SpringerLink
Log in

Overcoming anti-PD-1/PD-L1 immune checkpoint blockade resistance: the role of macrophage, neutrophils and mast cells in the tumor microenvironment

  • Review
  • Published:
Clinical and Experimental Medicine Aims and scope Submit manuscript

Abstract

In recent years, the anti-PD-1/PD-L1 blockade has become a game changer in cancer treatment following the unprecedented response rate. Regardless of the substantial therapy efficacy across various cancer types, some patients do not still respond to these therapies, indicating that a deeper understanding of the mechanisms of anti-PD-1/PD-L1 resistance is highly important. To overcome such resistance, the tumor-induced immunosuppressive mechanisms have been focused and several suppressor cell populations in the tumor microenvironment have been identified. Among these cells, macrophages, neutrophils, and mast cells are known to play key roles in anti-PD-1/PD-L1 resistance. Hence, gaining control over these innate immune cells can open opportunities for breaking tumor resistance to immune checkpoint inhibitors. Herein, a summary of the role of macrophages, neutrophils, and mast cells in anti-PD-1/PD-L1 resistance has been described. Also, strategies to overcome their therapeutic resistance to anti-PD-1/PD-L1 have been discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Germany)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72(1):7–33.

    PubMed  Google Scholar 

  2. Schlueter M, Chan K, Lasry R, Price M. The cost of cancer—a comparative analysis of the direct medical costs of cancer and other major chronic diseases in Europe. PLoS One. 2020;15(11).

  3. Debela DT, Muzazu SG, Heraro KD, et al. New approaches and procedures for cancer treatment: current perspectives. SAGE Open Med. 2021;9:205031212110343.

    Google Scholar 

  4. Shadbad MA, Safaei S, Brunetti O, et al. A systematic review on the therapeutic potentiality of pd-l1-inhibiting micrornas for triple-negative breast cancer: toward single-cell sequencing-guided biomimetic delivery. Genes. 2021;12.

  5. Kalkusova K, Smite S, Darras E, et al. Mast cells and dendritic cells as cellular immune checkpoints in immunotherapy of solid tumors. Int J Mol Sci. 2022; 23(19).

  6. Waldman AD, Fritz JM, Lenardo MJ. A guide to cancer immunotherapy: from T cell basic science to clinical practice. Nat Rev Immunol. 2020;20:651–68.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science. 2018;359:1350–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Tsoukalas N, Kiakou M, Tsapakidis K, et al. PD-1 and PD-L1 as immunotherapy targets and biomarkers in non-small cell lung cancer. J B.U.ON. 2019;24:883–8.

  9. Qin S, Ren Z, Meng Z, et al. Camrelizumab in patients with previously treated advanced hepatocellular carcinoma: a multicentre, open-label, parallel-group, randomised, phase 2 trial. Lancet Oncol. 2020;21(4):571–80.

    CAS  PubMed  Google Scholar 

  10. Garon EB, Hellmann MD, Rizvi NA, et al. Five-year overall survival for patients with advanced non-small-cell lung cancer treated with pembrolizumab: results from the phase i KEYNOTE-001 study. J Clin Oncol. 2019;37(28):2518–27.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Tang J, Yu JX, Hubbard-Lucey VM, Neftelinov ST, Hodge JP, Lin Y. The clinical trial landscape for PD1/PDl1 immune checkpoint inhibitors. Nat Rev Drug Discovery. 2018;17:854–5.

    CAS  PubMed  Google Scholar 

  12. Upadhaya S, Neftelinov ST, Hodge J, Campbell J. Challenges and opportunities in the PD1/PDL1 inhibitor clinical trial landscape. Nat Rev Drug Discov. 2022;21(7):482–3.

    CAS  PubMed  Google Scholar 

  13. Upadhaya S, Neftelino ST, Hodge JP, Oliva C, Campbell JR, Yu JX. Combinations take centre stage in PD1/PDL1 inhibitor clinical trials. Nat Rev. 2021;20:168–9.

    CAS  Google Scholar 

  14. Huang Z, Su W, Lu T, et al. First-line immune-checkpoint inhibitors in non-small cell lung cancer: current landscape and future progress. Front Pharmacol. 2020;11

  15. Borcoman E, Marret G, Le Tourneau C. Paradigm change in first-line treatment of recurrent and/or metastatic head and neck squamous cell carcinoma. Cancers (Basel). 2021;13(11):2573.

    CAS  PubMed  Google Scholar 

  16. Zhu J, Yan L, Wang Q. Efficacy of PD-1/PD-L1 inhibitors in ovarian cancer: a single-arm meta-analysis. J Ovarian Res. 2021; 14(1).

  17. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non–small-cell lung cancer. N Engl J Med. 2015;373(2):123–35.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Zou W, Wolchok JD, Chen L. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations. Sci Transl Med. 2016;8(328).

  19. Brahmer JR, Tykodi SS, Chow LQM, et al. Safety and activity of Anti–PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366(26):2455–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Kuo CL, Chou HY, Lien HW, et al. A Fc-VEGF chimeric fusion enhances PD-L1 immunotherapy via inducing immune reprogramming and infiltration in the immunosuppressive tumor microenvironment. Cancer Immunol Immunother. 2022. https://doi.org/10.1007/s00262-022-03255-9.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Cheng L, Creasy T, Pilataxi F, et al. Effects of combination treatment with durvalumab plus tremelimumab on the tumor microenvironment in non-small-cell lung carcinoma. Cancer Immunol Immunother. 2022;71(5):1167–81.

    CAS  PubMed  Google Scholar 

  22. Chen M, Sharma A, Lin Y, et al. Insluin and epithelial growth factor (EGF) promote programmed death ligand 1(PD-L1) production and transport in colon cancer stem cells. BMC Cancer. 2019;19(1).

  23. Jiang Z, Lim SO, Yan M, et al. TYRO3 induces anti-PD-1/PD-L1 therapy resistance by limiting innate immunity and tumoral ferroptosis. J Clin Invest. 2021;131(8).

  24. Faget J, Peters S, Quantin X, Meylan E, Bonnefoy N. Neutrophils in the era of immune checkpoint blockade. Vol. 9, Journal for ImmunoTherapy of Cancer. 2021.

  25. Lichterman JN, Reddy SM. Mast cells: a new frontier for cancer immunotherapy. Cells. 2021;10(6):1–17.

    Google Scholar 

  26. Sagiv JY, Michaeli J, Assi S, et al. Phenotypic diversity and plasticity in circulating neutrophil subpopulations in cancer. Cell Rep. 2015;10(4):562–73.

    CAS  PubMed  Google Scholar 

  27. Wu L, Saxena S, Awaji M, Singh RK. Tumor‐associated neutrophils in cancer: going pro. Cancers (Basel). 2019;11(4).

  28. Shaul ME, Fridlender ZG. Tumour-associated neutrophils in patients with cancer. Nat Rev Clin Oncol. 2019;16:601–20.

    PubMed  Google Scholar 

  29. Peng W, Sheng Y, **ao H, et al. Lung adenocarcinoma cells promote self-migration and self-invasion by activating neutrophils to upregulate Notch3 expression of cancer cells. Front Mol Biosci. 2022;8.

  30. Zhang X, Shi H, Yuan X, Jiang P, Qian H, Xu W. Tumor-derived exosomes induce N2 polarization of neutrophils to promote gastric cancer cell migration. Mol Cancer. 2018;17(1).

  31. Hattar K, Franz K, Ludwig M, et al. Interactions between neutrophils and non-small cell lung cancer cells: enhancement of tumor proliferation and inflammatory mediator synthesis. Cancer Immunol Immunother. 2014;63(12):1297–306.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Germann M, Zangger N, Sauvain M, et al. Neutrophils suppress tumor‐infiltrating T cells in colon cancer via matrix metalloproteinase‐mediated activation of TGF β. EMBO Mol Med. 2020;12(1).

  33. Ocana A, Nieto-Jiménez C, Pandiella A, Templeton AJ. Neutrophils in cancer: Prognostic role and therapeutic strategies. Molecular Cancer. 2017; 16.

  34. Xu H, Qi Z, Zhao Q, et al. Lentinan enhances the antitumor effects of Delta-like 1 via neutrophils. BMC Cancer. 2022;22(1):1–11. https://doi.org/10.1186/s12885-022-10011-w.

    Article  CAS  Google Scholar 

  35. Ralph SJ, Reynolds MJ. Intratumoral pro-oxidants promote cancer immunotherapy by recruiting and reprogramming neutrophils to eliminate tumors. Cancer Immunol Immunother. 2022. https://doi.org/10.1007/s00262-022-03248-8.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Zhang L, Yao J, Wei Y, et al. Blocking immunosuppressive neutrophils deters pY696-EZH2–driven brain metastases. Sci Transl Med. 2020;12(545).

  37. Hu X, **ang F, Feng Y, et al. Neutrophils promote tumor progression in oral squamous cell carcinoma by regulating EMT and JAK2/STAT3 Signaling Through Chemerin. Front Oncol. 2022;12.

  38. Valero C, Lee M, Hoen D, et al. Pretreatment neutrophil-to-lymphocyte ratio and mutational burden as biomarkers of tumor response to immune checkpoint inhibitors. Nat Commun. 2021;12(1).

  39. Geh D, Leslie J, Rumney R, Reeves HL, Bird TG, Mann DA. Neutrophils as potential therapeutic targets in hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2022;19:257–73.

    CAS  PubMed  Google Scholar 

  40. Kwantwi LB. Interplay between tumor-derived factors and tumor-associated neutrophils: opportunities for therapeutic interventions in cancer. Clin Transl Oncol. 2023. https://doi.org/10.1007/s12094-023-03100-0.

    Article  PubMed  Google Scholar 

  41. Kamran N, Kadiyala P, Saxena M, et al. Immunosuppressive myeloid cells’ blockade in the glioma microenvironment enhances the efficacy of immune-stimulatory gene therapy. Mol Ther. 2017;25(1):232–48.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Wen L, Lu H, Li Q, et al. Contributions of T cell dysfunction to the resistance against anti-PD-1 therapy in oral carcinogenesis. J Exp Clin Cancer Res. 2019;38(1).

  43. Khan SM, Desai R, Coxon A, et al. Impact of CD4 T cells on intratumoral cell exhaustion and responsiveness to PD-1 blockade therapy in mouse brain tumors. 2022;1–13.

  44. Kwantwi LB, Wang S, Zhang W, et al. Tumor-associated neutrophils activated by tumor-derived CCL20 (C-C motif chemokine ligand 20) promote T cell immunosuppression via programmed death-ligand 1 (PD-L1) in breast cancer. Bioengineered. 2021;12(1):6996–7006.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Tang D, Zhang D, Heng Y, et al. Tumor-infiltrating PD-L1+ neutrophils induced by GM-CSF suppress T cell function in laryngeal squamous cell carcinoma and predict unfavorable prognosis. J Inflamm Res. 2022;15:1079–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Shang A, Wang W, Gu C, et al. Long non-coding RNA HOTTIP enhances IL-6 expression to potentiate immune escape of ovarian cancer cells by upregulating the expression of PD-L1 in neutrophils. J Exp Clin Cancer Res. 2019; 38(1).

  47. Wang TT, Zhao YL, Peng LS, et al. Tumour-activated neutrophils in gastric cancer foster immune suppression and disease progression through GM-CSF-PD-L1 pathway. Gut. 2017;66(11):1900–11.

    CAS  PubMed  Google Scholar 

  48. Shi Y, Zhang J, Mao Z, et al. Extracellular vesicles from gastric cancer cells induce PD-L1 expression on neutrophils to suppress T-cell immunity. Front Oncol. 2020;10.

  49. Cheng Y, Li H, Deng Y, et al. Cancer-associated fibroblasts induce PDL1+ neutrophils through the IL6-STAT3 pathway that foster immune suppression in hepatocellular carcinoma. Cell Death Dis. 2018;9(4).

  50. He G, Zhang H, Zhou J, et al. Peritumoural neutrophils negatively regulate adaptive immunity via the PD-L1/PD-1 signalling pathway in hepatocellular carcinoma. J Exp Clin Cancer Res. 2015;34(1).

  51. Li M, Spakowicz D, Burkart J, et al. Change in neutrophil to lymphocyte ratio during immunotherapy treatment is a non-linear predictor of patient outcomes in advanced cancers. J Cancer Res Clin Oncol. 2019;145(10):2541–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Arasanz H, Bocanegra AI, Morilla I, et al. Circulating low density neutrophils are associated with resistance to first line anti-PD1/PDL1 immunotherapy in non-small cell lung cancer. Cancers (Basel). 2022;14(16)

  53. Wang R, Zhu Y, Liu Z, et al. Neutrophil extracellular traps promote tPA-induced brain hemorrhage via cGAS in mice with stroke. Blood. 2021;138(1):91–103.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Wong SL, Wagner DD. Peptidylarginine deiminase 4: A nuclear button triggering neutrophil extracellular traps in inflammatory diseases and aging. FASEB J. 2018;32:6358–70.

    CAS  PubMed Central  Google Scholar 

  55. Teijeira Á, Garasa S, Gato M, et al. CXCR1 and CXCR2 chemokine receptor agonists produced by tumors induce neutrophil extracellular traps that interfere with immune cytotoxicity. Immunity. 2020;52(5):856-71.e8.

    CAS  PubMed  Google Scholar 

  56. Zhang H, Wang Y, Onuma A, et al. Neutrophils extracellular traps inhibition improves pd-1 blockade immunotherapy in colorectal cancer. Cancers (Basel). 2021; 13(21).

  57. Zhang Y, Chandra V, Sanchez ER, et al. Interleukin-17-induced neutrophil extracellular traps mediate resistance to checkpoint blockade in pancreatic cancer. J Exp Med. 2020; 217(12).

  58. Chen D, Li Q, Liang H, et al. Exenatide enhanced the antitumor efficacy on PD-1 blockade by the attenuation of neutrophil extracellular traps. Biochem Biophys Res Commun. 2022;619:97–103. https://doi.org/10.1016/j.bbrc.2022.06.052.

    Article  CAS  PubMed  Google Scholar 

  59. Simoncello F, Piperno GM, Caronni N, et al. CXCL5-mediated accumulation of mature neutrophils in lung cancer tissues impairs the differentiation program of anticancer CD8 T cells and limits the efficacy of checkpoint inhibitors. Oncoimmunology. 2022. https://doi.org/10.1080/2162402X.2022.2059876.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Wang PF, Zhang YX, Su J, et al. Neutrophil depletion enhances the therapeutic effect of PD-1 antibody on glioma. Aging (Albany NY). 2020;12(15):15290–301.

    CAS  PubMed  Google Scholar 

  61. Akbay EA, Koyama S, Liu Y, et al. Interleukin-17A promotes lung tumor progression through neutrophil attraction to tumor sites and mediating resistance to PD-1 blockade. J Thorac Oncol. 2017;12(8):1268–79.

    PubMed  PubMed Central  Google Scholar 

  62. Kim GT, Kim EY, Shin SH, et al. Improving anticancer effect of aPD-L1 through lowering neutrophil infiltration by PLAG in tumor implanted with MB49 mouse urothelial carcinoma. BMC Cancer. 2022;22(1):1–11. https://doi.org/10.1186/s12885-022-09815-7.

    Article  CAS  Google Scholar 

  63. Sun L, Clavijo PE, Robbins Y, et al. Inhibiting myeloid-derived suppressor cell trafficking enhances T cell immunotherapy. JCI Insight. 2019;4(7).

  64. D’Alterio C, Barbieri A, Portella L, et al. Inhibition of stromal CXCR4 impairs development of lung metastases. Cancer Immunol Immunother. 2012;Vol. 61:1713–20.

    Google Scholar 

  65. Bockorny B, Semenisty V, Macarulla T, et al. BL-8040, a CXCR4 antagonist, in combination with pembrolizumab and chemotherapy for pancreatic cancer: the COMBAT trial. Nat Med. 2020;26(6):878–85.

    CAS  PubMed  Google Scholar 

  66. Cai Z, Zhang M, Boafo Kwantwi L, et al. Breast cancer cells promote self-migration by secreting interleukin 8 to induce NET formation. Gene. 2020;754.

  67. Kaunisto A, Henry WS, Montaser-Kouhsari L, et al. NFAT1 promotes intratumoral neutrophil infiltration by regulating IL8 expression in breast cancer. Mol Oncol. 2015;9(6):1140–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Tavazoie MF, Pollack I, Tanqueco R, et al. LXR/ApoE activation restricts innate immune suppression in cancer. Cell. 2018;172(4):825-40.e18.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Denk S, Taylor RP, Wiegner R, et al. Complement C5a-induced changes in neutrophil morphology during inflammation. Scand J Immunol. 2017;86(3):143–55.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Wang W, Marinis JM, Beal AM, et al. RIP1 kinase drives macrophage-mediated adaptive immune tolerance in pancreatic cancer. Cancer Cell. 2020;38(4):585–90.

    CAS  PubMed  Google Scholar 

  71. Seifert L, Werba G, Tiwari S, et al. The necrosome promotes pancreatic oncogenesis via CXCL1 and Mincle-induced immune suppression. Nature. 2016;532(7598):245–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Allen E, Jabouille A, Rivera LB, et al. Combined antiangiogenic and anti-PD-L1 therapy stimulates tumor immunity through HEV formation. Sci Transl Med. 2017; 9(385).

  73. Taylor MH, Lee CH, Makker V, et al. Phase Ib/II trial of lenvatinib plus pembrolizumab in patients with advanced renal cell carcinoma, endometrial cancer, and other selected advanced solid tumors. J Clin Oncol. 2020. p. 1154–63.

  74. Amin A, Plimack ER, Ernstoff MS, et al. Safety and efficacy of nivolumab in combination with sunitinib or pazopanib in advanced or metastatic renal cell carcinoma: The CheckMate 016 study. J Immunother Cancer. 2018;6(1).

  75. Guerriero JL. Macrophages: The Road Less Traveled, Changing Anticancer Therapy. Trends Mol Med. 2018;24:472–89.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Kumari N, Choi SH. Tumor-associated macrophages in cancer: recent advancements in cancer nanoimmunotherapies. J Exp Clin Cancer Res. 2022; 41.

  77. Sarode P, Zheng X, Giotopoulou GA, et al. Reprogramming of tumor-associated macrophages by targeting β-catenin/FOSL2/ARID5A signaling: a potential treatment of lung cancer. Sci Adv. 2020;6(23):1–17.

    Google Scholar 

  78. Biswas SK, Sica A, Lewis CE. Plasticity of macrophage function during tumor progression: regulation by distinct molecular mechanisms. J Immunol. 2008;180(4):2011–7.

    CAS  PubMed  Google Scholar 

  79. Pu J, Xu Z, Nian J, et al. M2 macrophage-derived extracellular vesicles facilitate CD8+T cell exhaustion in hepatocellular carcinoma via the miR-21–5p/YOD1/YAP/β-catenin pathway. Cell Death Discovery. 2021; 7.

  80. Morrissey SM, Zhang F, Ding C, et al. Tumor-derived exosomes drive immunosuppressive macrophages in a pre-metastatic niche through glycolytic dominant metabolic reprogramming. Cell Metab. 2021;33(10):2040-58.e10.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Hartley GP, Chow L, Ammons DT, Wheat WH, Dow SW. Programmedcell death ligand 1 (PD-L1) signaling regulates macrophage proliferation and activation. Cancer Immunol Res. 2018;6(10):1260–73.

    CAS  PubMed  Google Scholar 

  82. Shinchi Y, Ishizuka S, Komohara Y, et al. The expression of PD-1 ligand 1 on macrophages and its clinical impacts and mechanisms in lung adenocarcinoma. Cancer Immunol Immunother. 2022;71(11):2645–61. https://doi.org/10.1007/s00262-022-03187-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Kos K, Salvagno C, Wellenstein MD, et al. Tumor-associated macrophages promote intratumoral conversion of conventional CD4+ T cells into regulatory T cells via PD-1 signalling. Oncoimmunology. 2022. https://doi.org/10.1080/2162402X.2022.2063225.

    Article  PubMed  PubMed Central  Google Scholar 

  84. Wen ZF, Liu H, Gao R, et al. Tumor cell-released autophagosomes (TRAPs) promote immunosuppression through induction of M2-like macrophages with increased expression of PD-L1. J Immunother Cancer. 2018;6(1).

  85. Prima V, Kaliberova LN, Kaliberov S, Curiel DT, Kusmartsev S. COX2/mPGES1/PGE2 pathway regulates PD-L1 expression in tumor-associated macrophages and myeloid-derived suppressor cells. Proc Natl Acad Sci U S A. 2017;114(5):1117–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Zhang J, Liu Z, Cao P, et al. Tumor-associated macrophages regulate the function of cytotoxic T lymphocyte through PD-1/PD-L1 pathway in multiple myeloma. Cancer Med. 2022;11(24):4838–48.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Zhao R, Wan Q, Wang Y, et al. M1-like TAMs are required for the efficacy of PD-L1/PD-1 blockades in gastric cancer. Oncoimmunology. 2021;10(1).

  88. Dhupkar P, Gordon N, Stewart J, Kleinerman ES. Anti-PD-1 therapy redirects macrophages from an M2 to an M1 phenotype inducing regression of OS lung metastases. Cancer Med. 2018;7(6):2654–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Wu C, Qiu Y, Zhang R, et al. Association of peripheral basophils with tumor M2 macrophage infiltration and outcomes of the anti-PD-1 inhibitor plus chemotherapy combination in advanced gastric cancer. J Transl Med. 2022;20(1):1–15. https://doi.org/10.1186/s12967-022-03598-y.

    Article  CAS  Google Scholar 

  90. House IG, Savas P, Lai J, et al. Macrophage-derived CXCL9 and CXCL10 are required for antitumor immune responses following immune checkpoint blockade. Clin Cancer Res. 2020;26(2):487–504.

    CAS  PubMed  Google Scholar 

  91. Peranzoni E, Lemoine J, Vimeux L, et al. Macrophages impede CD8 T cells from reaching tumor cells and limit the efficacy of anti–PD-1 treatment. Proc Natl Acad Sci U S A. 2018;115(17):E4041–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Martinez-Usatorre A, Kadioglu E, Boivin G, et al. Overcoming microenvironmental resistance to PD-1 blockade in genetically engineered lung cancer models. Sci Transl Med. 2021;13(606).

  93. Li Z, Ding Y, Liu J, et al. Depletion of tumor associated macrophages enhances local and systemic platelet-mediated anti-PD-1 delivery for post-surgery tumor recurrence treatment. Nat Commun. 2022;13(1):1–15.

    Google Scholar 

  94. Quaranta V, Rainer C, Nielsen SR, et al. Macrophage-derived granulin drives resistance to immune checkpoint inhibition in metastatic pancreatic cancer. Cancer Res. 2018;78(15):4253–69.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Myers KV, Amend SR, Pienta KJ. Targeting Tyro3, Axl and MerTK (TAM receptors): Implications for macrophages in the tumor microenvironment. Molecular Cancer. 2019; 18.

  96. Tierney JF, Vogle A, Finnerty B, et al. Indoleamine 2,3-dioxygenase-1 expression in adrenocortical carcinoma. J Surg Res. 2020;256:90–5.

    CAS  PubMed  Google Scholar 

  97. Zamarin D, Postow MA. Immune checkpoint modulation: Rational design of combination strategies. Pharmacol Ther. 2015;150:23–32.

    CAS  PubMed  Google Scholar 

  98. Hsu SPC, Chen YC, Chiang HC, et al. Rapamycin and hydroxychloroquine combination alters macrophage polarization and sensitizes glioblastoma to immune checkpoint inhibitors. J Neurooncol. 2020;146(3):417–26. https://doi.org/10.1007/s11060-019-03360-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Li H, Somiya M, Kuroda S. Enhancing antibody-dependent cellular phagocytosis by Re-education of tumor-associated macrophages with resiquimod-encapsulated liposomes. Biomaterials. 2021;268.

  100. Binnemars-Postma K, Storm G, Prakash J. Nanomedicine strategies to target tumor-associated macrophages. Int J Molecul Sci. 2017; 18.

  101. Rodell CB, Arlauckas SP, Cuccarese MF, et al. TLR7/8-agonist-loaded nanoparticles promote the polarization of tumour-associated macrophages to enhance cancer immunotherapy. Nat Biomed Eng. 2018;2(8):578–88.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Wei Z, Zhang X, Yong T, et al. Boosting anti-PD-1 therapy with metformin-loaded macrophage-derived microparticles. Nat Commun. 2021;12(1).

  103. Toulmonde M, Penel N, Adam J, et al. Use of PD-1 targeting, macrophage infiltration, and IDO pathway activation in sarcomas a phase 2 clinical trial. JAMA Oncol. 2018;4(1):93–7.

    PubMed  Google Scholar 

  104. Mariathasan S, Turley SJ, Nickles D, et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature. 2018;554(7693):544–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Panagi M, Voutouri C, Mpekris F, et al. TGF-β inhibition combined with cytotoxic nanomedicine normalizes triple negative breast cancer microenvironment towards anti-tumor immunity. Theranostics. 2020;10(4):1910–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Knudson KM, Hicks KC, Luo X, Chen JQ, Schlom J, Gameiro SR. M7824, a novel bifunctional anti-PD-L1/TGFβ Trap fusion protein, promotes anti-tumor efficacy as monotherapy and in combination with vaccine. Oncoimmunology. 2018;7(5).

  107. Mittal P, Wang L, Akimova T, et al. The ccr2/mcp-1 chemokine pathway and lung adenocarcinoma. Cancers (Basel). 2020;12(12):1–19.

    Google Scholar 

  108. D’Alterio C, Buoncervello M, Ieranò C, et al. Targeting CXCR4 potentiates anti-PD-1 efficacy modifying the tumor microenvironment and inhibiting neoplastic PD-1. J Exp Clin Cancer Res. 2019;38(1).

  109. Frossi B, Mion F, Sibilano R, Danelli L, Pucillo CEM. Is it time for a new classification of mast cells? What do we know about mast cell heterogeneity? Immunol Rev. 2018;282:35–46.

    CAS  PubMed  Google Scholar 

  110. Brown JM, Wilson TM, Metcalfe DD. The mast cell and allergic diseases: Role in pathogenesis and implications for therapy. Clin Exp Allergy. 2008;38:4–18.

    CAS  PubMed  Google Scholar 

  111. Ribatti D, Tamma R, Crivellato E. The dual role of mast cells in tumor fate. Cancer Lett. 2018;433:252–8.

    CAS  PubMed  Google Scholar 

  112. Derakhshani A, Vahidian F, Alihasanzadeh M, Mokhtarzadeh A, Lotfi Nezhad P, Baradaran B. Mast cells: a double-edged sword in cancer. Immunol Lett. 2019;209:28–35.

    CAS  PubMed  Google Scholar 

  113. Gulubova M, Vlaykova T. Prognostic significance of mast cell number and microvascular density for the survival of patients with primary colorectal cancer. J Gastroenterol Hepatol. 2009;24(7):1265–75.

    PubMed  Google Scholar 

  114. Ribatti D, Ennas MG, Vacca A, et al. Tumor vascularity and tryptase-positive mast cells correlate with a poor prognosis in melanoma. Eur J Clin Invest. 2003;33(5):420–5.

    CAS  PubMed  Google Scholar 

  115. Della Rovere F, Granata A, Familiari D, D’Arrigo G, Mondello B, Basile G. Mast cells in invasive ductal breast cancer: Different behavior in high and minimum hormone-receptive cancers. Anticancer Res. 2007;27(4B):2465–71.

    CAS  PubMed  Google Scholar 

  116. Rajput AB, Turbin DA, Cheang MC, et al. Stromal mast cells in invasive breast cancer are a marker of favourable prognosis: A study of 4,444 cases. Breast Cancer Res Treat. 2008;107(2):249–57.

    PubMed  Google Scholar 

  117. Cao K, Zhang G, Zhang X, et al. Stromal infiltrating mast cells identify immunoevasive subtype high-grade serous ovarian cancer with poor prognosis and inferior immunotherapeutic response. Oncoimmunology. 2021;10(1).

  118. Somasundaram R, Connelly T, Choi R, et al. Tumor-infiltrating mast cells are associated with resistance to anti-PD-1 therapy. Nat Commun. 2021;12(1).

  119. Noto CN, Hoft SG, DiPaolo RJ. Mast Cells as Important Regulators in Autoimmunity and Cancer Development. Front Cell Dev Biol. 2021; 9.

  120. Lv Y, Zhao Y, Wang X, et al. Increased intratumoral mast cells foster immune suppression and gastric cancer progression through TNF-?-PD-L1 pathway. J Immunother Cancer. 2019;7(1).

  121. Dalton DK, Noelle RJ. The roles of mast cells in anticancer immunity. Cancer Immunol Immunother. 2012. p. 1511–20.

  122. Li J, Peng G, Zhu K, et al. PD-1+ mast cell enhanced by PD-1 blocking therapy associated with resistance to immunotherapy. Cancer Immunol Immunother. 2022. https://doi.org/10.1007/s00262-022-03282-6.

    Article  PubMed  PubMed Central  Google Scholar 

  123. Myrofora P, Mpekris F, Voutouri C, et al. Abstract 6382: Targeting mast cells restores T cell infiltration and sensitizes sarcomas to PD-L1 inhibition. Cancer Res. 2022;82(12).

  124. Cimpean AM, Raica M. The hidden side of disodium cromolyn: from mast cell stabilizer to an angiogenic factor and antitumor agent. Arch Immunol Ther Exp (Warsz). 2016;64(6):515–22.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

None

Funding

No financial support was received for this study.

Author information

Authors and Affiliations

  1. Department of Medical Imaging Sciences, Klintaps College of Health and Allied Sciences, Accra, DTD. TDC, 30A Klagon, Com. 19, Tema, Ghana

    Louis Boafo Kwantwi

Authors
  1. Louis Boafo Kwantwi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

LBK conceived the idea, wrote and revised the manuscript.

Corresponding author

Correspondence to Louis Boafo Kwantwi.

Ethics declarations

Conflict of interest

There is no conflict of interest to declare.

Consent for publication

All authors declare that they agree to submit the article for publication.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kwantwi, L.B. Overcoming anti-PD-1/PD-L1 immune checkpoint blockade resistance: the role of macrophage, neutrophils and mast cells in the tumor microenvironment. Clin Exp Med 23, 3077–3091 (2023). https://doi.org/10.1007/s10238-023-01059-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10238-023-01059-4

Keywords

Search

Navigation