Harnessing inflammatory monocytes to overcome resistance to anti-PD-1 immunotherapy
30 affiliations
- 1Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
- 2Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
- 3Department of Immunology, Harvard Medical School Blavatnik Institute, Boston, Massachusetts, USA
- 4Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
- 5Broad Institute, Cambridge, Massachusetts, USA
- 6Division of Population Sciences, Dana-Farber Cancer Institute, Boston, MA, USA
- 7Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- 8Department of Obstetrics and Gynecology, University of Washington, Seattle, Washington, USA
- 9Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin, USA
- 10Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada
- 11Genentech Inc, South San Francisco, California, USA
- 12Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- 13GC Therapeutics, Cambridge, Massachusetts, USA
- 14NC State University, Raleigh, North Carolina, USA
- 15The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
- 16Department of Medicine, University of California San Francisco, San Francisco, California, USA
- 17Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- 18Reglab, Stanford University, Stanford, California, USA
- 19Harvard Ludwig Center and Laboratory of Systems Pharmacology, Harvard Medical School, Boston, Massachusetts, USA
- 20Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA
- 21Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
- 22Cancer Center, Massachusetts General Hospital, Boston, Massachusetts, USA
- 23Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA
- 24Department of Pediatrics, Dana Farber Cancer Institute, Boston, Massachusetts, USA
- 25Arsenal Biosciences Inc, South San Francisco, California, USA
- 26Gene Lay Institute of Immunology and Inflammation, Brigham and Women’s Hospital, Boston, Massachusetts, USA
- 27Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA
- 28Department of Medicine, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA
- 29Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- 30Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Abstract
Background: Resistance to immune checkpoint inhibitors (ICIs) represents a major therapeutic challenge, as less than 50% of melanoma patients achieve long-term responses to ICIs. One mechanism of acquired resistance involves loss of genes required for antigen presentation, such as beta-2 microglobulin (B2m), that enable tumor cells to evade T cell-mediated killing.
Methods: This study used single-cell RNA-seq, flow cytometry, and ex vivo functional assays to define the functions of tumor-infiltrating immune cells in antigen presentation-deficient tumors after treatment with anti-PD-1 or CD40 agonist antibodies. Analysis of published human datasets was performed to dissect the contributions of inflammatory monocytes to patient outcomes.
Results: Macrophages with an immunosuppressive phenotype were increased in B2m-null tumors. Treatment with CD40 agonist antibody, which promotes differentiation of monocytes and macrophages toward a pro-inflammatory phenotype, reduced tumor growth and improved survival in B2m-null cancer models. Unexpectedly, both CD8+ T cells and NK cells, but not CD4+ T cells, were required for the efficacy of the CD40 agonist, even though CD8+ T cells cannot directly recognize tumor cells. Instead, these lymphocytes control tumor growth via secretion of IFN-γ, as depletion of IFN-γ inhibited the therapeutic effect of CD40 agonist. IFNγ receptor expression was required on host cells, not tumor cells, for tumor control. Single-cell analysis identified a distinct population of inflammatory monocytes enriched for an IFNγ response signature in CD40 agonist-treated tumors, suggesting these cells may be important for tumor control. Blocking iNOS or tumor necrosis factor ⍺ (TNF⍺), two mechanisms of monocyte-mediated killing, did not inhibit tumor control, and there was no increase in tumor cell phagocytosis by myeloid cells after treatment. However, suppression of TNF-related apoptosis-inducing ligand (TRAIL) signaling in tumor cells partially inhibited the efficacy of CD40 agonist. Analysis of patient datasets demonstrated that an inflammatory monocyte signature was associated with improved outcomes and response to ICI.
Conclusions: These data demonstrate that CD8+ T cells contribute to tumor control even in the absence of direct antigen presentation by tumor cells. More broadly, our work suggests that strategies to activate the effector functions of inflammatory monocytes, such as TRAIL-mediated killing, may limit tumor growth and overcome acquired resistance to ICI.
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BibTeX
@article{zimmerman2026harnessing,
title = {{Harnessing inflammatory monocytes to overcome resistance to anti-PD-1 immunotherapy}},
author = {Matthew P Zimmerman and Amy Y Huang and Emily K Cox and Rose Al Abosy and Wan Lin Chong and Alexander G Bastian and Katherine Vietor and Yacine A Choutri and Jenna L Collier and Vasyl Zhabotynsky and Haiyang Wang and Megan Fung and Siddharth Maruvada and Pristine C Onuoha and Sarah A Weiss and Emily J Robitschek and Jia-Ren Lin and Tuulia Vallius and Shishir M Pant and Peter K Sorger and Willy Hugo and Debattama R Sen and W Nicholas Haining and Arlene H Sharpe and Brian C Miller},
journal = {Journal for Immunotherapy of Cancer},
year = {2026},
month = nov,
doi = {10.1136/jitc-2026-015096},
url = {https://doi.org/10.1136/jitc-2026-015096},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - Harnessing inflammatory monocytes to overcome resistance to anti-PD-1 immunotherapy
AU - Matthew P Zimmerman
AU - Amy Y Huang
AU - Emily K Cox
AU - Rose Al Abosy
AU - Wan Lin Chong
AU - Alexander G Bastian
AU - Katherine Vietor
AU - Yacine A Choutri
AU - Jenna L Collier
AU - Vasyl Zhabotynsky
AU - Haiyang Wang
AU - Megan Fung
AU - Siddharth Maruvada
AU - Pristine C Onuoha
AU - Sarah A Weiss
AU - Emily J Robitschek
AU - Jia-Ren Lin
AU - Tuulia Vallius
AU - Shishir M Pant
AU - Peter K Sorger
AU - Willy Hugo
AU - Debattama R Sen
AU - W Nicholas Haining
AU - Arlene H Sharpe
AU - Brian C Miller
PY - 2026
DA - 2026/11/04
JO - Journal for Immunotherapy of Cancer
DO - 10.1136/jitc-2026-015096
UR - https://doi.org/10.1136/jitc-2026-015096
AB - Background: Resistance to immune checkpoint inhibitors (ICIs) represents a major therapeutic challenge, as less than 50% of melanoma patients achieve long-term responses to ICIs. One mechanism of acquired resistance involves loss of genes required for antigen presentation, such as beta-2 microglobulin (B2m), that enable tumor cells to evade T cell-mediated killing. Methods: This study used single-cell RNA-seq, flow cytometry, and ex vivo functional assays to define the functions of tumor-infiltrating immune cells in antigen presentation-deficient tumors after treatment with anti-PD-1 or CD40 agonist antibodies. Analysis of published human datasets was performed to dissect the contributions of inflammatory monocytes to patient outcomes. Results: Macrophages with an immunosuppressive phenotype were increased in B2m-null tumors. Treatment with CD40 agonist antibody, which promotes differentiation of monocytes and macrophages toward a pro-inflammatory phenotype, reduced tumor growth and improved survival in B2m-null cancer models. Unexpectedly, both CD8+ T cells and NK cells, but not CD4+ T cells, were required for the efficacy of the CD40 agonist, even though CD8+ T cells cannot directly recognize tumor cells. Instead, these lymphocytes control tumor growth via secretion of IFN-γ, as depletion of IFN-γ inhibited the therapeutic effect of CD40 agonist. IFNγ receptor expression was required on host cells, not tumor cells, for tumor control. Single-cell analysis identified a distinct population of inflammatory monocytes enriched for an IFNγ response signature in CD40 agonist-treated tumors, suggesting these cells may be important for tumor control. Blocking iNOS or tumor necrosis factor ⍺ (TNF⍺), two mechanisms of monocyte-mediated killing, did not inhibit tumor control, and there was no increase in tumor cell phagocytosis by myeloid cells after treatment. However, suppression of TNF-related apoptosis-inducing ligand (TRAIL) signaling in tumor cells partially inhibited the efficacy of CD40 agonist. Analysis of patient datasets demonstrated that an inflammatory monocyte signature was associated with improved outcomes and response to ICI. Conclusions: These data demonstrate that CD8+ T cells contribute to tumor control even in the absence of direct antigen presentation by tumor cells. More broadly, our work suggests that strategies to activate the effector functions of inflammatory monocytes, such as TRAIL-mediated killing, may limit tumor growth and overcome acquired resistance to ICI.
SN - 2051-1426
ER -