
- Bristol Myers Squibb, Seattle, WA, United States
- Christopher Loosbroock
- Bristol Myers Squibb, Seattle, WA, United States
- Moshe Sade-Feldman
- Department of Medicine, Harvard Medical School, Boston, MA, United States
- Moshe Sade-Feldman
- Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Boston, MA, United States
- Moshe Sade-Feldman
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, United States
- Daniel L. Faden
- Department of Otolaryngology-Head and Neck Surgery, Massachusetts Eye and Ear, Boston, MA, United States
- Daniel L. Faden
- Department of Medicine, Harvard Medical School, Boston, MA, United States
- Daniel L. Faden
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, United States
- Shannon L. Stott
- Department of Medicine, Harvard Medical School, Boston, MA, United States
- Shannon L. Stott
- Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Boston, MA, United States
- Shannon L. Stott
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, United States
- Shannon L. Stott
- Center for Engineering in Medicine and Bio MicroElectroMechanical Systems (BioMEMS) Resource Center, Surgical Services, Massachusetts General Hospital, Charlestown, MA, United States
- DOI
- https://doi.org/10.3389/fimmu.2024.1440530
- Journal volume & issue
-
Vol. 15
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.
Keywords
