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BRIEF RESEARCH REPORT article

Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1440530
This article is part of the Research Topic Spatial Architecture and Temporal Dynamics of Tumor Microenvironment: Implications in Tumor Immunity and Immunotherapies View all 5 articles

Dendritic cell effector mechanisms and tumor immune microenvironment infiltration define TLR8 modulation and PD-1 blockade

Provisionally accepted
Daniel A. Ruiz-Torres Daniel A. Ruiz-Torres 1,2,3Jillian Wise Jillian Wise 1,4,5,6*Brian Y. Zhao Brian Y. Zhao 2Joao Paulo Oliveira Da Costa Joao Paulo Oliveira Da Costa 1,6,7Sara Cavallaro Sara Cavallaro 1,6Peter Sadow Peter Sadow 2,3,5Jacy Fang Jacy Fang 1Osman Yilmaz Osman Yilmaz 7,8Moshe Sade-Feldman Moshe Sade-Feldman 1,6*Daniel L. Faden Daniel L. Faden 2,3,6*Shannon L. Stott Shannon L. Stott 1,6,9*
  • 1 Massachusetts General Hospital Cancer Center, Boston, Massachusetts, United States
  • 2 Department of Otolaryngology Head and Neck Surgery, Harvard Medical School, Boston, Massachusetts, United States
  • 3 Massachusetts Eye & Ear Infirmary, Harvard Medical School, Boston, Massachusetts, United States
  • 4 Salve Regina University, Newport, United States
  • 5 Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • 6 Broad Institute, Cambridge, MA, United States
  • 7 Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States
  • 8 Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States
  • 9 Center for Engineering in Medicine & Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States

The final, formatted version of the article will be published soon.

    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 preand 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 + Tcell 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: immune response, Dendritic Cells, checkpoint blockade, Immunotherapy, Cancer

    Received: 29 May 2024; Accepted: 08 Nov 2024.

    Copyright: © 2024 Ruiz-Torres, Wise, Zhao, Oliveira Da Costa, Cavallaro, Sadow, Fang, Yilmaz, Sade-Feldman, Faden and Stott. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Jillian Wise, Salve Regina University, Newport, United States
    Moshe Sade-Feldman, Massachusetts General Hospital Cancer Center, Boston, 02114, Massachusetts, United States
    Daniel L. Faden, Department of Otolaryngology Head and Neck Surgery, Harvard Medical School, Boston, 02115, Massachusetts, United States
    Shannon L. Stott, Massachusetts General Hospital Cancer Center, Boston, 02114, Massachusetts, United States

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.