Skip to main content
SpringerLink
Log in

Transforming Growth Factor-β1 in Cancer Immunology: Opportunities for Immunotherapy

  • Chapter
  • First Online:
Advances in Molecular Pathology

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1408))

Abstract

Transforming growth factor-beta1 (TGF-β) regulates a plethora of cell-intrinsic processes that modulate tumor progression in a context-dependent manner. Thus, although TGF-β acts as a tumor suppressor in the early stages of tumorigenesis, in late stages, this factor promotes tumor progression and metastasis. In addition, TGF-β also impinges on the tumor microenvironment by modulating the immune system. In this aspect, TGF-β exhibits a potent immunosuppressive effect, which allows both cancer cells to escape from immune surveillance and confers resistance to immunotherapy. While TGF-β inhibits the activation and antitumoral functions of T-cell lymphocytes, dendritic cells, and natural killer cells, it promotes the generation of T-regulatory cells and myeloid-derived suppressor cells, which hinder antitumoral T-cell activities. Moreover, TGF-β promotes tumor-associated macrophages and neutrophils polarization from M1 into M2 and N1 to N2, respectively. Altogether, these effects contribute to the generation of an immunosuppressive tumor microenvironment and support tumor promotion. This review aims to analyze the relevant evidence on the complex role of TGF-β in cancer immunology, the current outcomes of combined immunotherapies, and the anti-TGF-β therapies that may improve the success of current and new oncotherapies.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 139.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 179.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

ACT:

Adoptive cell therapy

B-cells:

B-cell lymphocytes

Bregs:

B regulatory cells

CAR:

Chimeric antigen receptor

CD:

Cluster of differentiation

CDK:

Cyclin-dependent kinase

COX-2:

Cyclooxygenase-2

CTLA-4:

Cytotoxic T lymphocyte-associated antigen-4

DAP:

Death-associated protein

DC:

Dendritic cells

ECM:

Extracellular matrix

HIF:

Hypoxia-inducible factor

ICIs:

Immune checkpoint inhibitors

IL:

Interleukin

IFN:

Interferon

M:

Monocytic

MAPK:

Mitogen-activated protein kinases

MDSC:

Myeloid-derived suppressor

MHC:

Major histocompatibility complex

mTOR:

Mammalian target of rapamycin

NK:

Natural killers

NKG2D:

Natural killer group 2 member D

NF-κB:

Nuclear factor κB (NF-κB)

PD-1:

Programmed cell death protein-1

PDL-1:

Programmed cell death ligand-1

PMN:

Polymorphonuclear

Rb:

Tumor-suppressor retinoblastoma (Rb)

SLC:

Small latent complex

T-cells:

T-cell lymphocytes

TAMs:

Tumor-associated macrophages

TANs:

Tumor-associated neutrophils

TCR:

T-cell receptor

TGF-β1 :

Transforming growth factor-β-1

TNF:

Tumor necrosis factor

TβR1:

TGF-β-type-I receptor kinase

TβR2:

TGF-β-type-II receptor kinase

Th:

Lymphocyte T helper

TME:

Tumor microenvironment.

References

  1. Trikha P (2014 Aug) Carson WE 3rd. Signaling pathways involved in MDSC regulation. Biochim Biophys Acta 1846(1):55–65. https://doi.org/10.1016/j.bbcan.2014.04.003. Epub 2014 Apr 13. PMID: 24727385; PMCID: PMC4140957

  2. Batlle E, Massagué J (2019) Transforming growth factor-β signaling in immunity and cancer. Immunity 50(4):924–940. https://doi.org/10.1016/j.immuni.2019.03.024.PMID:30995507;PMCID:PMC7507121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Derynck R, Turley SJ, Akhurst RJ (2021 Jan) TGFβ biology in cancer progression and immunotherapy. Nat Rev Clin Oncol 18(1):9–34. https://doi.org/10.1038/s41571-020-0403-1. Epub 2020 Jul 24. PMID: 32710082Zhai

  4. Zhao H, Wei J, Sun J (2020 Dec) Roles of TGF-β signaling pathway in tumor microenvironment and cancer therapy. Int Immunopharmacol 89(Pt B):107101. https://doi.org/10.1016/j.intimp.2020.107101. Epub 2020 Oct 21. PMID: 33099067

  5. Xue VW, Chung JY, Córdoba CAG, Cheung AH, Kang W, Lam EW, Leung KT, To KF, Lan HY, Tang PM (2020) Transforming growth factor-β: a multifunctional regulator of cancer immunity. Cancers (Basel) 12(11):3099. https://doi.org/10.3390/cancers12113099.PMID:33114183;PMCID:PMC7690808

    Article  CAS  PubMed  Google Scholar 

  6. Govinden R, Bhoola KD (2003) Genealogy, expression, and cellular function of transforming growth factor-beta. Pharmacol Ther 98(2):257–265. https://doi.org/10.1016/s0163-7258(03)00035-4. PMID: 12725873

    Article  CAS  PubMed  Google Scholar 

  7. Birchenall-Roberts MC, Ruscetti FW, Kasper J, Lee HD, Friedman R, Geiser A et al (1990) Transcriptional regulation of the transforming growth factor beta 1 promoter by v-src gene products is mediated through the AP-1 complex. Mol Cell Biol 10(9):4978–4983. https://doi.org/10.1128/mcb.10.9.4978.PMID:2117705;PMCID:PMC361127

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Annes JP, Munger JS, Rifkin DB (2003) Making sense of latent TGFbeta activation. J Cell Sci 116(Pt 2):217–224. https://doi.org/10.1242/jcs.00229. PMID: 12482908

    Article  CAS  PubMed  Google Scholar 

  9. Tzavlaki K, Moustakas A (2020 Mar 23) TGF-β Signaling. Biomolecules. 10(3):487. https://doi.org/10.3390/biom10030487. PMID: 32210029; PMCID: PMC7175140

  10. Robertson IB, Rifkin DB (2016) Regulation of the bioavailability of TGF-β and TGF-β-related proteins. Cold Spring Harb Perspect Biol 8(6):a021907. https://doi.org/10.1101/cshperspect.a021907.PMID:27252363;PMCID:PMC4888822

    Article  PubMed  PubMed Central  Google Scholar 

  11. Liénart S, Merceron R, Vanderaa C, Lambert F, Colau D, Stockis J et al (2018) Structural basis of latent TGF-β1 XE TGF-β1 presentation and activation by GARP on human regulatory T cells. Science 362(6417):952–956. https://doi.org/10.1126/science.aau2909. Epub 2018 Oct 25 PMID: 30361387

    Article  CAS  PubMed  Google Scholar 

  12. Yu Q, Stamenkovic I (2000 Jan 15) Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev 14(2):163–76. PMID: 10652271; PMCID: PMC316345

    Google Scholar 

  13. Nishimura SL (2009 Oct) Integrin-mediated transforming growth factor-beta activation, a potential therapeutic target in fibrogenic disorders. Am J Pathol 175(4):1362–70. https://doi.org/10.2353/ajpath.2009.090393. Epub 2009 Sep 3. PMID: 19729474; PMCID: PMC2751532

  14. Derynck R, Budi EH (2019 Feb 26) Specificity, versatility, and control of TGF-β family signaling. Sci Signal 12(570):eaav5183. https://doi.org/10.1126/scisignal.aav5183. PMID: 30808818; PMCID: PMC6800142

  15. Martinez-Hackert E, Sundan A, Holien T (2020 Oct) Receptor binding competition: A paradigm for regulating TGF-β family action. Cytokine Growth Factor Rev 6:S1359–6101(20)30206–9. https://doi.org/10.1016/j.cytogfr.2020.09.003. Epub ahead of print. PMID: 33087301

  16. López-Casillas F, Payne HM, Andres JL, Massagué J (1994) Betaglycan can act as a dual modulator of TGF-beta access to signaling receptors: mapping of ligand binding and GAG attachment sites. J Cell Biol 124(4):557–568. https://doi.org/10.1083/jcb.124.4.557.PMID:8106553;PMCID:PMC2119924

    Article  PubMed  Google Scholar 

  17. Shi Y, Massagué J (2003) Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 113(6):685–700. https://doi.org/10.1016/s0092-8674(03)00432-x. PMID: 12809600

    Article  CAS  PubMed  Google Scholar 

  18. Feng XH, Derynck R (2005) Specificity and versatility in TGF-beta signaling through Smads. Annu Rev Cell Dev Biol 21:659–693. https://doi.org/10.1146/annurev.cellbio.21.022404.142018. PMID: 16212511

    Article  CAS  PubMed  Google Scholar 

  19. Miyazawa K, Miyazono K (2017) Regulation of TGF-β family signaling by inhibitory Smads. Cold Spring Harb Perspect Biol 9(3):a022095. https://doi.org/10.1101/cshperspect.a022095.PMID:27920040;PMCID:PMC5334261

    Article  PubMed  PubMed Central  Google Scholar 

  20. Itoh S, ten Dijke P (2007) Negative regulation of TGF-beta receptor/Smad signal transduction. Curr Opin Cell Biol 19(2):176–184. https://doi.org/10.1016/j.ceb.2007.02.015. Epub 2007 Feb 20 PMID: 17317136

    Article  CAS  PubMed  Google Scholar 

  21. Mu Y, Gudey SK, Landström M (2012) Non-Smad signaling pathways. Cell Tissue Res 347(1):11–20. https://doi.org/10.1007/s00441-011-1201-y. Epub 2011 Jun 24 PMID: 21701805

    Article  CAS  PubMed  Google Scholar 

  22. Zhang YE (2017) Non-Smad signaling pathways of the TGF-β family. Cold Spring Harb Perspect Biol 9(2):a022129. https://doi.org/10.1101/cshperspect.a022129.PMID:27864313;PMCID:PMC5287080

    Article  PubMed  PubMed Central  Google Scholar 

  23. Chiang AC, Massagué J (2008) Molecular basis of metastasis. N Engl J Med 359(26):2814–2823. https://doi.org/10.1056/NEJMra0805239.PMID:19109576;PMCID:PMC4189180

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Hannon GJ, Beach D (1994) p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest. Nature 371(6494):257–261. https://doi.org/10.1038/371257a0. PMID: 8078588

    Article  CAS  PubMed  Google Scholar 

  25. Li CY, Suardet L, Little JB (1995) Potential role of WAF1/Cip1/p21 as a mediator of TGF-beta cytoinhibitory effect. J Biol Chem 270(10):4971–4974. https://doi.org/10.1074/jbc.270.10.4971. PMID: 7890601

    Article  CAS  PubMed  Google Scholar 

  26. Vijayachandra K, Higgins W, Lee J, Glick A (2009) Induction of p16ink4a and p19ARF by TGFbeta1 contributes to growth arrest and senescence response in mouse keratinocytes. Mol Carcinog 48(3):181–186. https://doi.org/10.1002/mc.20472. PMID: 18655107

    Article  CAS  PubMed  Google Scholar 

  27. Lin RL, Zhao LJ (2015) Mechanistic basis and clinical relevance of the role of transforming growth factor-β in cancer. Cancer Biol Med 12(4):385–393. https://doi.org/10.7497/j.issn.2095-3941.2015.0015.PMID:26779375;PMCID:PMC4706525

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Pietenpol JA, Stein RW, Moran E, Yaciuk P, Schlegel R, Lyons RM et al (1990) TGF-beta 1 inhibition of c-myc transcription and growth in keratinocytes is abrogated by viral transforming proteins with pRB binding domains. Cell 61(5):777–785. https://doi.org/10.1016/0092-8674(90)90188-k. PMID: 2140528

    Article  CAS  PubMed  Google Scholar 

  29. Papageorgis P (2015) TGFβ Signaling in tumor initiation, epithelial-to-mesenchymal transition, and metastasis. J Oncol 2015:587193. https://doi.org/10.1155/2015/587193. Epub 2015 Mar 25. PMID: 25883652; PMCID: PMC4389829

  30. Roschger C, Cabrele C (2017) The Id-protein family in developmental and cancer-associated pathways. Cell Commun Signal 15(1):7. https://doi.org/10.1186/s12964-016-0161-y.PMID:28122577;PMCID:PMC5267474

    Article  PubMed  PubMed Central  Google Scholar 

  31. Jang CW, Chen CH, Chen CC, Chen JY, Su YH, Chen RH (2002) TGF-beta induces apoptosis through Smad-mediated expression of DAP-kinase. Nat Cell Biol 4(1):51–58. https://doi.org/10.1038/ncb731.Erratum.In:NatCellBiol2002Apr;4(4):328. PMID: 11740493

    Article  CAS  PubMed  Google Scholar 

  32. Perlman R, Schiemann WP, Brooks MW, Lodish HF, Weinberg RA (2001) TGF-beta-induced apoptosis is mediated by the adapter protein Daxx that facilitates JNK activation. Nat Cell Biol 3(8):708–714. https://doi.org/10.1038/35087019.Erratum.In:NatCellBiol2002Feb;4(2):179. PMID: 11483955

    Article  CAS  PubMed  Google Scholar 

  33. Gottfried Y, Rotem A, Lotan R, Steller H, Larisch S (2004 Apr 7) The mitochondrial ARTS protein promotes apoptosis through targeting XIAP. EMBO J 23(7):1627–35. https://doi.org/10.1038/sj.emboj.7600155. Epub 2004 Mar 18. PMID: 15029247; PMCID: PMC391065

  34. Massagué J (2008) TGFbeta in cancer. Cell 134(2):215–230. https://doi.org/10.1016/j.cell.2008.07.001.PMID:18662538;PMCID:PMC3512574

    Article  PubMed  PubMed Central  Google Scholar 

  35. Ma Y, He S, Gao A, Zhang Y, Zhu Q, Wang P et al (2020) Methylation silencing of TGF-β receptor type II is involved in malignant transformation of esophageal squamous cell carcinoma. Clin Epigenetics 12(1):25. https://doi.org/10.1186/s13148-020-0819-6.PMID:32046777;PMCID:PMC7014638

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Yang G, Yang X (2010) Smad4-mediated TGF-beta signaling in tumorigenesis. Int J Biol Sci 6(1):1–8. https://doi.org/10.7150/ijbs.6.1.PMID:20087440;PMCID:PMC2808050

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. van Hattem WA, Brosens LA, de Leng WW, Morsink FH, Lens S, Carvalho R et al (2008) Large genomic deletions of SMAD4, BMPR1A and PTEN in juvenile polyposis. Gut 57(5):623–627. https://doi.org/10.1136/gut.2007.142927. Epub 2008 Jan 4 PMID: 18178612

    Article  CAS  PubMed  Google Scholar 

  38. Levy L, Hill CS (2006 Feb-Apr) Alterations in components of the TGF-beta superfamily signaling pathways in human cancer. Cytokine Growth Factor Rev 17(1–2):41–58. https://doi.org/10.1016/j.cytogfr.2005.09.009. Epub 2005 Nov 23. PMID: 16310402

  39. Mangone FR, Walder F, Maistro S, Pasini FS, Lehn CN, Carvalho MB, Brentani MM, Snitcovsky I, Federico MH (2010) Smad2 and Smad6 as predictors of overall survival in oral squamous cell carcinoma patients. Mol Cancer 12(9):106. https://doi.org/10.1186/1476-4598-9-106.PMID:20462450;PMCID:PMC2885344

    Article  Google Scholar 

  40. Dzieran J, Fabian J, Feng T, Coulouarn C, Ilkavets I, Kyselova A et al (2013) Comparative analysis of TGF-β/Smad signaling dependent cytostasis in human hepatocellular carcinoma cell lines. PLoS ONE 8(8):e72252. https://doi.org/10.1371/journal.pone.0072252.Erratum.In:PLoSOne.2014;9(5):e95952.PMID:23991075;PMCID:PMC3750029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Reis ST, Pontes-Júnior J, Antunes AA, Sousa-Canavez JM, Abe DK, Cruz JA et al (2011) Tgf-β1 expression as a biomarker of poor prognosis in prostate cancer. Clinics (Sao Paulo) 66(7):1143–1147. https://doi.org/10.1590/s1807-59322011000700004.PMID:21876965;PMCID:PMC3148455

    Article  PubMed  Google Scholar 

  42. Soleimani A, Pashirzad M, Avan A, Ferns GA, Khazaei M, Hassanian SM (2019) Role of the transforming growth factor-β signaling pathway in the pathogenesis of colorectal cancer. J Cell Biochem 120(6):8899–8907. https://doi.org/10.1002/jcb.28331. Epub 2018 Dec 16 PMID: 30556274

    Article  CAS  PubMed  Google Scholar 

  43. Maslankova J, Vecurkovska I, Rabajdova M, Katuchova J, Kicka M, Gayova M et al (2022) Regulation of transforming growth factor-β signaling as a therapeutic approach to treating colorectal cancer. World J Gastroenterol 28(33):4744–4761. https://doi.org/10.3748/wjg.v28.i33.4744.PMID:36156927;PMCID:PMC9476856

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Padua D, Massagué J (2009) Roles of TGFbeta in metastasis. Cell Res 19(1):89–102. https://doi.org/10.1038/cr.2008.316. PMID: 19050696

    Article  CAS  PubMed  Google Scholar 

  45. Ivanović V, Todorović-Raković N, Demajo M, Nesković-Konstantinović Z, Subota V, Ivanisević-et al. (2003 Mar) Elevated plasma levels of transforming growth factor-beta 1 (TGF-beta 1) in patients with advanced breast cancer: association with disease progression. Eur J Cancer 39(4):454–61. https://doi.org/10.1016/s0959-8049(02)00502-6. PMID: 12751375

  46. Krasagakis K, Thölke D, Farthmann B, Eberle J, Mansmann U, Orfanos CE (1998) Elevated plasma levels of transforming growth factor (TGF)-beta1 and TGF-beta2 in patients with disseminated malignant melanoma. Br J Cancer 77(9):1492–1494. https://doi.org/10.1038/bjc.1998.245.PMID:9652767;PMCID:PMC2150189

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Teicher BA (2007) Transforming growth factor-beta and the immune response to malignant disease. Clin Cancer Res 13(21):6247–6251. https://doi.org/10.1158/1078-0432.CCR-07-1654. PMID: 17975134

    Article  CAS  PubMed  Google Scholar 

  48. Caja F, Vannucci L (2015 Jul-Sep) TGFβ: A player on multiple fronts in the tumor microenvironment. J Immunotoxicol 12(3):300–7. doi: https://doi.org/10.3109/1547691X.2014.945667. Epub 2014 Aug 20. PMID: 25140864

  49. Mao Y, Keller ET, Garfield DH, Shen K, Wang J (2013) Stromal cells in tumor microenvironment and breast cancer. Cancer Metastasis Rev 32(1–2):303–315. https://doi.org/10.1007/s10555-012-9415-3.PMID:23114846;PMCID:PMC4432936

    Article  PubMed  PubMed Central  Google Scholar 

  50. Tang N, Cheng C, Zhang X, Qiao M, Li N, Mu W et al (2020) TGF-β inhibition via CRISPR promotes the long-term efficacy of CAR T cells against solid tumors. JCI Insight 5(4):e133977. https://doi.org/10.1172/jci.insight.133977.PMID:31999649;PMCID:PMC7101140

    Article  PubMed  PubMed Central  Google Scholar 

  51. Labani-Motlagh A, Ashja-Mahdavi M, Loskog A (2020) The tumor microenvironment: a milieu hindering and obstructing antitumor immune responses. Front Immunol 15(11):940. https://doi.org/10.3389/fimmu.2020.00940.PMID:32499786;PMCID:PMC7243284

    Article  Google Scholar 

  52. Park HY, Wakefield LM, Mamura M (2009 Aug) Regulation of tumor immune surveillance and tumor immune subversion by tgf-Beta. Immune Netw 9(4):122–126. https://doi.org/10.4110/in.2009.9.4.122. Epub 2009 Aug 31. PMID: 20157598; PMCID: PMC2816944

  53. Caja L, Dituri F, Mancarella S, Caballero-Diaz D, Moustakas A, Giannelli G et al (2018) TGF-β and the tissue microenvironment: relevance in fibrosis and cancer. Int J Mol Sci 19(5):1294. https://doi.org/10.3390/ijms19051294.PMID:29701666;PMCID:PMC5983604

    Article  PubMed  PubMed Central  Google Scholar 

  54. Ohtani H, Terashima T, Sato E (2018 Jun) Immune cell expression of TGFβ1 in cancer with lymphoid stroma: dendritic cell and regulatory T cell contact. Virchows Arch 472(6):1021–1028. https://doi.org/10.1007/s00428-018-2336-y. Epub 2018 Mar 28. PMID: 29594353; PMCID: PMC5999139

  55. Worthington JJ, Fenton TM, Czajkowska BI, Klementowicz JE, Travis MA (2012 Dec) Regulation of TGFβ in the immune system: an emerging role for integrins and dendritic cells. Immunobiology 217(12):1259–65. https://doi.org/10.1016/j.imbio.2012.06.009. Epub 2012 Jul 2. PMID: 22902140; PMCID: PMC3690473

  56. Kulkarni AB, Huh CG, Becker D, Geiser A, Lyght M, Flanders KC et al (1993) Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death. Proc Natl Acad Sci U S A 90(2):770–774. https://doi.org/10.1073/pnas.90.2.770.PMID:8421714;PMCID:PMC45747

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Yang X, Letterio JJ, Lechleider RJ, Chen L, Hayman R, Gu H, Roberts AB, Deng C (1999) Targeted disruption of SMAD3 results in impaired mucosal immunity and diminished T cell responsiveness to TGF-beta. EMBO J 18(5):1280–1291. https://doi.org/10.1093/emboj/18.5.1280.PMID:10064594;PMCID:PMC1171218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Malhotra N, Kang J (2013) SMAD regulatory networks construct a balanced immune system. Immunology 139(1):1–10. https://doi.org/10.1111/imm.12076.PMID:23347175;PMCID:PMC3634534

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Bierie B, Moses HL (2010 Feb) Transforming growth factor beta (TGF-beta) and inflammation in cancer. Cytokine Growth Factor Rev 21(1):49–59. https://doi.org/10.1016/j.cytogfr.2009.11.008. Epub 2009 Dec 16. PMID: 20018551; PMCID: PMC2834863

  60. Geiser AG, Letterio JJ, Kulkarni AB, Karlsson S, Roberts AB, Sporn MB (1993) Transforming growth factor beta 1 (TGF-beta 1) controls expression of major histocompatibility genes in the postnatal mouse: aberrant histocompatibility antigen expression in the pathogenesis of the TGF-beta 1 null mouse phenotype. Proc Natl Acad Sci U S A 90(21):9944–9948. https://doi.org/10.1073/pnas.90.21.9944.PMID:8234339;PMCID:PMC47689

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Strait AA, Wang XJ (2020 Jul) The role of transforming growth factor-beta in immune suppression and chronic inflammation of squamous cell carcinomas. Mol Carcinog 59(7):745–753. https://doi.org/10.1002/mc.23196. Epub 2020 Apr 17. PMID: 32301180; PMCID: PMC7282943

  62. Thomas DA, Massagué J (2005) TGF-beta directly targets cytotoxic T cell functions during tumor evasion of immune surveillance. Cancer Cell 8(5):369–380. https://doi.org/10.1016/j.ccr.2005.10.012. PMID: 16286245

    Article  CAS  PubMed  Google Scholar 

  63. Das L, Levine AD (2008) TGF-beta inhibits IL-2 production and promotes cell cycle arrest in TCR-activated effector/memory T cells in the presence of sustained TCR signal transduction. J Immunol 180(3):1490–1498. https://doi.org/10.4049/jimmunol.180.3.1490. PMID: 18209044

    Article  CAS  PubMed  Google Scholar 

  64. Chen CH, Seguin-Devaux C, Burke NA, Oriss TB, Watkins SC, Clipstone N, Ray A (2003) Transforming growth factor beta blocks Tec kinase phosphorylation, Ca2+ influx, and NFATc translocation causing inhibition of T cell differentiation. J Exp Med 197(12):1689–1699. https://doi.org/10.1084/jem.20021170.PMID:12810687;PMCID:PMC2193945

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Stephen TL, Rutkowski MR, Allegrezza MJ, Perales-Puchalt A, Tesone AJ, Svoronos N et al (2014) Transforming growth factor β-mediated suppression of antitumor T cells requires FoxP1 transcription factor expression. Immunity 41(3):427–439. https://doi.org/10.1016/j.immuni.2014.08.012.PMID:25238097;PMCID:PMC4174366

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Park IK, Shultz LD, Letterio JJ, Gorham JD (2005) TGF-beta1 inhibits T-bet induction by IFN-gamma in murine CD4+ T cells through the protein tyrosine phosphatase Src homology region 2 domain-containing phosphatase-1. J Immunol 175(9):5666–5674. https://doi.org/10.4049/jimmunol.175.9.5666. PMID: 16237056

    Article  CAS  PubMed  Google Scholar 

  67. Choudhry MA, Sir O, Sayeed MM (2001) TGF-beta abrogates TCR-mediated signaling by upregulating tyrosine phosphatases in T cells. Shock 15(3):193–199. https://doi.org/10.1097/00024382-200115030-00006. PMID: 11236902

    Article  CAS  PubMed  Google Scholar 

  68. Castro-Sanchez P, Teagle AR, Prade S, Zamoyska R (2020) Modulation of TCR signaling by tyrosine phosphatases: from autoimmunity to immunotherapy. Front Cell Dev Biol 9(8):608747. https://doi.org/10.3389/fcell.2020.608747.PMID:33425916;PMCID:PMC7793860

    Article  Google Scholar 

  69. Zhao H, Liao X, Kang Y (2017) Tregs: where we are and what comes next? Front Immunol 24(8):1578. https://doi.org/10.3389/fimmu.2017.01578.PMID:29225597;PMCID:PMC5705554

    Article  Google Scholar 

  70. Marie JC, Liggitt D, Rudensky AY (2006) Cellular mechanisms of fatal early-onset autoimmunity in mice with the T cell-specific targeting of transforming growth factor-beta receptor. Immunity 25(3):441–454. https://doi.org/10.1016/j.immuni.2006.07.012. PMID: 16973387

    Article  CAS  PubMed  Google Scholar 

  71. Dahmani A, Delisle JS (2018) TGF-β in T cell biology: implications for cancer immunotherapy. Cancers (Basel) 10(6):194. https://doi.org/10.3390/cancers10060194.PMID:29891791;PMCID:PMC6025055

    Article  PubMed  Google Scholar 

  72. Liu Y, Zhang P, Li J, Kulkarni AB, Perruche S, Chen W (2008) A critical function for TGF-β signaling in the development of natural CD4+CD25+Foxp3+ regulatory T cells. Nat Immunol 9:632–640. https://doi.org/10.1038/ni.1607

    Article  CAS  PubMed  Google Scholar 

  73. Zhou L, Lopes JE, Chong MM, Ivanov II, Min R, Victora GD et al. (2008 May 8) TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature 453(7192):236–40. https://doi.org/10.1038/nature06878. Epub 2008 Mar 26. PMID: 18368049; PMCID: PMC2597437

  74. Paul S, Lal G (2017) The molecular mechanism of natural killer cells function and its importance in cancer immunotherapy. Front Immunol 13(8):1124. https://doi.org/10.3389/fimmu.2017.01124.PMID:28955340;PMCID:PMC5601256

    Article  Google Scholar 

  75. Slattery K, Gardiner CM (2019) NK Cell Metabolism and TGFβ - implications for immunotherapy. Front Immunol 13(10):2915. https://doi.org/10.3389/fimmu.2019.02915.PMID:31921174;PMCID:PMC6927492

    Article  Google Scholar 

  76. Castriconi R, Cantoni C, Della Chiesa M, Vitale M, Marcenaro E, Conte R et al. (2003 Apr 1) Transforming growth factor beta 1 inhibits expression of NKp30 and NKG2D receptors: consequences for the NK-mediated killing of dendritic cells. Proc Natl Acad Sci U S A 100(7):4120–5. https://doi.org/10.1073/pnas.0730640100. Epub 2003 Mar 19. PMID: 12646700; PMCID: PMC153058

  77. Dasgupta S, Bhattacharya-Chatterjee M, O’Malley BW Jr, Chatterjee SK (2005) Inhibition of NK cell activity through TGF-beta 1 by down-regulation of NKG2D in a murine model of head and neck cancer. J Immunol 175(8):5541–5550. https://doi.org/10.4049/jimmunol.175.8.5541. PMID: 16210663

    Article  CAS  PubMed  Google Scholar 

  78. Dutta A, Banerjee A, Saikia N, Phookan J, Baruah MN, Baruah S (2015) Negative regulation of natural killer cell in tumor tissue and peripheral blood of oral squamous cell carcinoma. Cytokine 76(2):123–130. https://doi.org/10.1016/j.cyto.2015.09.006. Epub 2015 Sep 12 PMID: 26372424

    Article  CAS  PubMed  Google Scholar 

  79. Zamai L, Del Zotto G, Buccella F, Gabrielli S, Canonico B, Artico M et al (2020) Understanding the synergy of NKp46 and co-activating signals in various NK cell subpopulations: paving the way for more successful NK-cell-based immunotherapy. Cells 9(3):753. https://doi.org/10.3390/cells9030753.PMID:32204481;PMCID:PMC7140651

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Zaiatz-Bittencourt V, Finlay DK, Gardiner CM (2018) Canonical TGF-β signaling pathway represses human NK cell metabolism. J Immunol 200(12):3934–3941. https://doi.org/10.4049/jimmunol.1701461. Epub 2018 May 2 PMID: 29720425

    Article  CAS  PubMed  Google Scholar 

  81. Karen S, Vanessa Z-B, Elena W, Kiva B, Sam M, Sonya C et al. (2019) TGFβ drives mitochondrial dysfunction in peripheral blood NK cells during metastatic breast cancer. bioRxiv. https://doi.org/10.1101/648501

  82. Viel S, Marçais A, Guimaraes FS, Loftus R, Rabilloud J, Grau M et al. (2016 Feb) TGF-β inhibits the activation and functions of NK cells by repressing the mTOR pathway. Sci Signal 169(415):ra19. https://doi.org/10.1126/scisignal.aad1884. PMID: 26884601

  83. Gao Y, Souza-Fonseca-Guimaraes F, Bald T, Ng SS, Young A, Ngiow SF, Rautela J et al (2017) Tumor immunoevasion by the conversion of effector NK cells into type 1 innate lymphoid cells. Nat Immunol 18(9):1004–1015. https://doi.org/10.1038/ni.3800. Epub 2017 Jul 31 PMID: 28759001

    Article  CAS  PubMed  Google Scholar 

  84. Cortez VS, Ulland TK, Cervantes-Barragan L, Bando JK, Robinette ML, Wang Q, White AJ, Gilfillan S, Cella M, Colonna M (2017 Sep) SMAD4 impedes the conversion of NK cells into ILC1-like cells by curtailing non-canonical TGF-β signaling. Nat Immunol 18(9):995–1003. https://doi.org/10.1038/ni.3809. Epub 2017 Jul 31. PMID: 28759002; PMCID: PMC5712491

  85. Wang Y, Xiang Y, Xin VW, Wang XW, Peng XC, Liu XQ et al (2020) Dendritic cell biology and its role in tumor immunotherapy. J Hematol Oncol 13(1):107. https://doi.org/10.1186/s13045-020-00939-6.PMID:32746880;PMCID:PMC7397618

    Article  PubMed  PubMed Central  Google Scholar 

  86. Ghiringhelli F, Puig PE, Roux S, Parcellier A, Schmitt E, Solary E et al. (2005 Oct 3) Tumor cells convert immature myeloid dendritic cells into TGF-beta-secreting cells inducing CD4+CD25+ regulatory T cell proliferation. J Exp Med 202(7):919–29. https://doi.org/10.1084/jem.20050463. Epub 2005 Sep 26. PMID: 16186184; PMCID: PMC2213166

  87. Tian M, Schiemann WP (2009) The TGF-beta paradox in human cancer: an update. Future Oncol 5(2):259–271. https://doi.org/10.2217/14796694.5.2.259.PMID:19284383;PMCID:PMC2710615

    Article  CAS  PubMed  Google Scholar 

  88. Labidi-Galy SI, Sisirak V, Meeus P, Gobert M, Treilleux I, Bajard A et al (2011) Quantitative and functional alterations of plasmacytoid dendritic cells contribute to immune tolerance in ovarian cancer. Cancer Res 71(16):5423–5434. https://doi.org/10.1158/0008-5472.CAN-11-0367. Epub 2011 Jun 22 PMID: 21697280

    Article  CAS  PubMed  Google Scholar 

  89. Hanks BA, Holtzhausen A, Evans KS, Jamieson R, Gimpel P, Campbell OM, et al. (2013 Sep) Type III TGF-β receptor downregulation generates an immunotolerant tumor microenvironment. J Clin Invest 123(9):3925–40. https://doi.org/10.1172/JCI65745. Epub 2013 Aug 8. PMID: 23925295; PMCID: PMC3754240

  90. Papaspyridonos M, Matei I, Huang Y, do Rosario Andre M, Brazier-Mitouart H, Waite JC et al. (2015 Apr 29) Id1 suppresses anti-tumour immune responses and promotes tumour progression by impairing myeloid cell maturation. Nat Commun 6:6840. https://doi.org/10.1038/ncomms7840. PMID: 25924227; PMCID: PMC4423225

  91. Nagaraj S, Gabrilovich DI (2012 Aug) Regulation of suppressive function of myeloid-derived suppressor cells by CD4+ T cells. Semin Cancer Biol 22(4):282–288. https://doi.org/10.1016/j.semcancer.2012.01.010. Epub 2012 Jan 31. PMID: 22313876; PMCID: PMC3349790

  92. Yang Y, Li C, Liu T, Dai X, Bazhin AV (2020) Myeloid-derived suppressor cells in tumors: from mechanisms to antigen specificity and microenvironmental regulation. Front Immunol 22(11):1371. https://doi.org/10.3389/fimmu.2020.01371.PMID:32793192;PMCID:PMC7387650

    Article  Google Scholar 

  93. Casacuberta-Serra S, Parés M, Golbano A, Coves E, Espejo C, Barquinero J (2017) Myeloid-derived suppressor cells can be efficiently generated from human hematopoietic progenitors and peripheral blood monocytes. Immunol Cell Biol 95(6):538–548. https://doi.org/10.1038/icb.2017.4. Epub 2017 Jan 21 PMID: 28108746

    Article  CAS  PubMed  Google Scholar 

  94. Gonzalez-Junca A, Driscoll KE, Pellicciotta I, Du S, Lo CH, Roy R et al (2019 Feb) Autocrine TGFβ is a survival factor for monocytes and drives immunosuppressive lineage commitment. Cancer Immunol Res 7(2):306–320. https://doi.org/10.1158/2326-6066.CIR-18-0310. Epub 2018 Dec 11. PMID: 30538091; PMCID: PMC6828175

  95. Bodogai M, Moritoh K, Lee-Chang C, Hollander CM, Sherman-Baust CA, Wersto RP et al. (2015 Sep 1) Immunosuppressive and prometastatic functions of myeloid-derived suppressive cells rely upon education from tumor-associated B cells. Cancer Res 75(17):3456–65. https://doi.org/10.1158/0008-5472.CAN-14-3077. Epub 2015 Jul 16. PMID: 26183924; PMCID: PMC4558269

  96. Li J, Wang L, Chen X, Li L, Li Y, Ping Y et al (2017) CD39/CD73 upregulation on myeloid-derived suppressor cells via TGF-β-mTOR-HIF-1 signaling in patients with non-small cell lung cancer. Oncoimmunology 6(6):e1320011. https://doi.org/10.1080/2162402X.2017.1320011.PMID:28680754;PMCID:PMC5486179

    Article  PubMed  PubMed Central  Google Scholar 

  97. Filipazzi P, Valenti R, Huber V, Pilla L, Canese P, Iero M et al (2007) Identification of a new subset of myeloid suppressor cells in peripheral blood of melanoma patients with modulation by a granulocyte-macrophage colony-stimulation factor-based antitumor vaccine. J Clin Oncol 25(18):2546–2553. https://doi.org/10.1200/JCO.2006.08.5829. PMID: 17577033

    Article  CAS  PubMed  Google Scholar 

  98. Yang Z, Guo J, Weng L, Tang W, Jin S, Ma W (2020) Myeloid-derived suppressor cells-new and exciting players in lung cancer. J Hematol Oncol 13(1):10. https://doi.org/10.1186/s13045-020-0843-1.PMID:32005273;PMCID:PMC6995114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Chen X, Wang L, Li P, Song M, Qin G, Gao Q et al. (2018 Nov 15) Dual TGF-β and PD-1 blockade synergistically enhances MAGE-A3-specific CD8+ T cell response in esophageal squamous cell carcinoma. Int J Cancer 143(10):2561–2574. https://doi.org/10.1002/ijc.31730. Epub 2018 Sep 21. Erratum in: Int J Cancer. 2020 Jan 1;146(1):E24. PMID: 29981155

  100. Petty AJ, Owen DH, Yang Y, Huang X (2021) Targeting tumor-associated macrophages in cancer immunotherapy. Cancers (Basel) 13(21):5318. https://doi.org/10.3390/cancers13215318.PMID:34771482;PMCID:PMC8582510

    Article  CAS  PubMed  Google Scholar 

  101. Balkwill F, Charles KA, Mantovani A (2005) Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell 7(3):211–217. https://doi.org/10.1016/j.ccr.2005.02.013. PMID: 15766659

    Article  CAS  PubMed  Google Scholar 

  102. Lin Y, Xu J, Lan H (2019) Tumor-associated macrophages in tumor metastasis: biological roles and clinical therapeutic applications. J Hematol Oncol 12(1):76. https://doi.org/10.1186/s13045-019-0760-3.PMID:31300030;PMCID:PMC6626377

    Article  PubMed  PubMed Central  Google Scholar 

  103. Xu Y, Wang X, Liu L, Wang J, Wu J, Sun C (2022 May) Role of macrophages in tumor progression and therapy (Review). Int J Oncol 60(5):57. https://doi.org/10.3892/ijo.2022.5347. Epub 2022 Apr 1. PMID: 35362544; PMCID: PMC8997338

  104. Li M, He L, Zhu J, Zhang P, Liang S (2022) Targeting tumor-associated macrophages for cancer treatment. Cell Biosci 12(1):85. https://doi.org/10.1186/s13578-022-00823-5.PMID:35672862;PMCID:PMC9172100

    Article  PubMed  PubMed Central  Google Scholar 

  105. Bierie B, Moses HL (2006 Feb-Apr) TGF-beta and cancer. Cytokine Growth Factor Rev 17(1–2):29–40. https://doi.org/10.1016/j.cytogfr.2005.09.006. Epub 2005 Nov 10. PMID: 16289860

  106. Novitskiy SV, Pickup MW, Chytil A, Polosukhina D, Owens P, Moses HL (2012 Sep) Deletion of TGF-β signaling in myeloid cells enhances their anti-tumorigenic properties. J Leukoc Biol 92(3):641–51. https://doi.org/10.1189/jlb.1211639. Epub 2012 Jun 8. PMID: 22685318; PMCID: PMC3427612

  107. Krstic J, Santibanez JF (2014) Transforming growth factor-beta and matrix metalloproteinases: functional interactions in tumor stroma-infiltrating myeloid cells. Sci World J 21(2014):521754. https://doi.org/10.1155/2014/521754.PMID:24578639;PMCID:PMC3918721

    Article  Google Scholar 

  108. Liu Z, Kuang W, Zhou Q, Zhang Y (2018) TGF-β1 secreted by M2 phenotype macrophages enhances the stemness and migration of glioma cells via the SMAD2/3 signalling pathway. Int J Mol Med 42:3395–3403

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Masucci MT, Minopoli M, Carriero MV (2019 Nov 15) Tumor associated neutrophils. their role in tumorigenesis, metastasis, prognosis and therapy. Front Oncol 9:1146. https://doi.org/10.3389/fonc.2019.01146. PMID: 31799175; PMCID: PMC6874146

  110. Fridlender ZG, Sun J, Kim S, Kapoor V, Cheng G, Ling L et al (2009) Polarization of tumor-associated neutrophil phenotype by TGF-beta: N1 versus N2 TAN. Cancer Cell 16(3):183–194. https://doi.org/10.1016/j.ccr.2009.06.017.PMID:19732719;PMCID:PMC2754404

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Fridlender ZG, Albelda SM (2012) Tumor-associated neutrophils: friend or foe? Carcinogenesis 33(5):949–955. https://doi.org/10.1093/carcin/bgs123. Epub 2012 Mar 16 PMID: 22425643

    Article  CAS  PubMed  Google Scholar 

  112. Pekarek LA, Starr BA, Toledano AY, Schreiber H (1995) Inhibition of tumor growth by elimination of granulocytes. J Exp Med 181(1):435–440. https://doi.org/10.1084/jem.181.1.435.PMID:7807024;PMCID:PMC2191807

    Article  CAS  PubMed  Google Scholar 

  113. Mantovani A, Cassatella MA, Costantini C, Jaillon S (2011) Neutrophils in the activation and regulation of innate and adaptive immunity. Nat Rev Immunol 11(8):519–531. https://doi.org/10.1038/nri3024. PMID: 21785456

    Article  CAS  PubMed  Google Scholar 

  114. Fridlender ZG, Sun J, Mishalian I, Singhal S, Cheng G, Kapoor V et al. (2012b) Transcriptomic analysis comparing tumor-associated neutrophils with granulocytic myeloid-derived suppressor cells and normal neutrophils. PLoS One. 7(2):e31524. https://doi.org/10.1371/journal.pone.0031524. Epub 2012 Feb 14. PMID: 22348096; PMCID: PMC3279406

  115. Chen JJ, Sun Y, Nabel GJ (1998) Regulation of the proinflammatory effects of Fas ligand (CD95L). Science 282(5394):1714–1717. https://doi.org/10.1126/science.282.5394.1714. PMID: 9831564

    Article  CAS  PubMed  Google Scholar 

  116. Akhurst RJ (2017) Targeting TGF-β signaling for therapeutic gain. Cold Spring Harb Perspect Biol 9(10):a022301. https://doi.org/10.1101/cshperspect.a022301.PMID:28246179;PMCID:PMC5630004

    Article  PubMed  PubMed Central  Google Scholar 

  117. Haque S, Morris JC (2017 Aug 3) Transforming growth factor-β: a therapeutic target for cancer. Hum Vaccin Immunother 13(8):1741–1750. https://doi.org/10.1080/21645515.2017.1327107. Epub 2017 Jun 2. PMID: 28575585; PMCID: PMC5557219

  118. Yeh HW, Lee SS, Chang CY, Lang YD, Jou YS (2019) A new switch for TGFβ in cancer. Cancer Res 79(15):3797–3805. https://doi.org/10.1158/0008-5472.CAN-18-2019. Epub 2019 Jul 12 PMID: 31300476

    Article  CAS  PubMed  Google Scholar 

  119. Huynh LK, Hipolito CJ, Ten Dijke P (2019) A perspective on the development of TGF-β inhibitors for cancer treatment. Biomolecules 9(11):743. https://doi.org/10.3390/biom9110743.PMID:31744193;PMCID:PMC6921009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Santibañez JF, Quintanilla M, Bernabeu C (2011) TGF-β/TGF-β receptor system and its role in physiological and pathological conditions. Clin Sci (Lond) 121(6):233–251. https://doi.org/10.1042/CS20110086. PMID: 21615335

    Article  CAS  PubMed  Google Scholar 

  121. Teixeira AF, Ten Dijke P, Zhu HJ (2020) On-target anti-TGF-β therapies are not succeeding in clinical cancer treatments: what are remaining challenges? Front Cell Dev Biol 8(8):605. https://doi.org/10.3389/fcell.2020.00605.PMID:32733895;PMCID:PMC7360684

    Article  PubMed  PubMed Central  Google Scholar 

  122. Huang CY, Chung CL, Hu TH, Chen JJ, Liu PF, Chen CL (2020 Dec 16) Recent progress in TGF-β inhibitors for cancer therapy. Biomed Pharmacother 134:111046. https://doi.org/10.1016/j.biopha.2020.111046. Epub ahead of print. PMID: 33341049

  123. Huang PW, Chang JW (2019 Oct) Immune checkpoint inhibitors win the 2018 Nobel Prize. Biomed J 42(5):299–306. https://doi.org/10.1016/j.bj.2019.09.002. Epub 2019 Nov 5. PMID: 31783990; PMCID: PMC6889239

  124. Topalian SL, Taube JM, Anders RA, Pardoll DM (2016 May) Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat Rev Cancer 16(5):275–87. https://doi.org/10.1038/nrc.2016.36. Epub 2016 Apr 15. PMID: 27079802; PMCID: PMC5381938

  125. Wang Y, Zhang H, Liu C, Wang Z, Wu W, Zhang N et al (2022) Immune checkpoint modulators in cancer immunotherapy: recent advances and emerging concepts. J Hematol Oncol 15(1):111. https://doi.org/10.1186/s13045-022-01325-0.PMID:35978433;PMCID:PMC9386972.[125]RobertC.Adecadeofimmune-checkpointinhibitorsincancertherapy.NatCommun.2020Jul30;11(1):3801.doi:10.1038/s41467-020-17670-y.PMID:32732879;PMCID:PMC7393098

    Article  PubMed  PubMed Central  Google Scholar 

  126. Xin YuJ, Hubbard-Lucey VM, Tang J (2019) Immuno-oncology drug development goes global. Nat Rev Drug Discov 18(12):899–900. https://doi.org/10.1038/d41573-019-00167-9. PMID: 31780841

    Article  CAS  Google Scholar 

  127. Chen DS, Mellman I (2013) Oncology meets immunology: the cancer-immunity cycle. Immunity 39:1–10. https://doi.org/10.1016/j.immuni.2013.07.012

    Article  CAS  PubMed  Google Scholar 

  128. Bai X, Yi M, Jiao Y, Chu Q, Wu K (2019) Blocking TGF-β signaling to enhance the efficacy of immune checkpoint inhibitor. Onco Targets Ther 11(12):9527–9538. https://doi.org/10.2147/OTT.S224013.PMID:31807028;PMCID:PMC6857659

    Article  Google Scholar 

  129. Vinay DS, Ryan EP, Pawelec G et al (2015) Immune evasion in cancer: mechanistic basis and therapeutic strategies. Semin Cancer Biol 35(Suppl):S185–S198. https://doi.org/10.1016/j.semcancer.2015.03.004

    Article  CAS  PubMed  Google Scholar 

  130. Dodagatta-Marri E, Meyer DS, Reeves MQ, Paniagua R, To MD, Binnewies M et al (2019) α-PD-1 therapy elevates Treg/Th balance and increases tumor cell pSmad3 that are both targeted by α-TGFβ antibody to promote durable rejection and immunity in squamous cell carcinomas. J Immunother Cancer 7(1):62. https://doi.org/10.1186/s40425-018-0493-9.PMID:30832732;PMCID:PMC6399967

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Ravi R, Noonan KA, Pham V, Bedi R, Zhavoronkov A, Ozerov IV et al (2018) Bifunctional immune checkpoint-targeted antibody-ligand traps that simultaneously disable TGFβ enhance the efficacy of cancer immunotherapy. Nat Commun 9(1):741. https://doi.org/10.1038/s41467-017-02696-6.PMID:29467463;PMCID:PMC5821872

    Article  PubMed  PubMed Central  Google Scholar 

  132. Lan Y, Zhang D, Xu C, Hance KW, Marelli B, Qi J et al. (2018 Jan 17) Enhanced preclinical antitumor activity of M7824, a bifunctional fusion protein simultaneously targeting PD-L1 and TGF-β. Sci Transl Med 10(424):eaan5488. https://doi.org/10.1126/scitranslmed.aan5488. PMID: 29343622

  133. Strauss J, Heery CR, Schlom J, Madan RA, Cao L, Kang Z et al (2018) Phase I Trial of M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGFβ. Adv Solid Tumors Clin Cancer Res 24(6):1287–1295. https://doi.org/10.1158/1078-0432.CCR-17-2653. Epub 2018 Jan 3 PMID: 29298798

    Article  CAS  Google Scholar 

  134. Caldwell KJ, Gottschalk S, Talleur AC (2021) Allogeneic CAR cell therapy-more than a pipe dream. Front Immunol 11:618427. Published 2021 Jan 8. https://doi.org/10.3389/fimmu.2020.618427

  135. Hartley J, Abken H (2019) Chimeric antigen receptors designed to overcome transforming growth factor-β-mediated repression in the adoptive T-cell therapy of solid tumors. Clin Transl Immunology. 8(6):e1064. https://doi.org/10.1002/cti2.1064.PMID:31236274;PMCID:PMC6589154

    Article  PubMed  PubMed Central  Google Scholar 

  136. Golumba-Nagy V, Kuehle J, Hombach AA, Abken H (2018 Sep 5) CD28-ζ CAR T cells resist TGF-β repression through IL-2 signaling, which can be mimicked by an engineered IL-7 autocrine loop. Mol Ther 26(9):2218–2230. https://doi.org/10.1016/j.ymthe.2018.07.005. Epub 2018 Jul 10. PMID: 30055872; PMCID: PMC6127517

  137. Kloss CC, Lee J, Zhang A, Chen F, Melenhorst JJ, Lacey SF et al. (2018 Jul 5) Dominant-negative TGF-β receptor enhances PSMA-targeted human CAR T cell proliferation and augments prostate cancer eradication. Mol Ther 26(7):1855–1866. https://doi.org/10.1016/j.ymthe.2018.05.003. Epub 2018 May 8. PMID: 29807781; PMCID: PMC6037129

  138. Hou Chang ZL, Lorenzini MH, Chen X, Tran U, Bangayan NJ, Chen YY (2018 Mar) Rewiring T-cell responses to soluble factors with chimeric antigen receptors. Nat Chem Biol 14(3):317–324. https://doi.org/10.1038/nchembio.2565. Epub 2018 Jan 29. PMID: 29377003; PMCID: PMC6035732

  139. Wang Z, Liu Q, Risu N, Fu J, Zou Y, Tang J et al (2020) Galunisertib enhances chimeric antigen receptor-modified T cell function. Eur J Histochem 64(s2):3122. https://doi.org/10.4081/ejh.2020.3122.PMID:32705856;PMCID:PMC7388644

    Article  PubMed  PubMed Central  Google Scholar 

  140. Grimes JM, Carvajal RD, Muranski P (2021 Feb) Cellular therapy for the treatment of solid tumors. Transfus Apher Sci 60(1):103056. https://doi.org/10.1016/j.transci.2021.103056. Epub 2021 Jan 10. PMID: 33478888

  141. Tokarew N, Ogonek J, Endres S, von Bergwelt-Baildon M, Kobold S (2019 Jan) Teaching an old dog new tricks: next-generation CAR T cells. Br J Cancer 120(1):26–37. https://doi.org/10.1038/s41416-018-0325-1. Epub 2018 Nov 9. PMID: 30413825; PMCID: PMC6325111

  142. Mojsilovic SS, Mojsilovic S, Villar VH, Santibanez JF (2021) The Metabolic features of tumor-associated macrophages: opportunities for Immunotherapy? Anal Cell Pathol [Amst]. 14(2021):5523055. https://doi.org/10.1155/2021/5523055.PMID:34476174;PMCID:PMC8407977

    Article  Google Scholar 

  143. Anderson NR, Minutolo NG, Gill S, Klichinsky M (2021) Macrophage-based approaches for cancer immunotherapy. Cancer Res 81(5):1201–1208. https://doi.org/10.1158/0008-5472.CAN-20-2990. Epub 2020 Nov 17 PMID: 33203697

    Article  CAS  PubMed  Google Scholar 

Download references

Statements and Declarations

Funding: This study was funded by the Ministry of Education, Science and Technological Development of the Republic of Serbia (grant number 451-03-9/2021-14/200015), Fondo Nacional de Desarrollo Científico y Tecnológico FONDECYT [Grant number: 1201039 (FS)]; Millennium Science Initiative Program—ICN09_016/ICN2021_045: Millennium Institute on Immunology and Immunotherapy (ICN09_016/ICN2021_045; former P09/016-F) (FS); The Millennium Nucleus of Ion Channel-Associated Diseases (MiNICAD) is supported by the Iniciativa Científica Milenio ANID, Chile NCN19_168 (FS).

Disclosure of Interests: All authors declare they have no conflict of interest.

Ethical Approval: This article contains neither any studies with human participants nor performed studies with animals by any of the authors.

Data Availability Statement: The material supporting the conclusion of this review has been included within the article.

Acknowledgments: We thank the support of the visiting professor program of UBO to J.F.S.

Author information

Authors and Affiliations

  1. Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK

    Víctor H. Villar

  2. Institute for Medical Research, National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia

    Tijana Subotički, Dragoslava Đikić, Olivera Mitrović-Ajtić & Juan F. Santibanez

  3. Faculty of Life Sciences, Universidad Andres Bello, Santiago, Chile

    Felipe Simon

  4. Millennium Institute On Immunology and Immunotherapy, Santiago, Chile

    Felipe Simon

  5. Millennium Nucleus of Ion Channel-Associated Diseases, Santiago, Chile

    Felipe Simon

  6. Integrative Center for Biology and Applied Chemistry (CIBQA), Bernardo O’Higgins University, Santiago, Chile

    Juan F. Santibanez

  7. Molecular Oncology Group, Institute for Medical Research, University of Belgrade, Dr. Subotica 4, POB 102, 11129, Belgrade, Serbia

    Juan F. Santibanez

Authors
  1. Víctor H. Villar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tijana Subotički
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dragoslava Đikić
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Olivera Mitrović-Ajtić
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Felipe Simon
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Juan F. Santibanez
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Juan F. Santibanez .

Editor information

Editors and Affiliations

  1. Universidad Andres Bello, Santiago, Chile

    Felipe Simon

  2. Spanish National Research Council, Madrid, Spain

    Carmelo Bernabeu

Rights and permissions

Reprints and permissions

Copyright information

© 2023 The Author(s), under exclusive license to Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Villar, V.H., Subotički, T., Đikić, D., Mitrović-Ajtić, O., Simon, F., Santibanez, J.F. (2023). Transforming Growth Factor-β1 in Cancer Immunology: Opportunities for Immunotherapy. In: Simon, F., Bernabeu, C. (eds) Advances in Molecular Pathology. Advances in Experimental Medicine and Biology, vol 1408. Springer, Cham. https://doi.org/10.1007/978-3-031-26163-3_17

Download citation

Publish with us

Policies and ethics

Search

Navigation