Monocyte-derived APCs are central to the response of PD1 checkpoint blockade and provide a therapeutic target for combination therapy.
| Title: | Monocyte-derived APCs are central to the response of PD1 checkpoint blockade and provide a therapeutic target for combination therapy. |
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| Authors: | Schetters STT; Molecular Cell Biology and Immunology, Amsterdam Institute for Infection and Immunity, Cancer Center Amsterdam, Amsterdam UMC - Location VUMC, Amsterdam, The Netherlands y.vankooyk@amsterdamumc.nl sjoerds@irc.vib-ugent.be.; Rodriguez E; Molecular Cell Biology and Immunology, Amsterdam Institute for Infection and Immunity, Cancer Center Amsterdam, Amsterdam UMC - Location VUMC, Amsterdam, The Netherlands.; Kruijssen LJW; Molecular Cell Biology and Immunology, Amsterdam Institute for Infection and Immunity, Cancer Center Amsterdam, Amsterdam UMC - Location VUMC, Amsterdam, The Netherlands.; Crommentuijn MHW; Molecular Cell Biology and Immunology, Amsterdam Institute for Infection and Immunity, Cancer Center Amsterdam, Amsterdam UMC - Location VUMC, Amsterdam, The Netherlands.; Boon L; Polpharma Biologics, Utrecht, The Netherlands.; Van den Bossche J; Molecular Cell Biology and Immunology, Amsterdam Institute for Infection and Immunity, Cancer Center Amsterdam, Amsterdam UMC - Location VUMC, Amsterdam, The Netherlands.; Den Haan JMM; Molecular Cell Biology and Immunology, Amsterdam Institute for Infection and Immunity, Cancer Center Amsterdam, Amsterdam UMC - Location VUMC, Amsterdam, The Netherlands.; Van Kooyk Y; Molecular Cell Biology and Immunology, Amsterdam Institute for Infection and Immunity, Cancer Center Amsterdam, Amsterdam UMC - Location VUMC, Amsterdam, The Netherlands y.vankooyk@amsterdamumc.nl sjoerds@irc.vib-ugent.be. |
| Source: | Journal for immunotherapy of cancer [J Immunother Cancer] 2020 Jul; Vol. 8 (2). |
| Publication Type: | Journal Article; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: BMJ Publishing Group Ltd Country of Publication: England NLM ID: 101620585 Publication Model: Print Cited Medium: Internet ISSN: 2051-1426 (Electronic) Linking ISSN: 20511426 NLM ISO Abbreviation: J Immunother Cancer Subsets: MEDLINE |
| Imprint Name(s): | Publication: 2020- : London, United Kingdom : BMJ Publishing Group Ltd.; Original Publication: London : BioMed Central, 2013- |
| MeSH Terms: | Antigen-Presenting Cells/*metabolism ; Combined Modality Therapy/*methods ; Immune Checkpoint Inhibitors/*therapeutic use ; Immunotherapy/*methods ; Monocytes/*metabolism ; Programmed Cell Death 1 Receptor/*antagonists & inhibitors; Immune Checkpoint Inhibitors/pharmacology ; Animals ; Disease Models, Animal ; Female ; Humans ; Male ; Mice |
| Abstract: | Background: PD1 immune checkpoint blockade (αPD1 ICB) has shown unparalleled success in treating many types of cancer. However, response to treatment does not always lead to tumor rejection. While αPD1 ICB relies on cytotoxic CD8+ T cells, antigen-presenting cells (APCs) at the tumor site are also needed for costimulation of tumor-infiltrating lymphocytes (TILs). It is still unclear how these APCs develop and function before and during αPD1 ICB or how they are associated with tumor rejection.; Methods: Here, we used B16 mouse melanoma and MC38 colorectal carcinoma tumor models, which show differential responses to αPD1 ICB. The immune composition of ICB insensitive B16 and sensitive MC38 were extensively investigated using multi-parameter flow cytometry and unsupervised clustering and trajectory analyses. We additionally analyzed existing single cell RNA sequencing data of the myeloid compartment of patients with melanoma undergoing αPD1 ICB. Lastly, we investigated the effect of CD40 agonistic antibody on the tumor-infiltrating monocyte-derived cells during αPD1 ICB.; Results: We show that monocyte-derived dendritic cells (moDCs) express high levels of costimulatory molecules and are correlated with effector TILs in the tumor microenvironment (TME) after αPD1 ICB only in responding mouse tumor models. Tumor-resident moDCs showed distinct differentiation from monocytes in both mouse and human tumors. We further confirmed significant enrichment of tumor-resident differentiated moDCs in patients with melanoma responding to αPD1 ICB therapy compared with non-responding patients. Moreover, moDCs could be targeted by agonistic anti-CD40 antibody, supporting moDC differentiation, effector T-cell expansion and anti-tumor immunity.; Conclusion: The combined analysis of myeloid and lymphoid populations in the TME during successful and non-successful PD1 ICB led to the discovery of monocyte-to-DC differentiation linked to expanding T-cell populations. This differentiation was found in patients during ICB, which was significantly higher during successful ICB. The finding of tumor-infiltrating monocytes and differentiating moDCs as druggable target for rational combination therapy opens new avenues of anti-tumor therapy design.; (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.) |
| Competing Interests: | Competing interests: None declared. |
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| Contributed Indexing: | Keywords: costimulatory and inhibitory T-cell receptors; dendritic cells; immunotherapy; programmed cell death 1 receptor; tumor microenvironment |
| Substance Nomenclature: | 0 (Immune Checkpoint Inhibitors); 0 (Programmed Cell Death 1 Receptor) |
| Entry Date(s): | Date Created: 20200722 Date Completed: 20210920 Latest Revision: 20240731 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC7371367 |
| DOI: | 10.1136/jitc-2020-000588 |
| PMID: | 32690667 |
| Database: | MEDLINE |
Journal Article; Research Support, Non-U.S. Gov't