Regulatory T-cell Depletion Alters the Tumor Microenvironment and Accelerates Pancreatic Carcinogenesis
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Abstract
Regulatory T cells (Treg) are abundant in human and mouse pancreatic cancer. To understand the contribution to the immunosuppressive microenvironment, we depleted Tregs in a mouse model of pancreatic cancer. Contrary to our expectations, Treg depletion failed to relieve immunosuppression and led to accelerated tumor progression. We show that Tregs are a key source of TGFβ ligands and, accordingly, their depletion reprogramed the fibroblast population, with loss of tumor-restraining, smooth muscle actin–expressing fibroblasts. Conversely, we observed an increase in chemokines Ccl3, Ccl6, and Ccl8 leading to increased myeloid cell recruitment, restoration of immune suppression, and promotion of carcinogenesis, an effect that was inhibited by blockade of the common CCL3/6/8 receptor CCR1. Further, Treg depletion unleashed pathologic CD4+ T-cell responses. Our data point to new mechanisms regulating fibroblast differentiation in pancreatic cancer and support the notion that fibroblasts are a heterogeneous population with different and opposing functions in pancreatic carcinogenesis. Significance: Here, we describe an unexpected cross-talk between Tregs and fibroblasts in pancreatic cancer. Treg depletion resulted in differentiation of inflammatory fibroblast subsets, in turn driving infiltration of myeloid cells through CCR1, thus uncovering a potentially new therapeutic approach to relieve immunosuppression in pancreatic cancer. See related commentary by Aykut et al., p. 345. This article is highlighted in the In This Issue feature, p. 327
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The positive effect of Tregs depletion (increase in CD8+ T cells) was negated by an increase in other CD4+ Th cells, immunosuppressive myeloid cells, and fibroblast populations, ultimately failing to inhibit tumor growth.
“Additionally, this study analyzed tissue levels and found that the positive effect of Tregs depletion, which results in an increase in CD8+ T cells, was negated by an increase in other CD4+ Th cells, immunosuppressive myeloid cells, and fibroblast populations, ultimately failing to inhibit tumor growth [116, 131] (Fig. 2E).”
From Potential anti-tumor effects of regulatory T cells in the tumor microenvironment: a review (2024) · cites this paper as [116]
The Results sections on immune cells and CD4+ T cells report a modest CD8+ T-cell increase, increased suppressive myeloid cells and other CD4+ T cells after Treg depletion. The late-stage disease Results report continued tumor growth despite increased CD8+ T cells. However, the fibroblast Results explicitly report no increase in total fibroblast numbers; the population was reprogrammed, with fewer SMA+ fibroblasts. (LLM, conf=0.88)
Experimental — accuracy not yet measuredOther T cell populations in the PDAC TME, including Th17, Th22, CD4, and γδ T cells, play protumorigenic roles.
“Other T cell populations within the TME have all been noted to play protumorigenic roles, including Th17, Th22, CD4, and γδ T cells188–191”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [191]
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Pancreatic cancer: Advances and challenges
Halbrook, C. J., Lyssiotis, C. A., Pasca di Magliano, M., & Maitra, A. (2023) · Cell · doi:10.1016/j.cell.2023.02.014 · Cited by 1,321 · see citing works
Self-citationDiversity and biology of cancer-associated fibroblasts
Biffi, G., & Tuveson, D. A. (2021) · Physiological Reviews · doi:10.1152/physrev.00048.2019 · Cited by 1,265 · see citing works
Targeting TGF-β signal transduction for fibrosis and cancer therapy
Peng, D., Fu, M., Wang, M., Wei, Y., & Wei, X. (2022) · Molecular Cancer · doi:10.1186/s12943-022-01569-x · Cited by 1,106 · see citing works
Li, C., Jiang, P., Wei, S., Xu, X., & Wang, J. (2020) · Molecular Cancer · doi:10.1186/s12943-020-01234-1 · Cited by 935 · see citing works
Multimodal mapping of the tumor and peripheral blood immune landscape in human pancreatic cancer
Steele, N. G., Carpenter, E. S., Kemp, S. B., Sirihorachai, V. R., The, S., Delrosario, L., Lazarus, J., Amir, E.-A. D., Gunchick, V., Espinoza, C. E., et al. (2020) · Nature Cancer · doi:10.1038/s43018-020-00121-4 · Cited by 546 · see citing works
Self-citationHuang, H., Wang, Z., Zhang, Y., Pradhan, R. N., Ganguly, D., Chandra, R., Murimwa, G., Wright, S., Gu, X., Maddipati, R., et al. (2022) · Cancer Cell · doi:10.1016/j.ccell.2022.04.011 · Cited by 542 · see citing works
Self-citationSpeiser, D. E., Chijioke, O., Schaeuble, K., & Münz, C. (2023) · Nature Cancer · doi:10.1038/s43018-023-00521-2 · Cited by 486 · see citing works
Tumor Microenvironment in Pancreatic Cancer Pathogenesis and Therapeutic Resistance
Sherman, M. H., & Beatty, G. L. (2022) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathmechdis-031621-024600 · Cited by 481 · see citing works
Wang, S., Zheng, Y., Yang, F., Zhu, L., Zhu, X.-Q., Wang, Z.-F., Wu, X.-L., Zhou, C.-H., Yan, J.-Y., Hu, B.-Y., et al. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00659-4 · Cited by 369 · see citing works
Cell death in pancreatic cancer: from pathogenesis to therapy
Chen, X., Zeh, H. J., Kang, R., Kroemer, G., & Tang, D. (2021) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-021-00486-6 · Cited by 338 · see citing works
Inhibition of Hedgehog Signaling Alters Fibroblast Composition in Pancreatic Cancer
Steele, N. G., Biffi, G., Kemp, S. B., Zhang, Y., Drouillard, D., Syu, L.-J., Yuan, H., Oni, T. E., Brosnan, E., Elyada, E., et al. (2021) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-20-3715 · Cited by 289 · see citing works
Self-citationRelevance of immune cell and tumor microenvironment imaging in the new era of immunotherapy
Galli, F., Aguilera, J. V., Palermo, B., Markovic, S. N., Nisticò, P., & Signore, A. (2020) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-020-01586-y · Cited by 281 · see citing works
The Immune Microenvironment in Pancreatic Cancer
Huber, M., Brehm, C. U., Gress, T. M., Buchholz, M., Alhamwe, B. A., von Strandmann, E. P., Slater, E. P., Bartsch, J. W., Bauer, C. A., & Lauth, M. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21197307 · Cited by 243 · see citing works
Helms, E. J., Berry, M. W., Chaw, R. C., DuFort, C. C., Sun, D., Onate, M. K., Oon, C., Bhattacharyya, S., Sanford-Crane, H., Horton, W., et al. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-0601 · Cited by 238 · see citing works
Metabolic networks in mutant KRAS-driven tumours: tissue specificities and the microenvironment
Kerk, S. A., Papagiannakopoulos, T. Y., Shah, Y. M., & Lyssiotis, C. A. (2021) · Nature reviews. Cancer · doi:10.1038/s41568-021-00375-9 · Cited by 238 · see citing works
Self-citationCurrent 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
Chen, K., Wang, Q., Li, M., Guo, H., Liu, W., Wang, F., Tian, X., & Yang, Y. (2020) · EBioMedicine · doi:10.1016/j.ebiom.2021.103315 · Cited by 230 · see citing works
Stump, C. T., & Dougan, S. K. (2024) · Cancer Cell · doi:10.1016/j.ccell.2024.11.011 · Cited by 219 · see citing works
EGFR-activated myofibroblasts promote metastasis of pancreatic cancer
Mucciolo, G., Henríquez, J. A., Jihad, M., Teles, S. P., Manansala, J. S., Li, W., Ashworth, S., Lloyd, E. G., Cheng, P. S. W., Luo, W., et al. (2023) · Cancer Cell · doi:10.1016/j.ccell.2023.12.002 · Cited by 215 · see citing works
Regulation and modulation of antitumor immunity in pancreatic cancer
Leinwand, J., & Miller, G. (2020) · Nature Immunology · doi:10.1038/s41590-020-0761-y · Cited by 205 · see citing works
Context-Specific Determinants of the Immunosuppressive Tumor Microenvironment in Pancreatic Cancer
Falcomatà, C., Bärthel, S., Schneider, G., Rad, R., Schmidt‐Supprian, M., & Saur, D. (2023) · Cancer Discovery · doi:10.1158/2159-8290.cd-22-0876 · Cited by 213 · see citing works
Targeting CAFs to overcome anticancer therapeutic resistance
Saw, P. E., Chen, J., & Song, E. (2022) · Trends in cancer · doi:10.1016/j.trecan.2022.03.001 · Cited by 198 · see citing works
Regulatory T Cells: Barriers of Immune Infiltration Into the Tumor Microenvironment
Scott, E., Gocher, A., Workman, C., & Vignali, D. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.702726 · Cited by 174 · see citing works
GDF15 induces immunosuppression via CD48 on regulatory T cells in hepatocellular carcinoma
Wang, Z., He, L., Li, W., Xu, C., Zhang, J., Wang, D., Dou, K., Zhuang, R., Jin, B., Zhang, W., et al. (2021) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2021-002787 · Cited by 180 · see citing works
Self-citationInterferon-stimulated neutrophils as a predictor of immunotherapy response
Benguigui, M., Cooper, T. J., Kalkar, P., Schif‐Zuck, S., Halaban, R., Bacchiocchi, A., Kamer, I., Deo, A., Manobla, B., Rottem, M., et al. (2024) · Cancer Cell · doi:10.1016/j.ccell.2023.12.005 · Cited by 168 · see citing works
Barriers and opportunities in pancreatic cancer immunotherapy
Ju, Y., Xu, D., Liao, M.-M., Sun, Y., Bao, W.-D., Yao, F., & Ma, L. (2024) · npj Precision Oncology · doi:10.1038/s41698-024-00681-z · Cited by 167 · see citing works
Metabolic reprogramming and immune evasion: the interplay in the tumor microenvironment
Zhang, H., Li, S., Wang, D., Liu, S. M., Xiao, T., Gu, W., Yang, H., Wang, H. Z., Yang, M., & Chen, P. (2024) · Biomarker Research · doi:10.1186/s40364-024-00646-1 · Cited by 169 · see citing works
Carpenter, E. S., Elhossiny, A. M., Kadiyala, P., Li, J., McGue, J. J., Griffith, B. D., Zhang, Y., Edwards, J., Nelson, S., Lima, F., et al. (2023) · Cancer Discovery · doi:10.1158/2159-8290.cd-23-0013 · Cited by 152 · see citing works
Self-citationThe biological underpinnings of therapeutic resistance in pancreatic cancerPreprint
Beatty, G. L., Werba, G., Lyssiotis, C. A., & Simeone, D. M. (2021) · Genes & Development · doi:10.1101/gad.348523.121 · Cited by 133 · see citing works
Self-citationPancreatic cancer is marked by complement-high blood monocytes and tumor-associated macrophages
Kemp, S. B., Steele, N. G., Carpenter, E. S., Donahue, K. L., Bushnell, G. G., Morris, A. H., The, S., Orbach, S. M., Sirihorachai, V. R., Nwosu, Z. C., et al. (2021) · Life Science Alliance · doi:10.26508/lsa.202000935 · Cited by 129 · see citing works
Self-citationBelle, J. I., Sen, D., Baer, J. M., Liu, X., Lander, V. E., Ye, J., Sells, B. E., Knolhoff, B. L., Ahmad, F. F., Kang, L., et al. (2024) · Cancer Discovery · doi:10.1158/2159-8290.cd-23-0428 · Cited by 123 · see citing works
Turning cold into hot: emerging strategies to fire up the tumor microenvironment
Ma, K., Wang, L., Li, W., Tang, T., Ma, B., Zhang, L., & Zhang, L. (2024) · Trends in cancer · doi:10.1016/j.trecan.2024.11.011 · Cited by 121 · see citing works
Epithelial and stromal co-evolution and complicity in pancreatic cancer
Hingorani, S. R. (2023) · Nature Reviews Cancer · doi:10.1038/s41568-022-00530-w · Cited by 108 · see citing works
Lee, B. Y., Hogg, E. K. J., Below, C., Kononov, A., Blanco‐Gómez, A., Heider, F., Xu, J., Hutton, C., Zhang, X. M., Scheidt, T., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-27607-8 · Cited by 112 · see citing works
Pancreatic cancer tumor microenvironment is a major therapeutic barrier and target
Hartupee, C. D., Nagalo, B. M., Chabu, C. Y., Tesfay, M. Z., Coleman‐Barnett, J., West, J. T., & Moaven, O. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1287459 · Cited by 109 · see citing works
Truong, L.-H., & Pauklin, S. (2021) · Cancers · doi:10.3390/cancers13195028 · Cited by 102 · see citing works
Potential anti-tumor effects of regulatory T cells in the tumor microenvironment: a review
Li, Y., Zhang, C., Jiang, A., Lin, A., Liu, Z., Cheng, X., Wang, W., Cheng, Q., Zhang, J., Wei, T., et al. (2024) · Journal of Translational Medicine · doi:10.1186/s12967-024-05104-y · Cited by 105 · see citing works
“Depletion of Tregs in pancreatic cancer resulted in an increase in CD4 + T cells and accelerated oncogenesis [115, 116].”
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The impact of hypoxia on immune state in cancer
Mortezaee, K., & Majidpoor, J. (2021) · Life Sciences · doi:10.1016/j.lfs.2021.120057 · Cited by 100 · see citing works
Vaish, U., Jain, T., Are, A. C., & Dudeja, V. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222413408 · Cited by 94 · see citing works
Zhu, Y.-H., Zheng, J.-H., Jia, Q.-Y., Duan, Z., Yao, H., Yang, J., Sun, Y., Jiang, S.-H., Liu, D., & Huo, Y. (2022) · Cellular Oncology · doi:10.1007/s13402-022-00741-1 · Cited by 96 · see citing works
Peran, I., Dakshanamurthy, S., McCoy, M., Mavropoulos, A., Allo, B. A., Sebastian, A., Hum, N. R., Sprague, S. C., Martin, K. A., Pishvaian, M. J., et al. (2020) · Gastroenterology · doi:10.1053/j.gastro.2020.11.044 · Cited by 93 · see citing works
Gupta, V. K., Sharma, N., Durden, B. C., Garrido, V. T., Kesh, K., Edwards, D., Wang, D., Myer, C., Mateo-Victoriano, B., Kollala, S. S., et al. (2021) · Cancer Research · doi:10.1158/0008-5472.can-20-2562 · Cited by 94 · see citing works
Current Limitations and Novel Perspectives in Pancreatic Cancer Treatment
Robatel, S., & Schenk, M. (2022) · Cancers · doi:10.3390/cancers14040985 · Cited by 91 · see citing works
Trials and tribulations of pancreatic cancer immunotherapy
Principe, D. R., Korc, M., Kamath, S. D., Munshi, H. G., & Rana, A. (2021) · Cancer Letters · doi:10.1016/j.canlet.2021.01.031 · Cited by 90 · see citing works
TGFβ Signaling in the Pancreatic Tumor Microenvironment
Principe, D. R., Timbers, K. E., Atia, L. G., Koch, R. M., & Rana, A. (2021) · Cancers · doi:10.3390/cancers13205086 · Cited by 86 · see citing works
Picard, F. S. R., Lutz, V., Brichkina, A. I., Neuhaus, F., Ruckenbrod, T., Hupfer, A., Raifer, H., Klein, M., Bopp, T., Pfefferle, P. I., et al. (2023) · Gut · doi:10.1136/gutjnl-2022-327855 · Cited by 86 · see citing works
Nicheformer: a foundation model for single-cell and spatial omics
Tejada-Lapuerta, A., Schaar, A. C., Gutgesell, R., Palla, G., Halle, L., Minaeva, M., Vornholz, L., Dony, L., Drummer, F., Richter, T., et al. (2025) · Nature Methods · doi:10.1038/s41592-025-02814-z · Cited by 100 · see citing works
Regulatory T-Cells as an Emerging Barrier to Immune Checkpoint Inhibition in Lung Cancer
Principe, D. R., Chiec, L. S., Mohindra, N. A., & Munshi, H. G. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.684098 · Cited by 82 · see citing works
Chen, P., Wei, W.-F., Wu, H.-Z., Fan, L., & Wang, W. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.671595 · Cited by 78 · see citing works
Treg–tissue cell interactions in repair and regeneration
Loffredo, L. F., Savage, T. M., Ringham, O. R., & Arpaia, N. (2024) · The Journal of Experimental Medicine · doi:10.1084/jem.20231244 · Cited by 79 · see citing works
Therapeutic strategies to remodel immunologically cold tumors
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Liu, H., Shi, Y., & Qian, F. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2021.02.012 · Cited by 77 · see citing works
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Epigenetics in modulating immune functions of stromal and immune cells in the tumor microenvironment
Pan, X., & Zheng, L. (2020) · Cellular and Molecular Immunology · doi:10.1038/s41423-020-0505-9 · Cited by 75 · see citing works
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Wang, Y., Li, J., Nakahata, S., & Iha, H. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25137346 · Cited by 73 · see citing works
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Luo, W., Wen, T., & Qu, X. (2024) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-023-02935-3 · Cited by 68 · see citing works
Hilmi, M., Delaye, M., Muzzolini, M., Nicolle, R., Cros, J. F., Hammel, P. R., Cardot‐Ruffino, V., & Neuzillet, C. (2023) · The Lancet. Gastroenterology & hepatology · doi:10.1016/s2468-1253(23)00207-8 · Cited by 71 · see citing works
Endogenous Stimuli‐Activatable Nanomedicine for Immune Theranostics for Cancer
Wang, W., Jin, Y., Liu, X., Chen, F., Zheng, X., Liu, T., Yang, Y., & Yu, H. (2021) · Advanced Functional Materials · doi:10.1002/adfm.202100386 · Cited by 65 · see citing works
Immunotherapy in Pancreatic Adenocarcinoma: Beyond “Copy/Paste”
Hester, R., Mazur, P. K., & McAllister, F. (2021) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-18-0900 · Cited by 65 · see citing works
WNT signaling in the tumor microenvironment promotes immunosuppression in murine pancreatic cancer
Du, W., Menjivar, R. E., Donahue, K. L., Kadiyala, P., Velez-Delgado, A., Brown, K. L., Watkoske, H. R., He, X., Carpenter, E. S., Angeles, C. V., et al. (2022) · The Journal of Experimental Medicine · doi:10.1084/jem.20220503 · Cited by 65 · see citing works
Self-citationType I conventional dendritic cells facilitate immunotherapy in pancreatic cancer
Mahadevan, K. K., Dyevoich, A. M., Chen, Y., Li, B., Sugimoto, H., Sockwell, A. M., McAndrews, K. M., Sthanam, L. K., Wang, H., Shalapour, S., et al. (2024) · Science · doi:10.1126/science.adh4567 · Cited by 68 · see citing works
The tumour microenvironment in pancreatic cancer — new clinical challenges, but more opportunities
Kung, H., Zheng, K., Zimmerman, J. W., & Zheng, L. (2025) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-025-01077-z · Cited by 69 · see citing works
Targeting Tumor-Stromal Interactions in Pancreatic Cancer: Impact of Collagens and Mechanical Traits
Maneshi, P., Mason, J. E., Dongre, M., & Öhlund, D. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.787485 · Cited by 65 · see citing works
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Herting, C. J., Karpovsky, I., & Lesinski, G. B. (2021) · Cancer and Metastasis Reviews · doi:10.1007/s10555-021-09988-w · Cited by 61 · see citing works
Boucher, Y., Posada, J. M., Subudhi, S., Kumar, A. S., Rosario, S. R., Gu, L., Kumra, H., Mino-Kenudson, M. A., Talele, N. P., Duda, D. G., et al. (2023) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-22-1630 · Cited by 60 · see citing works
The Multifaceted Role of Regulatory T Cells in Breast Cancer
Kos, K., & de Visser, K. E. (2021) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-042920-104912 · Cited by 58 · see citing works
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Donahue, K. L., Watkoske, H. R., Kadiyala, P., Du, W., Brown, K. L., Scales, M. K., Elhossiny, A. M., Espinoza, C. E., Opsahl, E. L. L., Griffith, B. D., et al. (2024) · Cancer Discovery · doi:10.1158/2159-8290.cd-24-0100 · Cited by 58 · see citing works
Self-citationThe tumor microenvironment is an ecosystem sustained by metabolic interactions
Kay, E. J., & Zanivan, S. R. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.115432 · Cited by 60 · see citing works
Multimodal single cell-resolved spatial proteomics reveal pancreatic tumor heterogeneity
Xu, Y., Wang, X., Li, Y., Mao, Y., Su, Y., Mao, Y., Yang, Y., Gao, W., Fu, C., Chen, W., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-54438-0 · Cited by 61 · see citing works
Boyer, S., Lee, H.-J., Steele, N., Zhang, L., Sajjakulnukit, P., Andren, A., Ward, M. H., Singh, R., Basrur, V., Zhang, Y., et al. (2022) · eLife · doi:10.7554/elife.73796 · Cited by 56 · see citing works
Self-citationMyeloid Cell Mediated Immune Suppression in Pancreatic Cancer
Kemp, S. B., di Magliano, M. P., & Crawford, H. C. (2021) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2021.07.006 · Cited by 55 · see citing works
Self-citationImmune checkpoint blockade in pancreatic cancer: Trudging through the immune desert
Li, X., Gulati, M., Larson, A. C., Solheim, J. C., Jain, M., Sushil Kumar, K., & Batra, S. K. (2022) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2022.08.009 · Cited by 56 · see citing works
Li, Y., Xiang, S., Pan, W., Wang, J., Zhan, H., & Liu, S. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1166860 · Cited by 58 · see citing works
Sivakumar, S., Abu‐Shah, E., Ahern, D., Arbe-Barnes, E. H., Jainarayanan, A., Mangal, N., Reddy, S., Rendek, A., Easton, A., Kurz, E., et al. (2021) · Cancers · doi:10.3390/cancers13081776 · Cited by 56 · see citing works
Loss of Rnf31 and Vps4b sensitizes pancreatic cancer to T cell-mediated killing
Frey, N., Tortola, L., Egli, D., Janjuha, S., Rothgangl, T., Marquart, K. F., Ampenberger, F., Köpf, M., & Schwank, G. (2022) · Nature Communications · doi:10.1038/s41467-022-29412-3 · Cited by 57 · see citing works
NF-κB and Pancreatic Cancer; Chapter and Verse
Silke, J., & O’Reilly, L. A. (2021) · Cancers · doi:10.3390/cancers13184510 · Cited by 55 · see citing works
Tang, Y., Cui, G., Liu, H., Han, Y., Cai, C., Feng, Z., Shen, H., & Zeng, S. (2024) · 癌症：英文版 · doi:10.1002/cac2.12546 · Cited by 56 · see citing works
Mechanisms Governing Immunotherapy Resistance in Pancreatic Ductal Adenocarcinoma
Schmiechen, Z. C., & Stromnes, I. M. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2020.613815 · Cited by 53 · see citing works
Cytokines chattering in pancreatic ductal adenocarcinoma tumor microenvironment
Bhatia, R., Bhyravbhatla, N., Kisling, A., Li, X., Batra, S. K., & Sushil Kumar, K. (2022) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2022.03.021 · Cited by 52 · see citing works
Regulatory T cell heterogeneity and therapy in autoimmune diseases
Zhang, R., Miao, J., & Zhu, P. (2020) · Autoimmunity Reviews · doi:10.1016/j.autrev.2020.102715 · Cited by 52 · see citing works
Ye, Y., Zhang, R., & Feng, H. (2020) · Cell Biology International · doi:10.1002/cbin.11390 · Cited by 51 · see citing works
Role of the Tumor Microenvironment in Regulating Pancreatic Cancer Therapy Resistance
Deng, D., Patel, R. H., Chiang, C.-Y., & Hou, P. (2022) · Cells · doi:10.3390/cells11192952 · Cited by 50 · see citing works
Metabolic reprogramming of T regulatory cells in the hypoxic tumor microenvironment
Nair, V. S., Saleh, R., Toor, S. M., Cyprian, F. S., & Elkord, E. (2021) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-020-02842-y · Cited by 49 · see citing works
The inhibitory effect of adenosine on tumor adaptive immunity and intervention strategies
Wang, L., Zhang, J., Zhang, W., Zheng, M., Guo, H., Pan, X., Li, W., Yang, B., & Ding, L. (2023) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2023.12.004 · Cited by 53 · see citing works
Pancreatic Fibroblast Heterogeneity: From Development to Cancer
Garcia, P. E., Scales, M. K., Allen, B. L., & di Magliano, M. P. (2020) · Cells · doi:10.3390/cells9112464 · Cited by 46 · see citing works
Advance in the role of chemokines/chemokine receptors in carcinogenesis: Focus on pancreatic cancer
Song, N., Cui, K., Zeng, L., Li, M., Fan, Y., Shi, P., Wang, Z., Su, W., & Wang, H. (2024) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2024.176357 · Cited by 48 · see citing works
Recent advances in the role of Th17/Treg cells in tumor immunity and tumor therapy
Qianmei, Y., Su, Z., Wang, G., Li, H., & Lian, G. (2021) · Immunologic Research · doi:10.1007/s12026-021-09211-6 · Cited by 48 · see citing works
Immunocytes in the tumor microenvironment: recent updates and interconnections
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- Authors
- Zhang, Y., Lazarus, J., Steele, N. G., Yan, W., Lee, H.-J., Nwosu, Z. C., Halbrook, C. J., Menjivar, R. E., Kemp, S. B., Sirihorachai, V. R., Velez-Delgado, A., Donahue, K., Carpenter, E. S., Brown, K. L., Irizarry-Negron, V., Nevison, A. C., Vinta, A., Anderson, M. A., Crawford, H. C., Lyssiotis, C. A., Frankel, T. L., Bednar, F., & Pasca di Magliano, M.
- Affiliations
- University of Michigan (US)
- 1Department of Surgery, University of Michigan, Ann Arbor, Michigan.
- Corresponding author
- Zhang, Yaqing
- Bednar, Filip
- ORCID
- Zhang, Yaqing
- Lazarus, Jenny
- Steele, Nina G.
- Yan, Wei
- Lee, Ho-Joon
- Nwosu, Zeribe C.
- Halbrook, Christopher J.
- Menjivar, Rosa E.
- Kemp, Samantha B.
- Sirihorachai, Veerin R.
- Velez-Delgado, Ashley
- Donahue, Katelyn
- Carpenter, Eileen S.
- Brown, Kristee L.
- Irizarry-Negron, Valerie
- Anderson, Michelle A.
- Crawford, Howard C.
- Lyssiotis, Costas A.
- Frankel, Timothy L.
- Bednar, Filip
- Pasca di Magliano, Marina
- Venue
- Cancer Discovery
- Published
- 2020-03-01
- Volume
- 10
- Issue
- 3
- Pages
- 422-439
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC7224338
- OpenAlex
- W3000274143
- Cited by
- 385
- References
- 73
- Citations by year
- 2026: 34 · 2025: 49 · 2024: 73 · 2023: 62 · 2022: 66 · 2021: 70 · 2020: 30
- FWCI
- 20.58
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- HHS | NIH | National Cancer Institute (R01CA151588, R01CA198074, U01CA224145, P30CA046592, R50CA232985, 3-P30-CA-046592-28-S2, K08CA201581, T32-CA009676)
- American Cancer Society (Postdoctoral Award)
- University of Michigan Medical School (Michigan Postdoctoral Pioneer Program)
- HHS | NIH | National Institute of General Medical Sciences (T32-GM007315, T32-GM113900)
- Horace H. Rackham School of Graduate Studies, University of Michigan (Rackham Merit Fellowship)
- Association of Academic Surgery (Joel Roslyn Award)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- regulatory T cells, Treg depletion, pancreatic cancer, tumor microenvironment, immunosuppression, TGF-beta, cancer-associated fibroblasts, CCR1, myeloid cell recruitment, CD4+ T cells, pancreatic carcinogenesis, tumor progression
- MeSH terms
- Animals, Disease Models, Animal, Fibroblasts, Humans, Pancreas, Pancreatic Neoplasms, Transforming Growth Factor beta, Chemokines, CC, T-Lymphocytes, Regulatory, Mice, Receptors, CCR1, Chemokine CCL3, Chemokine CCL8, Tumor Microenvironment, Carcinogenesis
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