TGFβ: Signaling Blockade for Cancer Immunotherapy

Literature Cited

1. Adams B. 2021. GSK, German Merck's $4.2B bintrafusp alfa drug flops again, but companies squint to see glimmers of hope. Fierce Biotech Mar. 16. https://www.fiercebiotech.com/biotech/gsk-german-merck-s-4-2b-bintrafusp-alfa-drug-flops-again-but-companies-squint-to-see
   [Google Scholar]
2. Anido J, Saez-Borderias A, Gonzalez-Junca A, Rodon L, Folch G et al. 2010. TGF-β receptor inhibitors target the CD44^High/Id1^High glioma-initiating cell population in human glioblastoma. Cancer Cell 18:655–68
   [Google Scholar]
3. Arnold TD, Ferrero GM, Qiu H, Phan IT, Akhurst RJ et al. 2012. Defective retinal vascular endothelial cell development as a consequence of impaired integrin αvβ8-mediated activation of transforming growth factor-β. J. Neurosci. 32:1197–206
   [Google Scholar]
4. Arteaga CL, Hurd SD, Winnier AR, Johnson MD, Fendly BM, Forbes JT. 1993. Anti-transforming growth factor (TGF)-beta antibodies inhibit breast cancer cell tumorigenicity and increase mouse spleen natural killer cell activity. Implications for a possible role of tumor cell/host TGF-beta interactions in human breast cancer progression. J. Clin. Investig 92:2569–76First report of TGFβ antibodies potentiating NK cell activity in a mammary carcinoma model in vivo.
   [Google Scholar]
5. Asadzadeh Z, Mohammadi H, Safarzadeh E, Hemmatzadeh M, Mahdian-Shakib A et al. 2017. The paradox of Th17 cell functions in tumor immunity. Cell Immunol 322:15–25
   [Google Scholar]
6. Baras AS, Drake C, Liu JJ, Gandhi N, Kates M et al. 2016. The ratio of CD8 to Treg tumor-infiltrating lymphocytes is associated with response to cisplatin-based neoadjuvant chemotherapy in patients with muscle invasive urothelial carcinoma of the bladder. OncoImmunology 5:e1134412
   [Google Scholar]
7. Batlle E, Massague J. 2019. Transforming growth factor-β signaling in immunity and cancer. Immunity 50:924–40
   [Google Scholar]
8. Becker A, Thakur BK, Weiss JM, Kim HS, Peinado H, Lyden D. 2016. Extracellular vesicles in cancer: cell-to-cell mediators of metastasis. Cancer Cell 30:836–48
   [Google Scholar]
9. Budi EH, Muthusamy BP, Derynck R. 2015. The insulin response integrates increased TGF-β signaling through Akt-induced enhancement of cell surface delivery of TGF-β receptors. Sci. Signal. 8:ra96
   [Google Scholar]
10. Burvenich IJG, Goh YW, Guo N, Gan HK, Rigopoulos A et al. 2021. Radiolabelling and preclinical characterization of ⁸⁹Zr-Df-radiolabelled bispecific anti-PD-L1/TGF-βRII fusion protein bintrafusp alfa. Eur. J. Nucl. Med. Mol. Imaging 48:3075–88
    [Google Scholar]
11. Calcagno AM, Salcido CD, Gillet JP, Wu CP, Fostel JM et al. 2010. Prolonged drug selection of breast cancer cells and enrichment of cancer stem cell characteristics. J. Natl. Cancer Inst. 102:1637–52
    [Google Scholar]
12. Campbell MG, Cormier A, Ito S, Seed RI, Bondesson AJ et al. 2020. Cryo-EM reveals integrin-mediated TGF-β activation without release from latent TGF-β. Cell 180:490–501.e16Integrin β8–mediated TGFβ activation and signaling without release from the latent TGFβ complex.
    [Google Scholar]
13. Chakravarthy A, Khan L, Bensler NP, Bose P, De Carvalho DD. 2018. TGF-β-associated extracellular matrix genes link cancer-associated fibroblasts to immune evasion and immunotherapy failure. Nat. Commun. 9:4692
    [Google Scholar]
14. Chanier T, Chames P. 2019. Nanobody engineering: toward next generation immunotherapies and immunoimaging of cancer. Antibodies 8:113
    [Google Scholar]
15. Chatterjee S, Chatterjee A, Jana S, Dey S, Roy H et al. 2021. Transforming growth factor beta orchestrates PD-L1 enrichment in tumor-derived exosomes and mediates CD8 T-cell dysfunction regulating early phosphorylation of TCR signalome in breast cancer. Carcinogenesis 42:38–47
    [Google Scholar]
16. Chen W, Jin W, Hardegen N, Lei KJ, Li L et al. 2003. Conversion of peripheral CD4⁺CD25⁻ naive T cells to CD4⁺CD25⁺ regulatory T cells by TGF-β induction of transcription factor Foxp3. J. Exp. Med 198:1875–86First report that TGFβ induces FOXP3⁺ Treg differentiation.
    [Google Scholar]
17. Connolly EC, Saunier EF, Quigley D, Luu MT, De Sapio A et al. 2011. Outgrowth of drug-resistant carcinomas expressing markers of tumor aggression after long term TβRI/II kinase inhibition with Ly2109761. Cancer Res. 71:62339–49
    [Google Scholar]
18. Cooper J, Giancotti FG 2019. Integrin signaling in cancer: mechanotransduction, stemness, epithelial plasticity, and therapeutic resistance. Cancer Cell 35:347–67
    [Google Scholar]
19. Cuende J, Lienart S, Dedobbeleer O, Van Der Woning B, De Boeck G et al. 2015. Monoclonal antibodies against GARP/TGF-β1 complexes inhibit the immunosuppressive activity of human regulatory T cells in vivo. Sci. Transl. Med. 7:284ra56
    [Google Scholar]
20. Curran MA, Montalvo W, Yagita H, Allison JP. 2010. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. PNAS 107:4275–80
    [Google Scholar]
21. Dahmani A, Delisle JS. 2018. TGF-β in T cell biology: implications for cancer immunotherapy. Cancers 10:6194
    [Google Scholar]
22. Danilova L, Wang H, Sunshine J, Kaunitz GJ, Cottrell TR et al. 2016. Association of PD-1/PD-L axis expression with cytolytic activity, mutational load, and prognosis in melanoma and other solid tumors. PNAS 113:E7769–77
    [Google Scholar]
23. David JM, Dominguez C, McCampbell KK, Gulley JL, Schlom J, Palena C. 2017. A novel bifunctional anti-PD-L1/TGF-β trap fusion protein (M7824) efficiently reverts mesenchymalization of human lung cancer cells. OncoImmunology 6:e1349589
    [Google Scholar]
24. Derynck R, Budi EH. 2019. Specificity, versatility, and control of TGF-β family signaling. Sci. Signal. 12:570aav5183
    [Google Scholar]
25. Derynck R, Turley SJ, Akhurst RJ. 2021. TGFβ biology in cancer progression and immunotherapy. Nat. Rev. Clin. Oncol. 18:9–34
    [Google Scholar]
26. Desbois M, Udyavar AR, Ryner L, Kozlowski C, Guan Y et al. 2020. Integrated digital pathology and transcriptome analysis identifies molecular mediators of T-cell exclusion in ovarian cancer. Nat. Commun. 11:5583
    [Google Scholar]
27. Di Guglielmo GM, Le Roy C, Goodfellow AF, Wrana JL 2003. Distinct endocytic pathways regulate TGF-β receptor signalling and turnover. Nat. Cell Biol. 5:410–21
    [Google Scholar]
28. Dodagatta-Marri E, Ma HY, Liang B, Li J, Meyer DS et al. 2021. Integrin αvβ8 on T cells suppresses anti-tumor immunity in multiple models and is a promising target for tumor immunotherapy. Cell Rep 36:109309
    [Google Scholar]
29. Dodagatta-Marri E, Meyer DS, Reeves MQ, Paniagua R, To MD 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 7:62
    [Google Scholar]
30. Dong X, Hudson NE, Lu C, Springer TA 2014. Structural determinants of integrin β-subunit specificity for latent TGF-β. Nat. Struct. Mol. Biol. 21:1091–96
    [Google Scholar]
31. Dongre A, Weinberg RA. 2019. New insights into the mechanisms of epithelial-mesenchymal transition and implications for cancer. Nat. Rev. Mol. Cell Biol. 20:69–84
    [Google Scholar]
32. Donkor MK, Sarkar A, Li MO. 2012. TGF-β1 produced by activated CD4⁺ T cells antagonizes T cell surveillance of tumor development. OncoImmunology 1:162–71
    [Google Scholar]
33. Donkor MK, Sarkar A, Savage PA, Franklin RA, Johnson LK et al. 2011. T cell surveillance of oncogene-induced prostate cancer is impeded by T cell-derived TGF-β1 cytokine. Immunity 35:123–34
    [Google Scholar]
34. Du D, Katsuno Y, Meyer D, Budi EH, Chen SH et al. 2018. Smad3-mediated recruitment of the methyltransferase SETDB1/ESET controls Snail1 expression and epithelial–mesenchymal transition. EMBO Rep 19:135–55
    [Google Scholar]
35. Edwards JP, Thornton AM, Shevach EM 2014. Release of active TGF-β1 from the latent TGF-β1/GARP complex on T regulatory cells is mediated by integrin β8. J. Immunol. 193:2843–49
    [Google Scholar]
36. Ehrlich M, Shmuely A, Henis YI. 2001. A single internalization signal from the di-leucine family is critical for constitutive endocytosis of the type II TGF-β receptor. J. Cell Sci. 114:1777–86
    [Google Scholar]
37. Flavell RA, Sanjabi S, Wrzesinski SH, Licona-Limon P. 2010. The polarization of immune cells in the tumour environment by TGFβ. Nat. Rev. Immunol. 10:554–67
    [Google Scholar]
38. Formenti SC, Lee P, Adams S, Goldberg JD, Li X et al. 2018. Focal irradiation and systemic TGFβ blockade in metastatic breast cancer. Clin. Cancer Res. 24:2493–504
    [Google Scholar]
39. Gorelik L, Flavell RA. 2001. Immune-mediated eradication of tumors through the blockade of transforming growth factor-β signaling in T cells. Nat. Med 7:1118–22First report of tumor immune eradication by genetic deletion of TGFβ responses in T cells.
    [Google Scholar]
40. Griffin GK, Wu J, Iracheta-Vellve A, Patti JC, Hsu J et al. 2021. Epigenetic silencing by SETDB1 suppresses tumour intrinsic immunogenicity. Nature 595:309–14
    [Google Scholar]
41. Groeneveldt C, Van Hall T, Van Der Burg SH, Ten Dijke P, Van Montfoort N 2020. Immunotherapeutic potential of TGF-β inhibition and oncolytic viruses. Trends Immunol 41:406–20
    [Google Scholar]
42. Guerrero PA, Tchaicha JH, Chen Z, Morales JE, McCarty N et al. 2017. Glioblastoma stem cells exploit the αvβ8 integrin-TGFβ1 signaling axis to drive tumor initiation and progression. Oncogene 36:6568–80
    [Google Scholar]
43. Gulley JL, Madan RA, Pachynski R, Mulders P, Sheikh NA et al. 2017. Role of antigen spread and distinctive characteristics of immunotherapy in cancer treatment. J. Natl. Cancer Inst. 109:djw261
    [Google Scholar]
44. Gunderson AJ, Yamazaki T, McCarty K, Fox N, Phillips M et al. 2020. TGFβ suppresses CD8⁺ T cell expression of CXCR3 and tumor trafficking. Nat. Commun 11:1749Induction of CD8⁺ T cell trafficking into tumors by anti-TGFβ effects on CXCR3 expression.
    [Google Scholar]
45. Guo X, Zhang Y, Zheng L, Zheng C, Song J et al. 2018. Global characterization of T cells in non-small-cell lung cancer by single-cell sequencing. Nat. Med. 24:978–85
    [Google Scholar]
46. Gutcher I, Donkor MK, Ma Q, Rudensky AY, Flavell RA, Li MO. 2011. Autocrine transforming growth factor-β1 promotes in vivo Th17 cell differentiation. Immunity 34:396–408
    [Google Scholar]
47. Holmgaard RB, Schaer DA, Li Y, Castaneda SP, Murphy MY et al. 2018. Targeting the TGFβ pathway with galunisertib, a TGFβRI small molecule inhibitor, promotes anti-tumor immunity leading to durable, complete responses, as monotherapy and in combination with checkpoint blockade. J. Immunother. Cancer 6:47
    [Google Scholar]
48. Hoshino A, Costa-Silva B, Shen TL, Rodrigues G, Hashimoto A et al. 2015. Tumour exosome integrins determine organotropic metastasis. Nature 527:329–35
    [Google Scholar]
49. Hou AJ, Chang ZL, Lorenzini MH, Zah E, Chen YY. 2018. TGF-β–responsive CAR-T cells promote anti-tumor immune function. Bioeng. Transl. Med. 3:75–86
    [Google Scholar]
50. Huang AC, Orlowski RJ, Xu X, Mick R, George SM et al. 2019. A single dose of neoadjuvant PD-1 blockade predicts clinical outcomes in resectable melanoma. Nat. Med. 25:454–61
    [Google Scholar]
51. Huang S, Holzel M, Knijnenburg T, Schlicker A, Roepman P et al. 2012. MED12 controls the response to multiple cancer drugs through regulation of TGF-β receptor signaling. Cell 151:937–50
    [Google Scholar]
52. Hugo W, Zaretsky JM, Sun L, Song C, Moreno BH et al. 2016. Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma. Cell 165:35–44First report that resistance to anti-PD-1 therapy is marked by EMT, ECM, and immunosuppression.
    [Google Scholar]
53. Hynes RO. 2002. Integrins: bidirectional, allosteric signaling machines. Cell 110:673–87
    [Google Scholar]
54. Ishigame H, Mosaheb MM, Sanjabi S, Flavell RA. 2013a. Truncated form of TGF-βRII, but not its absence, induces memory CD8⁺ T cell expansion and lymphoproliferative disorder in mice. J. Immunol. 190:6340–50
    [Google Scholar]
55. Ishigame H, Zenewicz LA, Sanjabi S, Licona-Limón P, Nakayama M et al. 2013b. Excessive Th1 responses due to the absence of TGF-β signaling cause autoimmune diabetes and dysregulated Treg cell homeostasis. PNAS 110:6961–66
    [Google Scholar]
56. Jiao S, Subudhi SK, Aparicio A, Ge Z, Guan B et al. 2019. Differences in tumor microenvironment dictate T helper lineage polarization and response to immune checkpoint therapy. Cell 179:1177–90.e13
    [Google Scholar]
57. Jochems C, Tritsch SR, Pellom ST, Su Z, Soon-Shiong P et al. 2017. Analyses of functions of an anti-PD-L1/TGFβR2 bispecific fusion protein (M7824). Oncotarget 8:75217–31
    [Google Scholar]
58. Kamada T, Togashi Y, Tay C, Ha D, Sasaki A et al. 2019. PD-1(⁺) regulatory T cells amplified by PD-1 blockade promote hyperprogression of cancer. PNAS 116:9999–10008
    [Google Scholar]
59. Katsuno Y, Meyer DS, Zhang Z, Shokat KM, Akhurst RJ et al. 2019. Chronic TGF-β exposure drives stabilized EMT, tumor stemness, and cancer drug resistance with vulnerability to bitopic mTOR inhibition. Sci. Signal. 12:aau8544
    [Google Scholar]
60. Kavanagh B, O'Brien S, Lee D, Hou Y, Weinberg V et al. 2008. CTLA4 blockade expands FoxP3⁺ regulatory and activated effector CD4⁺ T cells in a dose-dependent fashion. Blood 112:1175–83
    [Google Scholar]
61. Kitamura T, Kometani K, Hashida H, Matsunaga A, Miyoshi H et al. 2007. SMAD4-deficient intestinal tumors recruit CCR1⁺ myeloid cells that promote invasion. Nat. Genet. 39:467–75
    [Google Scholar]
62. Kitano S, Tsuji T, Liu C, Hirschhorn-Cymerman D, Kyi C et al. 2013. Enhancement of tumor-reactive cytotoxic CD4⁺ T cell responses after ipilimumab treatment in four advanced melanoma patients. Cancer Immunol. Res. 1:235–44
    [Google Scholar]
63. Knudson KM, Hicks KC, Luo X, Chen JQ, Schlom J, Gameiro SR 2018. M7824, a novel bifunctional anti-PD-L1/TGFβ trap fusion protein, promotes anti-tumor efficacy as monotherapy and in combination with vaccine. OncoImmunology 7:e1426519
    [Google Scholar]
64. Konkel JE, Zhang D, Zanvit P, Chia C, Zangarle-Murray T et al. 2017. Transforming growth factor-β signaling in regulatory T cells controls T helper-17 cells and tissue-specific immune responses. Immunity 46:660–74
    [Google Scholar]
65. Kroger C, Afeyan A, Mraz J, Eaton EN, Reinhardt F et al. 2019. Acquisition of a hybrid E/M state is essential for tumorigenicity of basal breast cancer cells. PNAS 116:7353–62
    [Google Scholar]
66. Laine A, Labaid O, Hernandez-Vargas H, This S, Saniaville A et al. 2021. Cooperation between cancer cells and regulatory T cells to promote immune-escape through integrin αvβ8-mediated TGF-β activation. Nature Commun. 12:6228
    [Google Scholar]
67. Lan Y, Zhang D, Xu C, Hance KW, Marelli B et al. 2018. Enhanced preclinical antitumor activity of M7824, a bifunctional fusion protein simultaneously targeting PD-L1 and TGF-β. Sci. Transl. Med 10:424aan5488Enhanced preclinical activity of bintrafusp alfa, a bispecific protein targeting TGFβ and PD-L1.
    [Google Scholar]
68. Li S, Liu M, Do MH, Chou C, Stamatiades EG et al. 2020. Cancer immunotherapy via targeted TGF-β signalling blockade in T_H cells. Nature 587:121–25
    [Google Scholar]
69. Lind H, Gameiro SR, Jochems C, Donahue RN, Strauss J et al. 2020. Dual targeting of TGF-β and PD-L1 via a bifunctional anti-PD-L1/TGF-βRII agent: status of preclinical and clinical advances. J. Immunother. Cancer 8:e000433
    [Google Scholar]
70. Liu M, Kuo F, Capistrano KJ, Kang D, Nixon BG et al. 2020. TGF-β suppresses type 2 immunity to cancer. Nature 587:115–20
    [Google Scholar]
71. Ludbrook SB, Barry ST, Delves CJ, Horgan CM. 2003. The integrin αvβ3 is a receptor for the latency-associated peptides of transforming growth factors β1 and β3. Biochem. J. 369:311–18
    [Google Scholar]
72. Mariathasan S, Turley SJ, Nickles D, Castiglioni A, Yuen K et al. 2018. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 554:544–48
    [Google Scholar]
73. 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-β receptor. Immunity 25:441–54
    [Google Scholar]
74. Martin CJ, Datta A, Littlefield C, Kalra A, Chapron C et al. 2020. Selective inhibition of TGFβ1 activation overcomes primary resistance to checkpoint blockade therapy by altering tumor immune landscape. Sci. Transl. Med. 12:536eaay8456
    [Google Scholar]
75. Martin F, Apetoh L, Ghiringhelli F 2012. Controversies on the role of Th17 in cancer: a TGF-β-dependent immunosuppressive activity?. Trends Mol. Med. 18:742–49
    [Google Scholar]
76. McClymont SA, Putnam AL, Lee MR, Esensten JH, Liu W et al. 2011. Plasticity of human regulatory T cells in healthy subjects and patients with type 1 diabetes. J. Immunol. 186:3918–26
    [Google Scholar]
77. Miao Y, Yang H, Levorse J, Yuan S, Polak L et al. 2019. Adaptive immune resistance emerges from tumor-initiating stem cells. Cell 177:1172–86.e14CD80 expression on TGFβ-responsive CSCs causing SCC resistance to immunotherapy by dampening T cell cytotoxicity.
    [Google Scholar]
78. Michael M, Parsons M 2020. New perspectives on integrin-dependent adhesions. Curr. Opin. Cell Biol. 63:31–37
    [Google Scholar]
79. Mitra MS, Lancaster K, Adedeji AO, Palanisamy GS, Dave RA et al. 2020. A potent pan-TGFβ neutralizing monoclonal antibody elicits cardiovascular toxicity in mice and cynomolgus monkeys. Toxicol. Sci. 175:124–34
    [Google Scholar]
80. Morillon YMI, Smalley Rumfield C, Pellom ST, Sabzevari A, Roller NT et al. 2020. The use of a humanized NSG-β2m^−/− model for investigation of immune and anti-tumor effects mediated by the bifunctional immunotherapeutic bintrafusp alfa. Front. Oncol. 10:549
    [Google Scholar]
81. Mu D, Cambier S, Fjellbirkeland L, Baron JL, Munger JS et al. 2002. The integrin αvβ8 mediates epithelial homeostasis through MT1-MMP–dependent activation of TGF-β1. J. Cell Biol. 157:493–507
    [Google Scholar]
82. Munger JS, Harpel JG, Giancotti FG, Rifkin DB. 1998. Interactions between growth factors and integrins: latent forms of transforming growth factor-β are ligands for the integrin αvβ1. Mol. Biol. Cell 9:2627–38
    [Google Scholar]
83. Munger JS, Huang X, Kawakatsu H, Griffiths MJ, Dalton SL et al. 1999. The integrin αvβ6 binds and activates latent TGFβ1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell 96:319–28
    [Google Scholar]
84. Muroyama Y, Nirschl TR, Kochel CM, Lopez-Bujanda Z, Theodros D et al. 2017. Stereotactic radiotherapy increases functionally suppressive regulatory T cells in the tumor microenvironment. Cancer Immunol. Res. 5:992–1004
    [Google Scholar]
85. Nagarsheth N, Wicha MS, Zou W. 2017. Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy. Nat. Rev. Immunol. 17:559–72
    [Google Scholar]
86. Nanda R, Liu MC, Yau C, Shatsky R, Pusztai L et al. 2020. Effect of pembrolizumab plus neoadjuvant chemotherapy on pathologic complete response in women with early-stage breast cancer: an analysis of the ongoing phase 2 adaptively randomized I-SPY2 trial. JAMA Oncol. 6:676–84
    [Google Scholar]
87. Nolte M, Margadant C. 2020. Controlling immunity and inflammation through integrin-dependent regulation of TGF-β. Trends Cell Biol 30:49–59
    [Google Scholar]
88. Oh DY, Kwek SS, Raju SS, Li T, McCarthy E et al. 2020. Intratumoral CD4⁺ T cells mediate anti-tumor cytotoxicity in human bladder cancer. Cell 181:1612–25.e13
    [Google Scholar]
89. Oshimori N, Fuchs E. 2012. Paracrine TGF-β signaling counterbalances BMP-mediated repression in hair follicle stem cell activation. Cell Stem Cell 10:63–75
    [Google Scholar]
90. Oshimori N, Oristian D, Fuchs E. 2015. TGF-β promotes heterogeneity and drug resistance in squamous cell carcinoma. Cell 160:963–76
    [Google Scholar]
91. Ozawa A, Sato Y, Imabayashi T, Uemura T, Takagi J, Sekiguchi K. 2016. Molecular basis of the ligand binding specificity of αvβ8 integrin. J. Biol. Chem. 291:11551–65
    [Google Scholar]
92. Panda M, Biswal BK. 2019. Cell signaling and cancer: a mechanistic insight into drug resistance. Mol. Biol. Rep. 46:5645–59
    [Google Scholar]
93. Penheiter SG, Mitchell H, Garamszegi N, Edens M, Dore JJ Jr., Leof EB. 2002. Internalization-dependent and -independent requirements for transforming growth factor β receptor signaling via the Smad pathway. Mol. Cell. Biol. 22:4750–59
    [Google Scholar]
94. Poggio M, Hu T, Pai CC, Chu B, Belair CD et al. 2019. Suppression of exosomal PD-L1 induces systemic anti-tumor immunity and memory. Cell 177:414–27.e13
    [Google Scholar]
95. Punt S, Dronkers EA, Welters MJ, Goedemans R, Koljenović S et al. 2016. A beneficial tumor microenvironment in oropharyngeal squamous cell carcinoma is characterized by a high T cell and low IL-17(⁺) cell frequency. Cancer Immunol. Immunother. 65:393–403
    [Google Scholar]
96. Qin Y, Garrison BS, Ma W, Wang R, Jiang A et al. 2018. A milieu molecule for TGF-β required for microglia function in the nervous system. Cell 174:156–71.e16
    [Google Scholar]
97. Reichart F, Maltsev OV, Kapp TG, Räder AFB, Weinmüller M et al. 2019. Selective targeting of integrin αvβ8 by a highly active cyclic peptide. J. Med. Chem. 62:2024–37
    [Google Scholar]
98. Reyes SB, Narayanan AS, Lee HS, Tchaicha JH, Aldape KD et al. 2013. αvβ8 integrin interacts with RhoGDI1 to regulate Rac1 and Cdc42 activation and drive glioblastoma cell invasion. Mol. Biol. Cell 24:474–82
    [Google Scholar]
99. Robertson IB, Rifkin DB. 2016. Regulation of the bioavailability of TGF-β and TGF-β-related proteins. Cold Spring Harb. Perspect. Biol. 8:a021907
    [Google Scholar]
100. Rodríguez-Ruiz ME, Rodríguez I, Mayorga L, Labiano T, Barbes B et al. 2019. TGFβ blockade enhances radiotherapy abscopal efficacy effects in combination with anti-PD1 and anti-CD137 immunostimulatory monoclonal antibodies. Mol. Cancer Ther. 18:621–31
     [Google Scholar]
101. Sato Y, Tsuboi R, Lyons R, Moses H, Rifkin DB 1990. Characterization of the activation of latent TGF-β by co-cultures of endothelial cells and pericytes or smooth muscle cells: a self-regulating system. J. Cell Biol. 111:757–63
     [Google Scholar]
102. Schumacher TN, Schreiber RD. 2015. Neoantigens in cancer immunotherapy. Science 348:69–74
     [Google Scholar]
103. Seed RI, Kobayashi K, Ito S, Takasaka N, Cormier A et al. 2021. A tumor-specific mechanism of T_Reg enrichment mediated by the integrin αvβ8. Sci. Immunol. 6:57abf0558
     [Google Scholar]
104. Shi M, Zhu J, Wang R, Chen X, Mi L et al. 2011. Latent TGF-β structure and activation. Nature 474:343–49
     [Google Scholar]
105. Shipitsin M, Campbell LL, Argani P, Weremowicz S, Bloushtain-Qimron N et al. 2007. Molecular definition of breast tumor heterogeneity. Cancer Cell 11:259–73
     [Google Scholar]
106. Stockis J, Colau D, Coulie PG, Lucas S. 2009. Membrane protein GARP is a receptor for latent TGF-β on the surface of activated human Treg. Eur. J. Immunol. 39:3315–22
     [Google Scholar]
107. Stockis J, Lienart S, Colau D, Collignon A, Nishimura SL et al. 2017. Blocking immunosuppression by human Tregs in vivo with antibodies targeting integrin αvβ8. PNAS 114:E10161–68
     [Google Scholar]
108. Strauss J, Gatti-Mays ME, Cho BC, Hill A, Salas S et al. 2020. Bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in patients with human papillomavirus-associated malignancies. J. Immunother. Cancer 8:e001395
     [Google Scholar]
109. Strauss J, Heery CR, Schlom J, Madan RA, Cao L et al. 2018. Phase I trial of M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGFβ, in advanced solid tumors. Clin. Cancer Res. 24:1287–95
     [Google Scholar]
110. Takasaka N, Seed RI, Cormier A, Bondesson AJ, Lou J et al. 2018. Integrin αvβ8-expressing tumor cells evade host immunity by regulating TGF-β activation in immune cells. JCI Insight 3:20e122591
     [Google Scholar]
111. Tauriello DVF, Palomo-Ponce S, Stork D, Berenguer-Llergo A, Badia-Ramentol J et al. 2018. TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis. Nature 554:538–43
     [Google Scholar]
112. Thomas DA, Massague J 2005. TGF-β directly targets cytotoxic T cell functions during tumor evasion of immune surveillance. Cancer Cell 8:369–80First report of molecular mechanisms by which TGFβ targets cytotoxic T cells.
     [Google Scholar]
113. Thorsson V, Gibbs DL, Brown SD, Wolf D, Bortone DS et al. 2018. The immune landscape of cancer. Immunity 48:812–30.e14
     [Google Scholar]
114. Tran DQ, Andersson J, Wang R, Ramsey H, Unutmaz D, Shevach EM 2009. GARP (LRRC32) is essential for the surface expression of latent TGF-β on platelets and activated FOXP3⁺ regulatory T cells. PNAS 106:13445–50
     [Google Scholar]
115. Van Allen EM, Miao D, Schilling B, Shukla SA, Blank C et al. 2015. Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science 350:207–11
     [Google Scholar]
116. Wada J, Onishi H, Suzuki H, Yamasaki A, Nagai S et al. 2010. Surface-bound TGF-β1 on effusion-derived exosomes participates in maintenance of number and suppressive function of regulatory T-cells in malignant effusions. Anticancer Res 30:3747–57
     [Google Scholar]
117. Wang D, Quiros J, Mahuron K, Pai CC, Ranzani V et al. 2018. Targeting EZH2 reprograms intratumoral regulatory T cells to enhance cancer immunity. Cell Rep 23:3262–74
     [Google Scholar]
118. Wang L, Saci A, Szabo PM, Chasalow SD, Castillo-Martin M et al. 2018. EMT- and stroma-related gene expression and resistance to PD-1 blockade in urothelial cancer. Nat. Commun. 9:3503
     [Google Scholar]
119. Wang R, Zhu J, Dong X, Shi M, Lu C, Springer TA 2012. GARP regulates the bioavailability and activation of TGFβ. Mol. Biol. Cell 23:1129–39
     [Google Scholar]
120. Webber J, Steadman R, Mason MD, Tabi Z, Clayton A 2010. Cancer exosomes trigger fibroblast to myofibroblast differentiation. Cancer Res 70:9621–30
     [Google Scholar]
121. Worthington JJ, Kelly A, Smedley C, Bauché D, Campbell S et al. 2015. Integrin αvβ8-mediated TGF-β activation by effector regulatory T cells is essential for suppression of T-cell-mediated inflammation. Immunity 42:903–15
     [Google Scholar]
122. Xie Y, Bai O, Yuan J, Chibbar R, Slattery K et al. 2009. Tumor apoptotic bodies inhibit CTL responses and antitumor immunity via membrane-bound transforming growth factor-β1 inducing CD8⁺ T-cell anergy and CD4⁺ Tr1 cell responses. Cancer Res 69:7756–66
     [Google Scholar]
123. Yang L, Huang J, Ren X, Gorska AE, Chytil A et al. 2008. Abrogation of TGFβ signaling in mammary carcinomas recruits Gr-1⁺CD11b⁺ myeloid cells that promote metastasis. Cancer Cell 13:23–35
     [Google Scholar]
124. Yang L, Karin M 2014. Roles of tumor suppressors in regulating tumor-associated inflammation. Cell Death Differ 21:1677–86
     [Google Scholar]
125. Yin JJ, Selander K, Chirgwin JM, Dallas M, Grubbs BG et al. 1999. TGF-β signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development. J. Clin. Investig. 103:197–206
     [Google Scholar]
126. Yue J, Mulder KM. 2000. Requirement of Ras/Mapk pathway activation by transforming growth factor β for transforming growth factor β₁ production in a Smad-dependent pathway. J. Biol. Chem. 275:35656
     [Google Scholar]
127. Zhang N, Bevan MJ. 2012. TGF-β signaling to T cells inhibits autoimmunity during lymphopenia-driven proliferation. Nat. Immunol. 13:667–73
     [Google Scholar]
128. Zheng C, Zheng L, Yoo JK, Guo H, Zhang Y et al. 2017. Landscape of infiltrating T cells in liver cancer revealed by single-cell sequencing. Cell 169:1342–56.e16
     [Google Scholar]
129. Zhou M, Niu J, Wang J, Gao H, Shahbaz M et al. 2020. Integrin αvβ8 serves as a novel marker of poor prognosis in colon carcinoma and regulates cell invasiveness through the activation of TGF-β1. J. Cancer 11:3803–15
     [Google Scholar]
130. Zumwalt TJ, Arnold M, Goel A, Boland CR 2015. Active secretion of CXCL10 and CCL5 from colorectal cancer microenvironments associates with GranzymeB⁺ CD8⁺ T-cell infiltration. Oncotarget 6:2981–91
     [Google Scholar]