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Oncolytic virus-mediated reducing of myeloid-derived suppressor cells enhances the efficacy of PD-L1 blockade in gemcitabine-resistant pancreatic cancer

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) is often refractory to treatment with gemcitabine (GEM) and immune checkpoint inhibitors including anti-programmed cell death ligand 1 (PD-L1) antibody. However, the precise relationship between GEM-resistant PDAC and development of an immunosuppressive tumor microenvironment (TME) remains unclear. In this study, we investigated the immunosuppressive TME in parental and GEM-resistant PDAC tumors and assessed the therapeutic potential of combination therapy with the telomerase-specific replication-competent oncolytic adenovirus OBP-702, which induces tumor suppressor p53 protein and PD-L1 blockade against GEM-resistant PDAC tumors. Mouse PDAC cells (PAN02) and human PDAC cells (MIA PaCa-2, BxPC-3) were used to establish GEM-resistant PDAC lines. PD-L1 expression and the immunosuppressive TME were analyzed using parental and GEM-resistant PDAC cells. A cytokine array was used to investigate the underlying mechanism of immunosuppressive TME induction by GEM-resistant PAN02 cells. The GEM-resistant PAN02 tumor model was used to evaluate the antitumor effect of combination therapy with OBP-702 and PD-L1 blockade. GEM-resistant PDAC cells exhibited higher PD-L1 expression and produced higher granulocyte–macrophage colony-stimulating factor (GM-CSF) levels compared with parental cells, inducing an immunosuppressive TME and the accumulation of myeloid-derived suppressor cells (MDSCs). OBP-702 significantly inhibited GEM-resistant PAN02 tumor growth by suppressing GM-CSF-mediated MDSC accumulation. Moreover, combination treatment with OBP-702 significantly enhanced the antitumor efficacy of PD-L1 blockade against GEM-resistant PAN02 tumors. The present results suggest that combination therapy involving OBP-702 and PD-L1 blockade is a promising antitumor strategy for treating GEM-resistant PDAC with GM-CSF-induced immunosuppressive TME formation.

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Abbreviations

BMDC:

Bone marrow-derived cell

CFSE:

Carboxyfluorescein diacetate succinimidyl ester

CM:

Conditioned medium

CTL:

Cytotoxic T lymphocyte

ELISA:

Enzyme-linked immunosorbent assay

FBS:

Fetal bovine serum

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

GEM:

Gemcitabine

GM-CSF:

Granulocyte–macrophage colony-stimulating factor

hTERT:

Human telomerase reverse transcriptase

ICI:

Immune checkpoint inhibitor

ICD:

Immunogenic cell death

IC50 :

50% Inhibitory concentration

MDSC:

Myeloid-derived suppressor cell

MOI:

Multiplicity of infection

PDAC:

Pancreatic ductal adenocarcinoma

PD-L1:

Programmed cell death ligand 1

PD-1:

Programmed cell death 1

PFU:

Plaque-forming unit

TME:

Tumor microenvironment

Treg:

Regulatory T cell

References

  1. Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM (2014) Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res 74:2913–2921. https://doi.org/10.1158/0008-5472.CAN-14-0155

    Article  CAS  PubMed  Google Scholar 

  2. Siegel RL, Miller KD, Fuchs HE, Jemal A (2021) Cancer Statistics, 2021. CA Cancer J Clin 71:7–33. https://doi.org/10.3322/caac.21654

    Article  PubMed  Google Scholar 

  3. Burris HA 3rd, Moore MJ, Andersen J et al (1997) Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 15:2403–2413. https://doi.org/10.1200/JCO.1997.15.6.2403

    Article  CAS  PubMed  Google Scholar 

  4. Gu Z, Du Y, Zhao X, Wang C (2021) Tumor microenvironment and metabolic remodeling in gemcitabine-based chemoresistance of pancreatic cancer. Cancer Lett 521:98–108. https://doi.org/10.1016/j.canlet.2021.08.029

    Article  CAS  PubMed  Google Scholar 

  5. Sun C, Mezzadra R, Schumacher TN (2018) Regulation and function of the PD-L1 checkpoint. Immunity 48:434–452. https://doi.org/10.1016/j.immuni.2018.03.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Leinwand J, Miller G (2020) Regulation and modulation of antitumor immunity in pancreatic cancer. Nat Immunol 21:1152–1159. https://doi.org/10.1038/s41590-020-0761-y

    Article  CAS  PubMed  Google Scholar 

  7. Herbst RS, Soria JC, Kowanetz M et al (2014) Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515:563–567. https://doi.org/10.1038/nature14011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Yarchoan M, Albacker LA, Hopkins AC et al (2019) PD-L1 expression and tumor mutational burden are independent biomarkers in most cancers. JCI Insight 4:e126908. https://doi.org/10.1172/jci.insight.126908

    Article  PubMed  PubMed Central  Google Scholar 

  9. Gorchs L, Kaipe H (2021) Interactions between cancer-associated fibroblasts and T cells in the pancreatic tumor microenvironment and the role of chemokines. Cancers (Basel) 13:2995. https://doi.org/10.3390/cancers13122995

    Article  CAS  PubMed  Google Scholar 

  10. Blando J, Sharma A, Higa MG et al (2019) Comparison of immune infiltrates in melanoma and pancreatic cancer highlights VISTA as a potential target in pancreatic cancer. Proc Natl Acad Sci USA 116:1692–1697. https://doi.org/10.1073/pnas.1811067116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Stromnes IM, Brockenbrough JS, Izeradjene K, Carlson MA, Cuevas C, Simmons RM, Greenberg PD, Hingorani SR (2014) Targeted depletion of an MDSC subset unmasks pancreatic ductal adenocarcinoma to adaptive immunity. Gut 63:1769–1781. https://doi.org/10.1136/gutjnl-2013-306271

    Article  CAS  PubMed  Google Scholar 

  12. Candido JB, Morton JP, Bailey P et al (2018) CSF1R(+) macrophages sustain pancreatic tumor growth through T cell suppression and maintenance of key gene programs that define the squamous subtype. Cell Rep 23:1448–1460. https://doi.org/10.1016/j.celrep.2018.03.131

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Viehl CT, Moore TT, Liyanage UK, Frey DM, Ehlers JP, Eberlein TJ, Goedegebuure PS, Linehan DC (2006) Depletion of CD4+CD25+ regulatory T cells promotes a tumor-specific immune response in pancreas cancer-bearing mice. Ann Surg Oncol 13:1252–1258. https://doi.org/10.1245/s10434-006-9015-y

    Article  PubMed  Google Scholar 

  14. Doi T, Ishikawa T, Okayama T et al (2017) The JAK/STAT pathway is involved in the upregulation of PD-L1 expression in pancreatic cancer cell lines. Oncol Rep 37:545–554. https://doi.org/10.3892/or.2017.5399

    Article  CAS  Google Scholar 

  15. Takeuchi S, Baghdadi M, Tsuchikawa T et al (2015) Chemotherapy-derived inflammatory responses accelerate the formation of immunosuppressive myeloid cells in the tissue microenvironment of human pancreatic cancer. Cancer Res 75:2629–2640. https://doi.org/10.1158/0008-5472.CAN-14-2921

    Article  CAS  PubMed  Google Scholar 

  16. Dong H, Strome SE, Salomao DR et al (2002) Tumor-associated B7–H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 8:793–800. https://doi.org/10.1038/nm730

    Article  CAS  PubMed  Google Scholar 

  17. Gabrilovich DI, Nagaraj S (2009) Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 9:162–174. https://doi.org/10.1038/nri2506

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ady JW, Heffner J, Klein E, Fong Y (2014) Oncolytic viral therapy for pancreatic cancer: current research and future directions. Oncolytic Virother 3:35–46. https://doi.org/10.2147/OV.S53858

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Nattress CB, Hallden G (2018) Advances in oncolytic adenovirus therapy for pancreatic cancer. Cancer Lett 434:56–69. https://doi.org/10.1016/j.canlet.2018.07.006

    Article  CAS  PubMed  Google Scholar 

  20. Haller SD, Monaco ML, Essani K (2020) The present status of immuno-oncolytic viruses in the treatment of pancreatic cancer. Viruses 12:1318. https://doi.org/10.3390/v12111318

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kawashima T, Kagawa S, Kobayashi N et al (2004) Telomerase-specific replication-selective virotherapy for human cancer. Clin Cancer Res 10:285–292. https://doi.org/10.1158/1078-0432.ccr-1075-3

    Article  CAS  PubMed  Google Scholar 

  22. Hashimoto Y, Watanabe Y, Shirakiya Y et al (2008) Establishment of biological and pharmacokinetic assays of telomerase-specific replication-selective adenovirus. Cancer Sci 99:385–390. https://doi.org/10.1111/j.1349-7006.2007.00665.x

    Article  CAS  PubMed  Google Scholar 

  23. Yamasaki Y, Tazawa H, Hashimoto Y et al (2012) A novel apoptotic mechanism of genetically engineered adenovirus-mediated tumour-specific p53 overexpression through E1A-dependent p21 and MDM2 suppression. Eur J Cancer 48:2282–2291. https://doi.org/10.1016/j.ejca.2011.12.020

    Article  CAS  PubMed  Google Scholar 

  24. Hasei J, Sasaki T, Tazawa H et al (2013) Dual programmed cell death pathways induced by p53 transactivation overcome resistance to oncolytic adenovirus in human osteosarcoma cells. Mol Cancer Ther 12:314–325. https://doi.org/10.1158/1535-7163.MCT-12-0869

    Article  CAS  PubMed  Google Scholar 

  25. Koujima T, Tazawa H, Ieda T et al (2020) Oncolytic virus-mediated targeting of the ERK signaling pathway inhibits invasive propensity in human pancreatic cancer. Mol Ther Oncolytics 17:107–117. https://doi.org/10.1016/j.omto.2020.03.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kanaya N, Kuroda S, Kakiuchi Y et al (2020) Immune modulation by telomerase-specific oncolytic adenovirus synergistically enhances antitumor efficacy with Anti-PD1 antibody. Mol Ther 28:794–804. https://doi.org/10.1016/j.ymthe.2020.01.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Bayne LJ, Beatty GL, Jhala N, Clark CE, Rhim AD, Stanger BZ, Vonderheide RH (2012) Tumor-derived granulocyte-macrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer. Cancer Cell 21:822–835. https://doi.org/10.1016/j.ccr.2012.04.025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Pylayeva-Gupta Y, Lee KE, Hajdu CH, Miller G, Bar-Sagi D (2012) Oncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia. Cancer Cell 21:836–847. https://doi.org/10.1016/j.ccr.2012.04.024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Schreck R, Baeuerle PA (1990) NF-kappa B as inducible transcriptional activator of the granulocyte-macrophage colony-stimulating factor gene. Mol Cell Biol 10:1281–1286. https://doi.org/10.1128/mcb.10.3.1281-1286.1990

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Nomi T, Sho M, Akahori T et al (2007) Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer. Clin Cancer Res 13:2151–2157. https://doi.org/10.1158/1078-0432.CCR-06-2746

    Article  CAS  PubMed  Google Scholar 

  31. Danilova L, Ho WJ, Zhu Q et al (2019) Programmed cell death ligand-1 (PD-L1) and CD8 expression profiling identify an immunologic subtype of pancreatic ductal adenocarcinomas with favorable survival. Cancer Immunol Res 7:886–895. https://doi.org/10.1158/2326-6066.CIR-18-0822

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Sato H, Jeggo PA, Shibata A (2019) Regulation of programmed death-ligand 1 expression in response to DNA damage in cancer cells: Implications for precision medicine. Cancer Sci 110:3415–3423. https://doi.org/10.1111/cas.14197

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wang F, Ma J, Liu J, Jin H, Huang D (2012) Synthetic small peptides acting on B7H1 enhance apoptosis in pancreatic cancer cells. Mol Med Rep 6:553–557. https://doi.org/10.3892/mmr.2012.970

    Article  CAS  PubMed  Google Scholar 

  34. Vonderheide RH, Bear AS (2020) Tumor-derived myeloid cell chemoattractants and T cell exclusion in pancreatic cancer. Front Immunol 11:605619. https://doi.org/10.3389/fimmu.2020.605619

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ghansah T, Vohra N, Kinney K, Weber A, Kodumudi K, Springett G, Sarnaik AA, Pilon-Thomas S (2013) Dendritic cell immunotherapy combined with gemcitabine chemotherapy enhances survival in a murine model of pancreatic carcinoma. Cancer Immunol Immunother 62:1083–1091. https://doi.org/10.1007/s00262-013-1407-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Eriksson E, Wenthe J, Irenaeus S, Loskog A, Ullenhag G (2016) Gemcitabine reduces MDSCs, tregs and TGFbeta-1 while restoring the teff/treg ratio in patients with pancreatic cancer. J Transl Med 14:282. https://doi.org/10.1186/s12967-016-1037-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Porembka MR, Mitchem JB, Belt BA, Hsieh CS, Lee HM, Herndon J, Gillanders WE, Linehan DC, Goedegebuure P (2012) Pancreatic adenocarcinoma induces bone marrow mobilization of myeloid-derived suppressor cells which promote primary tumor growth. Cancer Immunol Immunother 61:1373–1385. https://doi.org/10.1007/s00262-011-1178-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Christmas BJ, Rafie CI, Hopkins AC et al (2018) Entinostat converts immune-resistant breast and pancreatic cancers into checkpoint-responsive tumors by reprogramming tumor-infiltrating MDSCs. Cancer Immunol Res 6:1561–1577. https://doi.org/10.1158/2326-6066.CIR-18-0070

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Wu C, Tan X, Hu X, Zhou M, Yan J, Ding C (2020) Tumor microenvironment following gemcitabine treatment favors differentiation of immunosuppressive Ly6C(high) myeloid cells. J Immunol 204:212–223. https://doi.org/10.4049/jimmunol.1900930

    Article  CAS  PubMed  Google Scholar 

  40. Fultang N, Li X, Li T, Chen YH (2020) Myeloid-derived suppressor cell differentiation in cancer: transcriptional regulators and enhanceosome-mediated mechanisms. Front Immunol 11:619253. https://doi.org/10.3389/fimmu.2020.619253

    Article  CAS  PubMed  Google Scholar 

  41. Mace TA, Ameen Z, Collins A et al (2013) Pancreatic cancer-associated stellate cells promote differentiation of myeloid-derived suppressor cells in a STAT3-dependent manner. Cancer Res 73:3007–3018. https://doi.org/10.1158/0008-5472.CAN-12-4601

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Ogawa T, Kikuchi S, Tabuchi M et al (2022) Modulation of p53 expression in cancer-associated fibroblasts prevents peritoneal metastasis of gastric cancer. Mol Ther Oncolytics 25:249–261. https://doi.org/10.1016/j.omto.2022.04.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Tan MC, Goedegebuure PS, Belt BA, Flaherty B, Sankpal N, Gillanders WE, Eberlein TJ, Hsieh CS, Linehan DC (2009) Disruption of CCR5-dependent homing of regulatory T cells inhibits tumor growth in a murine model of pancreatic cancer. J Immunol 182:1746–1755. https://doi.org/10.4049/jimmunol.182.3.1746

    Article  CAS  PubMed  Google Scholar 

  44. Wang X, Lang M, Zhao T et al (2017) Cancer-FOXP3 directly activated CCL5 to recruit FOXP3(+)Treg cells in pancreatic ductal adenocarcinoma. Oncogene 36:3048–3058. https://doi.org/10.1038/onc.2016.458

    Article  CAS  PubMed  Google Scholar 

  45. Wang X, Li X, Wei X et al (2020) PD-L1 is a direct target of cancer-FOXP3 in pancreatic ductal adenocarcinoma (PDAC), and combined immunotherapy with antibodies against PD-L1 and CCL5 is effective in the treatment of PDAC. Signal Transduct Target Ther 5:38. https://doi.org/10.1038/s41392-020-0144-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Bhattacharya P, Budnick I, Singh M, Thiruppathi M, Alharshawi K, Elshabrawy H, Holterman MJ, Prabhakar BS (2015) Dual role of GM-CSF as a pro-inflammatory and a regulatory cytokine: implications for immune therapy. J Interferon Cytokine Res 35:585–599. https://doi.org/10.1089/jir.2014.0149

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Serafini P, Carbley R, Noonan KA, Tan G, Bronte V, Borrello I (2004) High-dose granulocyte-macrophage colony-stimulating factor-producing vaccines impair the immune response through the recruitment of myeloid suppressor cells. Cancer Res 64:6337–6343. https://doi.org/10.1158/0008-5472.CAN-04-0757

    Article  CAS  PubMed  Google Scholar 

  48. Tsujikawa T, Crocenzi T, Durham JN et al (2020) Evaluation of cyclophosphamide/gvax pancreas followed by Listeria–Mesothelin (CRS-207) with or without Nivolumab in patients with pancreatic cancer. Clin Cancer Res 26:3578–3588. https://doi.org/10.1158/1078-0432.CCR-19-3978

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Jiang J, Zhou H, Ni C, Hu X, Mou Y, Huang D, Yang L (2019) Immunotherapy in pancreatic cancer: new hope or mission impossible? Cancer Lett 445:57–64. https://doi.org/10.1016/j.canlet.2018.10.045

    Article  CAS  PubMed  Google Scholar 

  50. Azad A, Yin Lim S, D’Costa Z, et al (2017) PD-L1 blockade enhances response of pancreatic ductal adenocarcinoma to radiotherapy. EMBO Mol Med 9:167–180. https://doi.org/10.15252/emmm.201606674

    Article  CAS  PubMed  Google Scholar 

  51. Sugiu K, Tazawa H, Hasei J et al (2021) Oncolytic virotherapy reverses chemoresistance in osteosarcoma by suppressing MDR1 expression. Cancer Chemother Pharmacol 88:513–524. https://doi.org/10.1007/s00280-021-04310-5

    Article  CAS  PubMed  Google Scholar 

  52. Liu D, Kojima T, Ouchi M, Kuroda S, Watanabe Y, Hashimoto Y, Onimatsu H, Urata Y, Fujiwara T (2009) Preclinical evaluation of synergistic effect of telomerase-specific oncolytic virotherapy and gemcitabine for human lung cancer. Mol Cancer Ther 8:980–987. https://doi.org/10.1158/1535-7163.MCT-08-0901

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Tomoko Sueishi, Yuko Hoshijima, and Tae Yamanishi for their excellent technical support.

Funding

This study was supported in part by grants from the Japan Agency for Medical Research and Development (17ck0106285h0001 and 20ck0106569h0001 to T. Fujiwara) and JSPS KAKENHI grants JP16K10596 and JP21K07219 to H. Tazawa and JP16H05416 and JP19H03731 to T. Fujiwara.

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Authors and Affiliations

  1. Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan

    Yoshinori Kajiwara, Hiroshi Tazawa, Motohiko Yamada, Nobuhiko Kanaya, Takuro Fushimi, Satoru Kikuchi, Shinji Kuroda, Toshiaki Ohara, Kazuhiro Noma, Ryuichi Yoshida, Yuzo Umeda, Shunsuke Kagawa & Toshiyoshi Fujiwara

  2. Center for Innovative Clinical Medicine, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan

    Hiroshi Tazawa

  3. Department of Pathology and Experimental Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan

    Toshiaki Ohara

  4. Oncolys BioPharma Inc., Tokyo, 105-0001, Japan

    Yasuo Urata

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  1. Yoshinori Kajiwara
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Contributions

Conception and design: HT, SKa, TFuj; development of methodology: YK, MY, NK, TFus; acquisition of data: YK, MY, TFus; analysis and interpretation of data: YK, MY, TFus; writing, review, and/or revision of the manuscript: YK, HT, TFuj; administrative, technical, or material support: YU; study supervision: HT, SKi, SKu, TO, KN, RY, YU, SKa, TFuj

Corresponding author

Correspondence to Hiroshi Tazawa.

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Competing interests

Y. Urata is President & CEO of Oncolys BioPharma Inc. H. Tazawa and T. Fujiwara are consultants of Oncolys BioPharma Inc. The other authors have no potential conflicts of interest to disclose.

Conflict of interest

Y. Urata is President & CEO of Oncolys BioPharma Inc. H. Tazawa and T. Fujiwara are consultants of Oncolys BioPharma Inc. The other authors have no potential conflicts of interest to disclose.

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Kajiwara, Y., Tazawa, H., Yamada, M. et al. Oncolytic virus-mediated reducing of myeloid-derived suppressor cells enhances the efficacy of PD-L1 blockade in gemcitabine-resistant pancreatic cancer. Cancer Immunol Immunother 72, 1285–1300 (2023). https://doi.org/10.1007/s00262-022-03334-x

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