CD40 stimulation obviates innate sensors and drives T cell immunity in cancer

Byrne, Katelyn T.; Vonderheide, Robert H.

doi:10.1016/j.celrep.2016.05.058

Cited by 283Cancer Immunotherapy and BiomarkersImmunotherapy and Immune ResponsesT-cell and B-cell Immunology

CD40 stimulation obviates innate sensors and drives T cell immunity in cancer

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Byrne, Katelyn T., Vonderheide, Robert H.·2016·Cell Reports

DOI 10.1016/j.celrep.2016.05.058PMC PMC4917417

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Abstract

Cancer immunotherapies are more effective in tumors with robust T cell infiltrates, but mechanisms to convert T cell-devoid tumors with active immunosuppression to those capable of recruiting T cells remain incompletely understood. Here, using genetically engineered mouse models of pancreatic ductal adenocarcinoma (PDA), we demonstrate that a single dose of agonistic CD40 antibody with chemotherapy rendered PDA susceptible to T cell-dependent destruction and potentiated durable remissions. CD40 stimulation caused a clonal expansion of T cells in the tumor, but the addition of chemotherapy optimized myeloid activation and T cell function. Although recent data highlight the requirement for innate sensors in cancer immunity, these canonical pathways-including TLRs, inflammasome, and type I interferon/STING-played no role in mediating the efficacy of CD40 and chemotherapy. Thus, CD40 functions as a non-redundant mechanism to convert the tumor microenvironment immunologically. Our data provide a rationale for a newly initiated clinical trial of CD40 and chemotherapy in PDA.

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Dendritic cells are found in low numbers in PDAC compared with other tumor types, and the DCs present are of poor quality for antigen presentation.
“Dendritic cells (DCs) are found in low numbers in PDAC, as compared to other tumor types, and the DCs present are of poor quality for antigen presentation186”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [186]

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Fundamental Mechanisms of Immune Checkpoint Blockade Therapy
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Challenges and Opportunities for Pancreatic Cancer Immunotherapy
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Combination Cancer Therapy with Immune Checkpoint Blockade: Mechanisms and Strategies
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Immunotherapy and Prevention of Pancreatic Cancer
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Dendritic Cell Paucity Leads to Dysfunctional Immune Surveillance in Pancreatic Cancer
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Therapeutic developments in pancreatic cancer
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A neutrophil response linked to tumor control in immunotherapy
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Dendritic cells as orchestrators of anticancer immunity and immunotherapy
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Ovarian Cancer Immunotherapy and Personalized Medicine
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Crosstalk between Regulatory T Cells and Tumor-Associated Dendritic Cells Negates Anti-tumor Immunity in Pancreatic Cancer
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Remodeling of the immune and stromal cell compartment by PD-1 blockade in mismatch repair-deficient colorectal cancer
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Harnessing tumor‐associated macrophages as aids for cancer immunotherapy
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CD40 agonistic monoclonal antibody APX005M (sotigalimab) and chemotherapy, with or without nivolumab, for the treatment of metastatic pancreatic adenocarcinoma: an open-label, multicentre, phase 1b study
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Therapeutic targeting of tumour myeloid cells
Barry, S. T., Gabrilovich, D. I., Sansom, O. J., Campbell, A. D., & Morton, J. P. (2023) · Nature Reviews Cancer · doi:10.1038/s41568-022-00546-2 · Cited by 305 · see citing works
Tumour microenvironment of pancreatic cancer: immune landscape is dictated by molecular and histopathological features
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The functional crosstalk between myeloid-derived suppressor cells and regulatory T cells within the immunosuppressive tumor microenvironment
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The Immune Revolution: A Case for Priming, Not Checkpoint
Vonderheide, R. H. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.03.008 · Cited by 294 · see citing works
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The CD155/TIGIT axis promotes and maintains immune evasion in neoantigen-expressing pancreatic cancer
Freed-Pastor, W. A., Lambert, L. J., Ely, Z. A., Pattada, N. B., Bhutkar, A., Eng, G., Mercer, K. L., Garcia, A. P., Lin, L., Rideout, W. M., et al. (2021) · Cancer Cell · doi:10.1016/j.ccell.2021.07.007 · Cited by 273 · see citing works
Antigen cross-presentation and T-cell cross-priming in cancer immunology and immunotherapy
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Cancer therapy with antibodies
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Translational advances in pancreatic ductal adenocarcinoma therapy
Hosein, A. N., Dougan, S. K., Aguirre, A. J., & Maitra, A. (2022) · Nature Cancer · doi:10.1038/s43018-022-00349-2 · Cited by 249 · see citing works
CXCR2-Dependent Accumulation of Tumor-Associated Neutrophils Regulates T-cell Immunity in Pancreatic Ductal Adenocarcinoma
Chao, T., Furth, E. E., & Vonderheide, R. H. (2016) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-16-0188 · Cited by 248 · see citing works
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CD40 Ligand-Modified Chimeric Antigen Receptor T Cells Enhance Antitumor Function by Eliciting an Endogenous Antitumor Response
Kuhn, N. F., Purdon, T. J., van Leeuwen, D. G., Lopez, A. V., Curran, K. J., Daniyan, A. F., & Brentjens, R. J. (2019) · Cancer Cell · doi:10.1016/j.ccell.2019.02.006 · Cited by 245 · see citing works
Current and future immunotherapeutic approaches in pancreatic cancer treatment
Farhangnia, P., Khorramdelazad, H., Nickho, H., & Delbandi, A. (2024) · Journal of Hematology & Oncology · doi:10.1186/s13045-024-01561-6 · Cited by 247 · see citing works
CXCL13 shapes immunoactive tumor microenvironment and enhances the efficacy of PD-1 checkpoint blockade in high-grade serous ovarian cancer
Yang, M., Lu, J., Zhang, G., Wang, Y., He, M., Xu, Q., Xu, C., & Liu, H. (2021) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2020-001136 · Cited by 228 · see citing works
Emerging strategies for combination checkpoint modulators in cancer immunotherapy
Popović, A., Jaffee, E. M., & Zaidi, N. (2018) · Journal of Clinical Investigation · doi:10.1172/jci120775 · Cited by 209 · see citing works
Neoadjuvant Selicrelumab, an agonist CD40 antibody, induces changes in the tumor microenvironment in patients with resectable pancreatic cancer
Byrne, K. T., Betts, C. B., Mick, R., Sivagnanam, S., Bajor, D. L., Laheru, D. A., Chiorean, E. G., O'Hara, M. H., Liudahl, S. M., Newcomb, C., et al. (2021) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-21-1047 · Cited by 199 · see citing works
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Immunobiology of high-grade serous ovarian cancer: lessons for clinical translation
Kandalaft, L. E., Laniti, D. D., & Coukos, G. (2022) · Nature reviews. Cancer · doi:10.1038/s41568-022-00503-z · Cited by 186 · see citing works
Lack of immunoediting in murine pancreatic cancer reversed with neoantigen
Evans, R. A., Diamond, M. S., Rech, A. J., Chao, T., Richardson, M. W., Lin, J., Bajor, D. L., Byrne, K. T., Stanger, B. Z., Riley, J. L., et al. (2016) · JCI Insight · doi:10.1172/jci.insight.88328 · Cited by 180 · see citing works
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Low neoantigen expression and poor T-cell priming underlie early immune escape in colorectal cancer
Westcott, P. M. K., Sacks, N. J., Schenkel, J. M., Ely, Z. A., Smith, O. C. G., Hauck, H., Jaeger, A. M., Zhang, D., Backlund, C. M., Beytagh, M. C., et al. (2021) · Nature Cancer · doi:10.1038/s43018-021-00247-z · Cited by 180 · see citing works
Immune Checkpoint Inhibition for Pancreatic Ductal Adenocarcinoma: Current Limitations and Future Options
Kabacaoğlu, D., Ciecielski, K. J., Ruess, D. A., & Algül, H. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01878 · Cited by 175 · see citing works
Type 1 conventional dendritic cells are systemically dysregulated early in pancreatic carcinogenesis
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Linking macrophage metabolism to function in the tumor microenvironment
Jin, R., Neufeld, L. A., & McGaha, T. L. (2025) · Nature Cancer · doi:10.1038/s43018-025-00909-2 · Cited by 182 · see citing works
Tumor cell–intrinsic EPHA2 suppresses antitumor immunity by regulating PTGS2 (COX-2)
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Tumor Burden and Immunotherapy: Impact on Immune Infiltration and Therapeutic Outcomes
Kim, S. I., Cassella, C. R., & Byrne, K. T. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2020.629722 · Cited by 169 · see citing works
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Combination of CD40 Agonism and CSF-1R Blockade Reconditions Tumor-Associated Macrophages and Drives Potent Antitumor Immunity
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Agonistic CD40 therapy induces tertiary lymphoid structures but impairs responses to checkpoint blockade in glioma
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Cancer immunotherapy: activating innate and adaptive immunity through CD40 agonists
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CD40-mediated immune cell activation enhances response to anti-PD-1 in murine intrahepatic cholangiocarcinoma
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The molecular and functional landscape of resistance to immune checkpoint blockade in melanoma
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Cancer Immunotherapy: Beyond Checkpoint Blockade
Dougan, M. L., Dranoff, G., & Dougan, S. K. (2018) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-030518-055552 · Cited by 147 · see citing works
A Four-Chemokine Signature Is Associated with a T-cell–Inflamed Phenotype in Primary and Metastatic Pancreatic Cancer
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Immune regulation of metastasis: mechanistic insights and therapeutic opportunities
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Epigenetic and Transcriptional Control of the Epidermal Growth Factor Receptor Regulates the Tumor Immune Microenvironment in Pancreatic Cancer
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Trial Watch: Immunomodulatory monoclonal antibodies for oncological indications
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Beyond cDC1: Emerging Roles of DC Crosstalk in Cancer Immunity
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Recent insights into the biology of pancreatic cancer
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CCL5 mediates CD40-driven CD4+ T cell tumor infiltration and immunity
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Targeting Innate Immunity in Cancer Therapy
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Immunotherapy in Pancreatic Cancer: Why Do We Keep Failing? A Focus on Tumor Immune Microenvironment, Predictive Biomarkers and Treatment Outcomes
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Radiotherapy and CD40 Activation Separately Augment Immunity to Checkpoint Blockade in Cancer
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CD40 stimulation as a molecular adjuvant for cancer vaccines and other immunotherapies
Bullock, T. N. J. (2021) · Cellular and Molecular Immunology · doi:10.1038/s41423-021-00734-4 · Cited by 110 · see citing works
Agonistic CD40 Antibodies in Cancer Treatment
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Intratumoral CD40 activation and checkpoint blockade induces T cell-mediated eradication of melanoma in the brain
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Emerging trends in the immunotherapy of pancreatic cancer
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Targeting CDK12 for Cancer Therapy: Function, Mechanism, and Drug Discovery
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Tumor-associated macrophages in pancreatic ductal adenocarcinoma: therapeutic opportunities and clinical challenges
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Consensus, debate, and prospective on pancreatic cancer treatments
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Immune modulation resulting from MR-guided high intensity focused ultrasound in a model of murine breast cancer
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Identification of a novel serum biomarker for pancreatic cancer, C4b-binding protein α-chain (C4BPA) by quantitative proteomic analysis using tandem mass tags
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The interplay between innate and adaptive immunity in cancer shapes the productivity of cancer immunosurveillance
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Cellular determinants and therapeutic implications of inflammation in pancreatic cancer
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Self-citation

Abstract A076: CD40 stimulation overrides role of innate immune sensors for priming of T cells in cancer
Byrne, K. T., & Vonderheide, R. H. (2016) · Cancer Immunology Research · doi:10.1158/2326-6074.cricimteatiaacr15-a076
Self-citation
Abstract IA005: Generating T cell responses against pancreatic cancer
Byrne, K. T. (2022) · Cancer Research · doi:10.1158/1538-7445.panca22-ia005
Self-citation
CD40 immunotherapy for pancreatic cancer
Vonderheide, R. H., Bajor, D. L., Winograd, R., Evans, R. A., Bayne, L. J., & Beatty, G. L. (2013) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-013-1427-5 · Cited by 115 · see citing works
Self-citation
CD40 Agonists Alter Tumor Stroma and Show Efficacy Against Pancreatic Carcinoma in Mice and Humans
Beatty, G. L., Chiorean, E. G., Fishman, M. P., Saboury, B., Teitelbaum, U. R., Sun, W., Huhn, R. D., Song, W., Li, D., Sharp, L. L., et al. (2011) · Science · doi:10.1126/science.1198443 · Cited by 1,678 · see citing works
Self-citation
Abstract PR4: Restoring T cell immuno-surveillance in pancreatic carcinoma using CD40 agonists.
Beatty, G. L., Winograd, R., Evans, R. A., Luque, S. L., Guirnalda, P. D., & Vonderheide, R. H. (2013) · Cancer Research · doi:10.1158/1538-7445.tumimm2012-pr4
Self-citation

Authors: Byrne, K. T., & Vonderheide, R. H.
Affiliations: Abramson Cancer Center (US)
Corresponding author: Vonderheide, Robert H.
ORCID: Byrne, Katelyn T.
Vonderheide, Robert H.
Venue: Cell Reports
Publisher: Elsevier BV
Published: 2016-06
Volume: 15
Issue: 12
Pages: 2719-2732
ISSN: 2211-1247 (ISSN-L)
DOI: 10.1016/j.celrep.2016.05.058
PMC: PMC4917417
OpenAlex: W2418018584
Cited by: 282
References: 74
Citations by year: 2026: 18 · 2025: 26 · 2024: 27 · 2023: 40 · 2022: 31 · 2021: 40 · 2020: 33 · 2019: 27 · 2018: 21 · 2017: 9 · 2016: 8 · 2015: 1
FWCI: 11.67
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by-nc-nd
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
creativecommons.org/licenses/by-nc-nd/4.0/ (vor)
Locations: Cell Reports (publishedVersion, cc-by-nc-nd)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: National Cancer Institute (R01CA169123)
Topics: Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords: CD40 stimulation, pancreatic ductal adenocarcinoma, T cell immunity, innate immune sensors, T cell clonal expansion, combination chemotherapy, tumor microenvironment, myeloid activation, cancer immunotherapy, STING, type I interferon, inflammasome, Toll-like receptors
MeSH terms: Gemcitabine, Albumins, Animals, Antibodies, Antigen-Presenting Cells, Clone Cells, Deoxycytidine, Immunity, Innate, Interferon-gamma, Mice, Inbred C57BL, Neoplasms, Pancreatic Neoplasms, T-Lymphocytes, Lymphocyte Subsets, Treatment Outcome, Paclitaxel, Mice, Knockout, CD8-Positive T-Lymphocytes, CD40 Antigens, Carcinoma, Pancreatic Ductal, Tumor Microenvironment

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CD40 stimulation obviates innate sensors and drives T cell immunity in cancer

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