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Cited by 10T-cell and B-cell ImmunologyCancer Immunotherapy and BiomarkersPsoriasis: Treatment and Pathogenesis

Graded RhoA GTPase Expression in Treg Cells Distinguishes Tumor Immunity From Autoimmunity

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Kalim, Khalid W., Yang, Jun-Qi, Modur, Vishnu, Nguyen, Phuong, Li, Yuan, Zheng, Yi, Guo, Fukun·2021·Frontiers in Immunology
DOI 10.3389/fimmu.2021.726393PMC PMC8554290
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Abstract

RhoA of the Rho GTPase family is prenylated at its C-terminus. Prenylation of RhoA has been shown to control T helper 17 (Th17) cell-mediated colitis. By characterizing T cell-specific RhoA conditional knockout mice, we have recently shown that RhoA is required for Th2 and Th17 cell differentiation and Th2/Th17 cell-mediated allergic airway inflammation. It remains unclear whether RhoA plays a cell-intrinsic role in regulatory T (Treg) cells that suppress effector T cells such as Th2/Th17 cells to maintain immune tolerance and to promote tumor immune evasion. Here we have generated Treg cell-specific RhoA-deficient mice. We found that homozygous RhoA deletion in Treg cells led to early, fatal systemic inflammatory disorders. The autoimmune responses came from an increase in activated CD4+ and CD8+ T cells and in effector T cells including Th17, Th1 and Th2 cells. The immune activation was due to impaired Treg cell homeostasis and increased Treg cell plasticity. Interestingly, heterozygous RhoA deletion in Treg cells did not affect Treg cell homeostasis nor cause systemic autoimmunity but induced Treg cell plasticity and an increase in effector T cells. Importantly, heterozygous RhoA deletion significantly inhibited tumor growth, which was associated with tumor-infiltrating Treg cell plasticity and increased tumor-infiltrating effector T cells. Collectively, our findings suggest that graded RhoA expression in Treg cells distinguishes tumor immunity from autoimmunity and that rational targeting of RhoA in Treg cells may trigger anti-tumor T cell immunity without causing autoimmune responses.

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  • The ability of taxanes to activate RhoA can be relevant for understanding their efficacy in cancer therapy, because RhoA can promote anti-tumour immune responses.

    “The ability of taxanes to activate RhoA can be relevant for understanding their efficacy in cancer therapy, because RhoA can promote anti-tumour immune responses 19,75,76 .”

    From Taxane-induced conformational changes in the microtubule lattice activate GEF-H1-dependent RhoA signalling (2026) · cites this paper as [76]

    The Results (page unavailable) report that reducing RhoA expression in regulatory T cells triggered anti-tumour T-cell immunity and suppressed tumour growth—the opposite direction from the claim that activating RhoA promotes that response. The paper does not discuss taxanes. (LLM, conf=0.90)

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References 37 · Cited by 10

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  1. [1]Annunziato F Romagnani C Romagnani S. The 3 Major Types of Innate and Adaptive Cell-Mediated Effector Immunity. J Allergy Clin Immunol (2015) 135: 626–35. doi: 10.1016/j.jaci.2014.11.001 25528359 · DOI · Paper page
  2. [2]Finn OJ. A Believer's Overview of Cancer Immunosurveillance and Immunotherapy. J Immunol (2018) 200: 385–91. doi: 10.4049/jimmunol.1701302 PMC5763509 29311379 · DOI
  3. [3]Uqba Khan U Ghazanfar H. T Lymphocytes and Autoimmunity. Int Rev Cell Mol Biol (2018) 341: 125–68. doi: 10.1016/bs.ircmb.2018.05.008 30262031 · DOI
  4. [4]Ohkura N Kitagawa Y Sakaguchi S. Development and Maintenance of Regulatory T Cells. Immunity (2013) 38: 414–23. doi: 10.1016/j.immuni.2013.03.002 23521883 · DOI
  5. [5]Dang EV Barbi J Yang HY Jinasena D Yu H Zheng Y. Control of T(H)17/T(reg) Balance by Hypoxia-Inducible Factor 1. Cell (2011) 146: 772–84. doi: 10.1016/j.cell.2011.07.033 PMC3387678 21871655 · DOI · Paper page
  6. [6]Gomez-Rodriguez J Wohlfert EA Handon R Meylan F Wu JZ Anderson SM. Itk- Mediated Integration of T Cell Receptor and Cytokine Signaling Regulates the Balance Between Th17 and Regulatory T Cells. J Exp Med (2014) 211: 529–43. doi: 10.1084/jem.20131459 PMC3949578 24534190 · DOI
  7. [7]Byrne WL Mills KH Lederer JA O'Sullivan GC. Targeting Regulatory T Cells in Cancer. Cancer Res (2011) 71: 6915–20. doi: 10.1158/0008-5472.CAN-11-1156 PMC4287207 22068034 · DOI
  8. [8]Shitara K Nhshikawa H. Regulatory T Cells: A Potential Target in Cancer Immunotherapy. Ann NY Acad Sci (2018) 1417: 104–15. doi: 10.1111/nyas.13625 29566262 · DOI
  9. [9]Colamatteo A Carbone F Bruzzaniti S Galgani M Fusco C Maniscalco GT. Molecular Mechanisms Controlling Foxp3 Expression in Health and Autoimmunity: From Epigenetic to Post-Translational Regulation. Front Immunol (2020) 10: 3136. doi: 10.3389/fimmu.2019.03136 32117202 PMC7008726 · DOI
  10. [10]Cortez JT Montauti E Shifrut E Gatchalian J Zhang Y Shaked O. CRISPR Screen in Regulatory T Cells Reveals Modulators of Foxp3. Nature (2020) 582: 416–20. doi: 10.1038/s41586-020-2246-4 PMC7305989 32499641 · DOI
  11. [11]Takahashi R Nishimoto S Muto G Sekiya T Tamiya T Kimura A. SOCS1 Is Essential for Regulatory T Cell Functions by Preventing Loss of Foxp3 Expression as Well as IFN-{Gamma} and IL-17A Production. J Exp Med (2011) 208: 2055–67. doi: 10.1084/jem.20110428 PMC3182063 21893603 · DOI
  12. [12]Tnimov Z Guo Z Gambin Y Nguyen UTT Wu YW Abankwa D. Quantitative Analysis of Prenylated RhoA Interaction With Its Chaperone, RhoGDI. J Biol Chem (2012) 287: 26549–62. doi: 10.1074/jbc.M112.371294 PMC3410996 22628549 · DOI
  13. [13]Nobes CD Hall A. Rho, Rac, and Cdc42 GTPases Regulate the Assembly of Multimolecular Focal Complexes Associated With Actin Stress Fibers, Lamellipodia, and Filopodia. Cell (1995) 81: 53– 62. doi: 10.1016/0092-8674(95)90370-4 7536630 · DOI
  14. [14]Lin R Cerione RA Manor D. Specific Contributions of the Small GTPases Rho,Rac, and Cdc42 to Dbl Transformation. J Biol Chem (1999) 274: 23633–41. doi: 10.1074/jbc.274.33.23633 10438546 · DOI
  15. [15]Guo F Zheng Y. Involvement of Rho Family GTPases in p19Arf- and P53-Mediated Proliferation of Primary Mouse Embryonic Fibroblasts. Mol Cell Biol (2004) 24: 1426–38. doi: 10.1128/mcb.24.3.1426-1438.2004 PMC321455 14729984 · DOI
  16. [16]Zohn IM Campbell SL Khosravi-Far R Rossman KL Der CJ. Rho Family Proteins and Ras Transformation: The RHOad Less Traveled Gets Congested. Oncogene (1998) 17: 1415–38. doi: 10.1038/sj.onc.1202181 9779988 · DOI · Paper page
  17. [17]Olson MF Ashworth A Hall A. An Essential Role for Rho, Rac, and Cdc42 GTPases in Cell Progression Through G1. Science (1995) 269: 1270–2. doi: 10.1126/science.7652575 7652575 · DOI
  18. [18]Rougerie P Largeteau Q Megrelis L Carrette F Lejeune T Toffali L. Fam65b Is a New Transcriptional Target of FOXO1 That Regulates RhoA Signaling for T Lymphocyte Migration. J Immunol (2013) 190: 748–55. doi: 10.4049/jimmunol.1201174 23241886 · DOI
  19. [19]del Pozo MA Vicente-Manzanares M Tejedor R Serrador JM Sanchez-Madrid F. Rho GTPases Control Migration and Polarization of Adhesion Molecules and Cytoskeletal ERM Components in T Lymphocytes. Eur J Immunol (1999) 29: 3609–20. doi: 10.1002/(SICI)1521-4141(199911)29:11<3609::AID-IMMU3609>3.0.CO;2-S 10556816 · DOI
  20. [20]Heasman SJ Carlin LM Cox S Ng T Ridley AJ. Coordinated RhoA Signaling at the Leading Edge and Uropod Is Required for T Cell Transendothelial Migration. J Cell Biol (2010) 190: 553–63. doi: 10.1083/jcb.201002067 PMC2928012 20733052 · DOI
  21. [21]Vielkind S Gallagher-Gambarelli M Gomez M Hinton HJ Cantrell DA. Integrin Regulation by RhoA in Thymocytes. J Immunol (2005) 175: 350–7. doi: 10.4049/jimmunol.175.1.350 15972668 · DOI
  22. [22]Mou F Praskova M Xia F Van Buren D Hock H Avruch J. The Mst1 and Mst2 Kinases Control Activation of Rho Family GTPases and Thymic Egress of Mature Thymocytes. J Exp Med (2012) 209: 741–59. doi: 10.1084/jem.20111692 PMC3328371 22412158 · DOI
  23. [23]Corre I Gomez M Vielkind S Cantrell DA. Analysis of Thymocyte Development Reveals Thath Te GTPase RhoA Is a Positive Regulator of T Cell Receptor Responses In Vivo. J Exp Med (2001) 194: 903–14. doi: 10.1084/jem.194.7.903 PMC2193481 11581313 · DOI
  24. [24]Henning SW Galandrini R Hall A Cantrell DA. The GTPase Rho Has a Critical Regulatory Role in Thymus Development. EMBO J (1997) 16: 2397–407. doi: 10.1093/emboj/16.9.2397 PMC1169840 9171353 · DOI
  25. [25]Galandrini R Henning SW Cantrell DA. Different Functions of the GTPase Rho in Prothymocytes and Late Pre-T Cells. Immunity (1997) 7: 163–74. doi: 10.1016/s1074-7613(00)80519-1 9252129 · DOI
  26. [26]López-Posadas R Fastancz P Carmen Martínez-Sánchez LD Julia Panteleev-Ivlev J Thonn V Kisseleva T. Inhibiting PGGT1B Disrupts Function of RHOA, Resulting in T-Cell Expression of Integrin α4β7 and Development of Colitis in Mice. Gastroenterology (2019) 157: 1293–309. doi: 10.1053/j.gastro.2019.07.007 31302143 · DOI
  27. [27]Yang JQ Kalim KW Li Y Zhang S Hinge A Filippi MD. RhoA Orchestrates Glycolysis for Th2 Cell Differentiation and Allergic Airway Inflammation. J Allergy Clin Immunol (2016) 137: 231–45. doi: 10.1016/j.jaci.2015.05.004 PMC4684821 26100081 · DOI
  28. [28]Yang JQ Kalim KW Li Y Zheng Y Guo F. Ablation of RhoA Impairs Th17 Cell Differentiation and Alleviates House Dust Mite-Triggered Allergic Airway Inflammation. J Leukoc Biol (2019) 106: 1139–51. doi: 10.1002/JLB.3A0119-025RRR PMC7747217 31260596 · DOI
  29. [29]Melendez J Stengel K Zhou X Chauhan BK Debidda M Andreassen P. RhoA GTPase Is Dispensable for Actomyosin Regulation But Is Essential for Mitosis in Primary Mouse Embryonic Fibroblasts. J Biol Chem (2011) 286: 15132–7. doi: 10.1074/jbc.C111.229336 PMC3083211 21454503 · DOI
  30. [30]Kalim KW Yang JQ Li Y Meng Y Zheng Y Guo F. Reciprocal Regulation of Glycolysis- Driven Th17 Pathogenicity and Treg Stability by Cdc42. J Immunol (2018) 200: 2313–26. doi: 10.4049/jimmunol.1601765 PMC5860966 29440353 · DOI
  31. [32]Wei J Long L Yang K Guy C Shrestha S Chen Z. Autophagy Enforces Functional Integrity of Regulatory T Cells by Coupling Environmental Cues and Metabolic Homeostasis. Nat Immunol (2016) 17(3): 277–85. doi: 10.1038/ni.3365 PMC4755832 26808230 · DOI · Paper page
  32. [33]Wan YY Flavell RA. Regulatory T-Cell Functions Are Subverted and Converted Owing to Attenuated Foxp3 Expression. Nature (2007) 445: 766–70. doi: 10.1038/nature05479 17220876 · DOI
  33. [34]Ueno A Ghosh A Hung D Li J Jijon H. Th17 Plasticity and Its Changes Associated With Inflammatory Bowel Disease. World J Gastroenterol (2015) 21: 12283–95. doi: 10.3748/wjg.v21.i43.12283 PMC4649113 26604637 · DOI
  34. [35]Li S Liu M Do MH Chou C Stamatiades EG Nixon BG. Cancer Immunotherapy via Targeted TGF-β Signalling Blockade in TH Cells. Nature (2020) 587: 121–5. doi: 10.1038/s41586-020-2850-3 PMC8353603 33087933 · DOI
  35. [36]Yang K Blanco DB Neale G Vogel P Avila J Clish CB. Homeostatic Control of Metabolic and Functional Fitness of Treg Cells by LKB1 Signalling. Nature (2017) 548(7669): 602–6. doi: 10.1038/nature23665 PMC5804356 28847007 · DOI

Authors
Kalim, K. W., Yang, J.-Q., Modur, V., Nguyen, P., Li, Y., Zheng, Y., & Guo, F.
Affiliations
University of Cincinnati (US)
Corresponding author
  • Zheng, Yi
  • Guo, Fukun
ORCID
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2021-10-15
Volume
12
Pages
726393-726393
ISSN
1664-3224 (ISSN-L)
DOI
10.3389/fimmu.2021.726393
PMC
PMC8554290
OpenAlex
W3206025534
Cited by
10
References
37
Citations by year
2026: 3 · 2025: 1 · 2024: 1 · 2023: 3 · 2022: 2
FWCI
0.56
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Immunology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Institutes of Health (R01GM108661, R56 HL141499, R01CA234038)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
Keywords
RhoA, regulatory T cells, autoimmunity, antitumor immunity, tumor-infiltrating T cells, Th17 cells, Th1 cells, Th2 cells, immune tolerance, tumor immune evasion, systemic inflammation
MeSH terms
Animals, Female, Immune Tolerance, Neoplasms, Autoimmunity, CD8-Positive T-Lymphocytes, Th2 Cells, Tumor Escape, rhoA GTP-Binding Protein, Cell Line, Tumor, T-Lymphocytes, Regulatory, Mice, Th17 Cells

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