{
  "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.\n\nMethods: 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.\n\nResults: 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.\n\nConclusions: 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.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA",
    "Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA",
    "Department of Immunology, Harvard Medical School Blavatnik Institute, Boston, Massachusetts, USA",
    "Massachusetts Institute of Technology, Cambridge, Massachusetts, USA",
    "Broad Institute, Cambridge, Massachusetts, USA",
    "Division of Population Sciences, Dana-Farber Cancer Institute, Boston, MA, USA",
    "Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA",
    "Department of Obstetrics and Gynecology, University of Washington, Seattle, Washington, USA",
    "Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin, USA",
    "Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada",
    "Genentech Inc, South San Francisco, California, USA",
    "Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA",
    "GC Therapeutics, Cambridge, Massachusetts, USA",
    "NC State University, Raleigh, North Carolina, USA",
    "The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA",
    "Department of Medicine, University of California San Francisco, San Francisco, California, USA",
    "Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA",
    "Reglab, Stanford University, Stanford, California, USA",
    "Harvard Ludwig Center and Laboratory of Systems Pharmacology, Harvard Medical School, Boston, Massachusetts, USA",
    "Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA",
    "Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA",
    "Cancer Center, Massachusetts General Hospital, Boston, Massachusetts, USA",
    "Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA",
    "Department of Pediatrics, Dana Farber Cancer Institute, Boston, Massachusetts, USA",
    "Arsenal Biosciences Inc, South San Francisco, California, USA",
    "Gene Lay Institute of Immunology and Inflammation, Brigham and Women’s Hospital, Boston, Massachusetts, USA",
    "Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA",
    "Department of Medicine, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA",
    "Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA",
    "Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 25,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Matthew P Zimmerman",
      "orcid": "0000-0002-2979-9624"
    },
    {
      "affs": [
        2,
        3,
        4,
        5
      ],
      "name": "Amy Y Huang"
    },
    {
      "affs": [
        1
      ],
      "name": "Emily K Cox"
    },
    {
      "affs": [
        6,
        7
      ],
      "name": "Rose Al Abosy"
    },
    {
      "affs": [
        1
      ],
      "name": "Wan Lin Chong",
      "orcid": "0009-0008-9180-195X"
    },
    {
      "affs": [
        1
      ],
      "name": "Alexander G Bastian"
    },
    {
      "affs": [
        1,
        8
      ],
      "name": "Katherine Vietor"
    },
    {
      "affs": [
        2,
        9
      ],
      "name": "Yacine A Choutri"
    },
    {
      "affs": [
        2,
        10
      ],
      "name": "Jenna L Collier"
    },
    {
      "affs": [
        1
      ],
      "name": "Vasyl Zhabotynsky",
      "orcid": "0000-0003-1575-5732"
    },
    {
      "affs": [
        1,
        11
      ],
      "name": "Haiyang Wang"
    },
    {
      "affs": [
        2,
        12
      ],
      "name": "Megan Fung"
    },
    {
      "affs": [
        1,
        13
      ],
      "name": "Siddharth Maruvada"
    },
    {
      "affs": [
        1,
        14
      ],
      "name": "Pristine C Onuoha"
    },
    {
      "affs": [
        2,
        15
      ],
      "name": "Sarah A Weiss"
    },
    {
      "affs": [
        16,
        17
      ],
      "name": "Emily J Robitschek"
    },
    {
      "affs": [
        18,
        19
      ],
      "name": "Jia-Ren Lin"
    },
    {
      "affs": [
        18,
        19
      ],
      "name": "Tuulia Vallius"
    },
    {
      "affs": [
        18,
        19
      ],
      "name": "Shishir M Pant",
      "orcid": "0000-0002-2686-7898"
    },
    {
      "affs": [
        18,
        19
      ],
      "name": "Peter K Sorger"
    },
    {
      "affs": [
        20
      ],
      "name": "Willy Hugo",
      "orcid": "0000-0002-1426-7190"
    },
    {
      "affs": [
        2,
        4,
        21,
        22
      ],
      "name": "Debattama R Sen",
      "orcid": "0000-0002-0947-8284"
    },
    {
      "affs": [
        4,
        23,
        24
      ],
      "name": "W Nicholas Haining"
    },
    {
      "affs": [
        2,
        4,
        25,
        26
      ],
      "name": "Arlene H Sharpe"
    },
    {
      "affs": [
        1,
        2,
        16,
        27,
        28,
        29
      ],
      "name": "Brian C Miller",
      "orcid": "0000-0001-5931-4184"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/4vbahve07xndb.bib",
  "cited_by": 0,
  "doi": "10.1136/jitc-2026-015096",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13735362/",
  "id": "4vbahve07xndb",
  "issns": [
    "2051-1426"
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  "landing_url": "https://doi.org/10.1136/jitc-2026-015096",
  "language": "en",
  "licence": "CC-BY-NC-4.0",
  "licence_label": "CC BY-NC 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "1506"
    ],
    [
      "heading",
      "Basic and Translational Cancer Immunology"
    ],
    [
      "heading",
      "Original Research"
    ],
    [
      "openalex",
      "2730|Cancer Immunotherapy and Biomarkers"
    ]
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  "openalex": "W7128366618",
  "pdf_url": "https://jitc.bmj.com/content/14/11/e015096.full.pdf",
  "pmcid": "PMC13735362",
  "pmid": "42982509",
  "published": "2026-11-04",
  "publisher": "BMJ Publishing Group",
  "ris": "https://research.draconitic.com/paper/4vbahve07xndb.ris",
  "sources": [
    {
      "first_seen": "2026-11-09T12:21:03Z",
      "native_id": "PMC13735362",
      "source": "pmc",
      "url": "https://doi.org/10.1136/jitc-2026-015096"
    }
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  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2730|Cancer Immunotherapy and Biomarkers",
      "subfield": "oncology"
    }
  ],
  "title": "Harnessing inflammatory monocytes to overcome resistance to anti-PD-1 immunotherapy",
  "title_text": "Harnessing inflammatory monocytes to overcome resistance to anti-PD-1 immunotherapy",
  "type": "peer-reviewed",
  "updated_at": "2026-11-09T12:21:03Z",
  "url": "https://research.draconitic.com/paper/4vbahve07xndb",
  "venue": "Journal for Immunotherapy of Cancer",
  "versions": []
}