Dendritic cell effector mechanisms and tumor immune microenvironment infiltration define TLR8 modulation and PD-1 blockade
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 e...
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Frontiers Media S.A.
2024-12-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1440530/full |
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| author | 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 |
| author_facet | 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 |
| author_sort | Daniel A. Ruiz-Torres |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-35fa217099bf401997c467b0569a1902 |
| institution | OA Journals |
| issn | 1664-3224 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj-art-35fa217099bf401997c467b0569a19022025-08-20T02:30:34ZengFrontiers Media S.A.Frontiers in Immunology1664-32242024-12-011510.3389/fimmu.2024.14405301440530Dendritic cell effector mechanisms and tumor immune microenvironment infiltration define TLR8 modulation and PD-1 blockadeDaniel A. Ruiz-Torres0Daniel A. Ruiz-Torres1Daniel A. Ruiz-Torres2Daniel A. Ruiz-Torres3Jillian F. Wise4Jillian F. Wise5Jillian F. Wise6Jillian F. Wise7Jillian F. Wise8Brian Yinge Zhao9Joao Paulo Oliveira-Costa10Joao Paulo Oliveira-Costa11Joao Paulo Oliveira-Costa12Sara Cavallaro13Sara Cavallaro14Sara Cavallaro15Peter M. Sadow16Peter M. Sadow17Jacy Fang18Jacy Fang19Osman Yilmaz20Amar Patel21Christopher Loosbroock22Moshe Sade-Feldman23Moshe Sade-Feldman24Moshe Sade-Feldman25Daniel L. Faden26Daniel L. Faden27Daniel L. Faden28Shannon L. Stott29Shannon L. Stott30Shannon L. Stott31Shannon L. Stott32Department of Otolaryngology-Head and Neck Surgery, Massachusetts Eye and Ear, Boston, MA, United StatesDepartment of Medicine, Harvard Medical School, Boston, MA, United StatesKrantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Boston, MA, United StatesBroad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, United StatesDepartment of Medicine, Harvard Medical School, Boston, MA, United StatesKrantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Boston, MA, United StatesBroad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, United StatesDepartment of Biology and Biomedical Sciences, Salve Regina University, Newport, RI, United StatesDepartment of Pathology, Massachusetts General Hospital, Boston, MA, United StatesDepartment of Otolaryngology-Head and Neck Surgery, Massachusetts Eye and Ear, Boston, MA, United StatesKrantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Boston, MA, United StatesBroad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, United StatesDepartment of Pathology, Massachusetts General Hospital, Boston, MA, United StatesDepartment of Medicine, Harvard Medical School, Boston, MA, United StatesKrantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Boston, MA, United StatesBroad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, United StatesDepartment of Medicine, Harvard Medical School, Boston, MA, United StatesDepartment of Pathology, Massachusetts General Hospital, Boston, MA, United StatesKrantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Boston, MA, United StatesBroad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, United StatesDepartment of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, United StatesBristol Myers Squibb, Seattle, WA, United StatesBristol Myers Squibb, Seattle, WA, United StatesDepartment of Medicine, Harvard Medical School, Boston, MA, United StatesKrantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Boston, MA, United StatesBroad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, United StatesDepartment of Otolaryngology-Head and Neck Surgery, Massachusetts Eye and Ear, Boston, MA, United StatesDepartment of Medicine, Harvard Medical School, Boston, MA, United StatesBroad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, United StatesDepartment of Medicine, Harvard Medical School, Boston, MA, United StatesKrantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Boston, MA, United StatesBroad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, United StatesCenter for Engineering in Medicine and Bio MicroElectroMechanical Systems (BioMEMS) Resource Center, Surgical Services, Massachusetts General Hospital, Charlestown, MA, United StatesThe 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.https://www.frontiersin.org/articles/10.3389/fimmu.2024.1440530/fullimmune responsedendritic cellscheckpoint blockadeimmunotherapycancer |
| spellingShingle | 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 Dendritic cell effector mechanisms and tumor immune microenvironment infiltration define TLR8 modulation and PD-1 blockade Frontiers in Immunology immune response dendritic cells checkpoint blockade immunotherapy cancer |
| title | Dendritic cell effector mechanisms and tumor immune microenvironment infiltration define TLR8 modulation and PD-1 blockade |
| title_full | Dendritic cell effector mechanisms and tumor immune microenvironment infiltration define TLR8 modulation and PD-1 blockade |
| title_fullStr | Dendritic cell effector mechanisms and tumor immune microenvironment infiltration define TLR8 modulation and PD-1 blockade |
| title_full_unstemmed | Dendritic cell effector mechanisms and tumor immune microenvironment infiltration define TLR8 modulation and PD-1 blockade |
| title_short | Dendritic cell effector mechanisms and tumor immune microenvironment infiltration define TLR8 modulation and PD-1 blockade |
| title_sort | dendritic cell effector mechanisms and tumor immune microenvironment infiltration define tlr8 modulation and pd 1 blockade |
| topic | immune response dendritic cells checkpoint blockade immunotherapy cancer |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1440530/full |
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