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Combination of p38 MAPK inhibitor with PD-L1 antibody effectively prolongs survivals of temozolomide-resistant glioma-bearing mice via reduction of infiltrating glioma-associated macrophages and PD-L1 expression on resident glioma-associated microglia

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Abstract

Current conventional treatment strategies for glioblastoma (GBM) have limited efficacy due to the rapid development of resistance to temozolomide (TMZ). It is particularly urgent to develop novel therapeutic strategies that can overcome TMZ resistance and provide patients with better prognoses. Here, a TMZ-resistant GBM cell strain and a mouse model of TMZ resistance are established as valuable tools to explore novel therapeutic strategies against TMZ resistance. Experimentally, p38MAPK inhibitor reduces the accumulation of F4/80+/CD11b+ macrophages/microglia in glioma and prolongs the survivals of glioma-bearing mice. Glioma-associated macrophages/microglia have a significanct expression of PD-L1. p38MAPK inhibitor in combination with PD-L1 antibody can effectively prolongs the survivals of TMZ-resistant GBM-bearing hosts, and differentially reduces the accumulation of circulating monocytes-derived tumor-associated macrophages and PD-L1 abundances of resident glioma-associated microglia. This combination therapy could be a treatment option for patients at the recurrence or chronic TMZ maintenance stages. A clinical study to confirm the safety and effectiveness of this combination therapy is warranted.

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References

  1. Stupp R, Hegi ME, Mason WP et al (2009) Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 10(5):459–466

    Article  CAS  PubMed  Google Scholar 

  2. Stupp R, Hegi ME, Gilbert MR et al (2007) Chemoradiotherapy in malignant glioma: standard of care and future directions. J Clin Oncol 25(26):4127–4136

    Article  CAS  PubMed  Google Scholar 

  3. Miyazaki T, Ishikawa E, Matsuda M et al (2020) Infiltration of CD163-positive macrophages in glioma tissues after treatment with anti-PD-L1 antibody and role of PI3Kgamma inhibitor as a combination therapy with anti-PD-L1 antibody in in vivo model using temozolomide-resistant murine glioma-initiating cells. Brain Tumor Pathol 37(2):41–49

    Article  CAS  PubMed  Google Scholar 

  4. Cohen EEW, Soulieres D, Le Tourneau C et al (2019) Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. Lancet 393(10167):156–167

    Article  CAS  PubMed  Google Scholar 

  5. Garon EB, Rizvi NA, Hui R et al (2015) Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 372(21):2018–2028

    Article  PubMed  Google Scholar 

  6. Kang YK, Boku N, Satoh T et al (2017) Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 390(10111):2461–2471

    Article  CAS  PubMed  Google Scholar 

  7. Powles T, Duran I, van der Heijden MS et al (2018) Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet 391(10122):748–757

    Article  CAS  PubMed  Google Scholar 

  8. Litak J, Mazurek M, Grochowski C et al (2019) PD-L1/PD-1 axis in glioblastoma multiforme. Int J Mol Sci 20(21):5347

    Article  CAS  PubMed Central  Google Scholar 

  9. Saha D, Martuza RL, Rabkin SD (2017) Macrophage polarization contributes to glioblastoma eradication by combination immunovirotherapy and immune checkpoint blockade. Cancer Cell 32(2):253–267

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Antonios JP, Soto H, Everson RG et al (2017) Immunosuppressive tumor-infiltrating myeloid cells mediate adaptive immune resistance via a PD-1/PD-L1 mechanism in glioblastoma. Neuro Oncol 19(6):796–807

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Shu C, Li Q (2020) Current advances in PD-1/PD-L1 axis-related tumour-infiltrating immune cells and therapeutic regimens in glioblastoma. Crit Rev Oncol Hematol 151:102965

    Article  PubMed  Google Scholar 

  12. Qian J, Wang C, Wang B et al (2018) The IFN-gamma/PD-L1 axis between T cells and tumor microenvironment: hints for glioma anti-PD-1/PD-L1 therapy. J Neuroinflamm 15(1):290

    Article  CAS  Google Scholar 

  13. Cao MF, Chen L, Dang WQ et al (2019) Hybrids by tumor-associated macrophages × glioblastoma cells entail nuclear reprogramming and glioblastoma invasion. Cancer Lett 442:445–452

    Article  CAS  PubMed  Google Scholar 

  14. Hambardzumyan D, Gutmann DH, Kettenmann H (2016) The role of microglia and macrophages in glioma maintenance and progression. Nat Neurosci 19(1):20–27

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ye XZ, Xu SL, Xin YH et al (2012) Tumor-associated microglia/macrophages enhance the invasion of glioma stem-like cells via TGF-beta1 signaling pathway. J Immunol 189(1):444–453

    Article  CAS  PubMed  Google Scholar 

  16. Shi Y, Ping YF, Zhou W et al (2017) Tumour-associated macrophages secrete pleiotrophin to promote PTPRZ1 signalling in glioblastoma stem cells for tumour growth. Nat Commun 8:15080

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Azambuja JH, da Silveira EF, de Carvalho TR et al (2017) Glioma sensitive or chemoresistant to temozolomide differentially modulate macrophage protumor activities. Biochim Biophys Acta Gen Subj 1861(11):2652–2662

    Article  CAS  PubMed  Google Scholar 

  18. Bloch O, Crane CA, Kaur R et al (2013) Gliomas promote immunosuppression through induction of B7–H1 expression in tumor-associated macrophages. Clin Cancer Res 19(12):3165–3175

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Akbay EA, Koyama S, Carretero J et al (2013) Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors. Cancer Discov 3(12):1355–1363

    Article  CAS  PubMed  Google Scholar 

  20. Lastwika KJ, Wilson W 3rd, Li QK et al (2016) Control of PD-L1 expression by oncogenic activation of the AKT-mTOR pathway in non-small cell lung cancer. Cancer Res 76(2):227–238

    Article  CAS  PubMed  Google Scholar 

  21. Marzec M, Zhang Q, Goradia A et al (2008) Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274 (PD-L1, B7–H1). Proc Natl Acad Sci USA 105(52):20852–20857

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Chen N, Fang W, Zhan J et al (2015) Upregulation of PD-L1 by EGFR activation mediates the immune escape in EGFR-driven NSCLC: implication for optional immune targeted therapy for NSCLC patients with EGFR mutation. J Thorac Oncol 10(6):910–923

    Article  CAS  PubMed  Google Scholar 

  23. Ota K, Azuma K, Kawahara A et al (2015) Induction of PD-L1 expression by the EML4-ALK oncoprotein and downstream signaling pathways in non-small cell lung cancer. Clin Cancer Res 21(17):4014–4021

    Article  CAS  PubMed  Google Scholar 

  24. Schutz F, Stefanovic S, Mayer L et al (2017) PD-1/PD-L1 pathway in breast cancer. Oncol Res Treat 40(5):294–297

    Article  PubMed  CAS  Google Scholar 

  25. Han SJ, Ahn BJ, Waldron JS et al (2009) Gamma interferon-mediated superinduction of B7–H1 in PTEN-deficient glioblastoma: a paradoxical mechanism of immune evasion. NeuroReport 20(18):1597–1602

    Article  CAS  PubMed  Google Scholar 

  26. Szatmari T, Lumniczky K, Desaknai S et al (2006) Detailed characterization of the mouse glioma 261 tumor model for experimental glioblastoma therapy. Cancer Sci 97(6):546–553

    Article  CAS  PubMed  Google Scholar 

  27. Shi Y, Zhou W, Cheng L et al (2017) Tetraspanin CD9 stabilizes gp130 by preventing its ubiquitin-dependent lysosomal degradation to promote STAT3 activation in glioma stem cells. Cell Death Differ 24(1):167–180

    Article  CAS  PubMed  Google Scholar 

  28. Wang Z, Wang B, Shi Y et al (2015) Oncogenic miR-20a and miR-106a enhance the invasiveness of human glioma stem cells by directly targeting TIMP-2. Oncogene 34(11):1407–1419

    Article  CAS  PubMed  Google Scholar 

  29. Campbell RM, Anderson BD, Brooks NA et al (2014) Characterization of LY2228820 dimesylate, a potent and selective inhibitor of p38 MAPK with antitumor activity. Mol Cancer Ther 13(2):364–374

    Article  CAS  PubMed  Google Scholar 

  30. Ma L, Liu J, Zhang X et al (2015) p38 MAPK-dependent Nrf2 induction enhances the resistance of glioma cells against TMZ. Med Oncol 32(3):69

    Article  PubMed  CAS  Google Scholar 

  31. Zhang J, Zhu ZQ, Li YX et al (2019) Tim-3 expression in glioma cells is associated with drug resistance. J Cancer Res Ther 15(4):882–888

    Article  CAS  PubMed  Google Scholar 

  32. Jarnicki AG, Conroy H, Brereton C et al (2008) Attenuating regulatory T cell induction by TLR agonists through inhibition of p38 MAPK signaling in dendritic cells enhances their efficacy as vaccine adjuvants and cancer immunotherapeutics. J Immunol 180(6):3797–3806

    Article  CAS  PubMed  Google Scholar 

  33. Yang Z, Zhang X, Darrah PA et al (2010) The regulation of Th1 responses by the p38 MAPK. J Immunol 185(10):6205–6213

    Article  CAS  PubMed  Google Scholar 

  34. Franks HA, Wang Q, Lax SJ et al (2014) Novel function for the p38-MK2 signaling pathway in circulating CD1c+ (BDCA-1+) myeloid dendritic cells from healthy donors and advanced cancer patients; inhibition of p38 enhances IL-12 whilst suppressing IL-10. Int J Cancer 134(3):575–586

    Article  CAS  PubMed  Google Scholar 

  35. Zhou W, Chen C, Shi Y et al (2017) Targeting glioma stem cell-derived pericytes disrupts the blood-tumor barrier and improves chemotherapeutic efficacy. Cell Stem Cell 21(5):591–603

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Omuro A, Vlahovic G, Lim M et al (2018) Nivolumab with or without ipilimumab in patients with recurrent glioblastoma: results from exploratory phase I cohorts of CheckMate 143. Neuro Oncol 20(5):674–686

    Article  CAS  PubMed  Google Scholar 

  37. Ebert PJR, Cheung J, Yang Y et al (2016) MAP kinase inhibition promotes T cell and anti-tumor activity in combination with PD-L1 checkpoint blockade. Immunity 44(3):609–621

    Article  CAS  PubMed  Google Scholar 

  38. Deken MA, Gadiot J, Jordanova ES et al (2016) Targeting the MAPK and PI3K pathways in combination with PD1 blockade in melanoma. Oncoimmunology 5(12):e1238557

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Miyazaki T, Ishikawa E, Matsuda M et al (2017) Assessment of PD-1 positive cells on initial and secondary resected tumor specimens of newly diagnosed glioblastoma and its implications on patient outcome. J Neurooncol 133(2):277–285

    Article  CAS  PubMed  Google Scholar 

  40. Shen X, Zhao B (2018) Efficacy of PD-1 or PD-L1 inhibitors and PD-L1 expression status in cancer: meta-analysis. BMJ 362:k3529

    Article  PubMed  PubMed Central  Google Scholar 

  41. Xu C, Chen YP, Du XJ et al (2018) Comparative safety of immune checkpoint inhibitors in cancer: systematic review and network meta-analysis. BMJ 363:k4226

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (Grant numbers: 81372273 and 81773145 to Xia Zhang).

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Authors and Affiliations

  1. Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China

    Weiqi Dang, Jingfang Xiao, Qinghua Ma, Jingya Miao, Mianfu Cao, Lu Chen, Yu Shi, Xiaohong Yao, Shichang Yu, Xindong Liu, Youhong Cui, Xia Zhang & Xiuwu Bian

  2. Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, 400038, China

    Weiqi Dang, Jingfang Xiao, Qinghua Ma, Jingya Miao, Mianfu Cao, Lu Chen, Yu Shi, Xiaohong Yao, Shichang Yu, Xindong Liu, Youhong Cui, Xia Zhang & Xiuwu Bian

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  1. Weiqi Dang
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  2. Jingfang Xiao
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  12. Xia Zhang
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Contributions

Conceptualization: XZ; methodology: WD, JX, QM, JM, YS and XL; resources: MC, LC, XL, XZ and XB; writing of original draft: WD, XZ; manuscript review and editing: YS, XY, SY, XL, YC and XZ; supervision: XZ, XB.

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Correspondence to Xia Zhang or Xiuwu Bian.

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The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

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Dang, W., Xiao, J., Ma, Q. et al. Combination of p38 MAPK inhibitor with PD-L1 antibody effectively prolongs survivals of temozolomide-resistant glioma-bearing mice via reduction of infiltrating glioma-associated macrophages and PD-L1 expression on resident glioma-associated microglia. Brain Tumor Pathol 38, 189–200 (2021). https://doi.org/10.1007/s10014-021-00404-3

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