Thymosin α1 protects from CTLA-4 intestinal immunopathology
Giorgia Renga, Marina M Bellet, Marilena Pariano, Marco Gargaro, Claudia Stincardini, Fiorella D'Onofrio, Paolo Mosci, Stefano Brancorsini, Andrea Bartoli, Allan L Goldstein, Enrico Garaci, Luigina Romani, Claudio Costantini, Giorgia Renga, Marina M Bellet, Marilena Pariano, Marco Gargaro, Claudia Stincardini, Fiorella D'Onofrio, Paolo Mosci, Stefano Brancorsini, Andrea Bartoli, Allan L Goldstein, Enrico Garaci, Luigina Romani, Claudio Costantini
Abstract
The advent of immune checkpoint inhibitors has represented a major boost in cancer therapy, but safety concerns are increasingly being recognized. Indeed, although beneficial at the tumor site, unlocking a safeguard mechanism of the immune response may trigger autoimmune-like effects at the periphery, thus making the safety of immune checkpoint inhibitors a research priority. Herein, we demonstrate that thymosin α1 (Tα1), an endogenous peptide with immunomodulatory activities, can protect mice from intestinal toxicity in a murine model of immune checkpoint inhibitor-induced colitis. Specifically, Tα1 efficiently prevented immune adverse pathology in the gut by promoting the indoleamine 2,3-dioxygenase (IDO) 1-dependent tolerogenic immune pathway. Notably, Tα1 did not induce IDO1 in the tumor microenvironment, but rather modulated the infiltration of T-cell subsets by inverting the ratio between CD8+ and Treg cells, an effect that may depend on Tα1 ability to regulate the differentiation and chemokine expression profile of DCs. Thus, through distinct mechanisms that are contingent upon the context, Tα1 represents a plausible candidate to improve the safety/efficacy profile of immune checkpoint inhibitors.
Conflict of interest statement
A patent application on “Thymosin α1 for use in treatment of checkpoint inhibitor immune adverse events” by G Renga, MM Bellet, M Pariano, C Costantini, E Garaci, and L Romani is pending (IT201900016310).
© 2020 Renga et al.
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References
- Angell HK, Bruni D, Barrett JC, Herbst R, Galon J (2020) The immunoscore: Colon cancer and beyond. Clin Cancer Res 26: 332–339. 10.1158/1078-0432.CCR-18-1851
- Anz D, Rapp M, Eiber S, Koelzer VH, Thaler R, Haubner S, Knott M, Nagel S, Golic M, Wiedemann GM, et al. (2015) Suppression of intratumoral CCL22 by type i interferon inhibits migration of regulatory T cells and blocks cancer progression. Cancer Res 75: 4483–4493. 10.1158/0008-5472.CAN-14-3499
- Bozza S, Gaziano R, Bonifazi P, Zelante T, Pitzurra L, Montagnoli C, Moretti S, Castronari R, Sinibaldi P, Rasi G, et al. (2007) Thymosin alpha1 activates the TLR9/MyD88/IRF7-dependent murine cytomegalovirus sensing for induction of anti-viral responses in vivo. Int Immunol 19: 1261–1270. 10.1093/intimm/dxm097
- Chen GY, Shaw MH, Redondo G, Nunez G (2008) The innate immune receptor Nod1 protects the intestine from inflammation-induced tumorigenesis. Cancer Res 68: 10060–10067. 10.1158/0008-5472.CAN-08-2061
- Costantini C, Bellet MM, Pariano M, Renga G, Stincardini C, Goldstein AL, Garaci E, Romani L (2019) A reappraisal of thymosin Alpha1 in cancer therapy. Front Oncol 9: 873 10.3389/fonc.2019.00873
- Downes JE, Marshall-Clarke S (2010) Innate immune stimuli modulate bone marrow-derived dendritic cell production in vitro by toll-like receptor-dependent and -independent mechanisms. Immunology 131: 513–524. 10.1111/j.1365-2567.2010.03324.x
- Engel MA, Leffler A, Niedermirtl F, Babes A, Zimmermann K, Filipovic MR, Izydorczyk I, Eberhardt M, Kichko TI, Mueller-Tribbensee SM, et al. (2011) TRPA1 and substance P mediate colitis in mice. Gastroenterology 141: 1346–1358. 10.1053/j.gastro.2011.07.002
- Giuliani C, Napolitano G, Mastino A, Di Vincenzo S, D’Agostini C, Grelli S, Bucci I, Singer DS, Kohn LD, Monaco F, et al. (2000) Thymosin-alpha1 regulates MHC class I expression in FRTL-5 cells at transcriptional level. Eur J Immunol 30: 778–786. 10.1002/1521-4141(200003)30:3<778::AID-IMMU778>;2-I
- Goldstein AL, Low TL, McAdoo M, McClure J, Thurman GB, Rossio J, Lai CY, Chang D, Wang SS, Harvey C, et al. (1977) Thymosin alpha1: Isolation and sequence analysis of an immunologically active thymic polypeptide. Proc Natl Acad Sci U S A 74: 725–729. 10.1073/pnas.74.2.725
- Helft J, Bottcher J, Chakravarty P, Zelenay S, Huotari J, Schraml BU, Goubau D, Reis e Sousa C (2015) GM-CSF mouse bone marrow cultures comprise a heterogeneous population of CD11c(+)MHCII(+) macrophages and dendritic cells. Immunity 42: 1197–1211. 10.1016/j.immuni.2015.05.018
- Holmgaard RB, Zamarin D, Li Y, Gasmi B, Munn DH, Allison JP, Merghoub T, Wolchok JD (2015) Tumor-expressed IDO recruits and activates MDSCs in a treg-dependent manner. Cell Rep 13: 412–424. 10.1016/j.celrep.2015.08.077
- Holmgaard RB, Zamarin D, Munn DH, Wolchok JD, Allison JP (2013) Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4. J Exp Med 210: 1389–1402. 10.1084/jem.20130066
- House IG, Savas P, Lai J, Chen AXY, Oliver AJ, Teo ZL, Todd KL, Henderson MA, Giuffrida L, Petley EV, et al. (2020) Macrophage-Derived CXCL9 and CXCL10 are required for antitumor immune responses following immune checkpoint blockade. Clin Cancer Res 26: 487–504. 10.1158/1078-0432.CCR-19-1868
- Janker F, Weder W, Jang JH, Jungraithmayr W (2018) Preclinical, non-genetic models of lung adenocarcinoma: A comparative survey. Oncotarget 9: 30527–30538. 10.18632/oncotarget.25668
- Kaesler S, Wolbing F, Kempf WE, Skabytska Y, Koberle M, Volz T, Sinnberg T, Amaral T, Mockel S, Yazdi A, et al. (2019) Targeting tumor-resident mast cells for effective anti-melanoma immune responses. JCI Insight 4: e125057 10.1172/jci.insight.125057
- Kelly PN. (2018) The cancer immunotherapy revolution. Science 359: 1344–1345. 10.1126/science.359.6382.1344
- Kiesler P, Fuss IJ, Strober W (2015) Experimental models of inflammatory bowel diseases. Cell Mol Gastroenterol Hepatol 1: 154–170. 10.1016/j.jcmgh.2015.01.006
- King R, Tuthill C (2016) Immune modulation with thymosin alpha 1 treatment. Vitam Horm 102: 151–178. 10.1016/bs.vh.2016.04.003
- Kumpers C, Jokic M, Haase O, Offermann A, Vogel W, Gratz V, Langan EA, Perner S, Terheyden P (2019) Immune cell infiltration of the primary tumor, not PD-L1 status, is associated with improved response to checkpoint inhibition in metastatic melanoma. Front Med (Lausanne) 6: 27 10.3389/fmed.2019.00027
- Li HY, McSharry M, Bullock B, Nguyen TT, Kwak J, Poczobutt JM, Sippel TR, Heasley LE, Weiser-Evans MC, Clambey ET, et al. (2017) The tumor microenvironment regulates sensitivity of murine lung tumors to PD-1/PD-L1 antibody blockade. Cancer Immunol Res 5: 767–777. 10.1158/2326-6066.CIR-16-0365
- Martins F, Sofiya L, Sykiotis GP, Lamine F, Maillard M, Fraga M, Shabafrouz K, Ribi C, Cairoli A, Guex-Crosier Y, et al. (2019) Adverse effects of immune-checkpoint inhibitors: Epidemiology, management and surveillance. Nat Rev Clin Oncol 16: 563–580. 10.1038/s41571-019-0218-0
- McGettrick AF, O’Neill LA (2007) Toll-like receptors: Key activators of leucocytes and regulator of haematopoiesis. Br J Haematol 139: 185–193. 10.1111/j.1365-2141.2007.06802.x
- Montagnoli C, Perruccio K, Bozza S, Bonifazi P, Zelante T, De Luca A, Moretti S, D’Angelo C, Bistoni F, Martelli M, et al. (2008) Provision of antifungal immunity and concomitant alloantigen tolerization by conditioned dendritic cells in experimental hematopoietic transplantation. Blood Cells Mol Dis 40: 55–62. 10.1016/j.bcmd.2007.06.016
- Muller AJ, Manfredi MG, Zakharia Y, Prendergast GC (2019) Inhibiting IDO pathways to treat cancer: Lessons from the ECHO-301 trial and beyond. Semin Immunopathol 41: 41–48. 10.1007/s00281-018-0702-0
- Nagai Y, Garrett KP, Ohta S, Bahrun U, Kouro T, Akira S, Takatsu K, Kincade PW (2006) Toll-like receptors on hematopoietic progenitor cells stimulate innate immune system replenishment. Immunity 24: 801–812. 10.1016/j.immuni.2006.04.008
- Naik SH, Proietto AI, Wilson NS, Dakic A, Schnorrer P, Fuchsberger M, Lahoud MH, O’Keeffe M, Shao QX, Chen WF, et al. (2005) Cutting edge: Generation of splenic CD8+ and CD8− dendritic cell equivalents in Fms-like tyrosine kinase 3 ligand bone marrow cultures. J Immunol 174: 6592–6597. 10.4049/jimmunol.174.11.6592
- National Academies of Sciences, Engineering, and Medicine (2019) Advancing Progress in the Development of Combination Cancer Therapies with Immune Checkpoint Inhibitors: Proceedings of a Workshop. Washington, DC: The National Academies Press; 10.17226/25405
- Pages F, Mlecnik B, Marliot F, Bindea G, Ou FS, Bifulco C, Lugli A, Zlobec I, Rau TT, Berger MD, et al. (2018) International validation of the consensus immunoscore for the classification of colon cancer: A prognostic and accuracy study. Lancet 391: 2128–2139. 10.1016/S0140-6736(18)30789-X
- Pai CS, Simons DM, Lu X, Evans M, Wei J, Wang YH, Chen M, Huang J, Park C, Chang A, et al. (2019) Tumor-conditional anti-CTLA4 uncouples antitumor efficacy from immunotherapy-related toxicity. J Clin Invest 129: 349–363. 10.1172/JCI123391
- Perez-Ruiz E, Minute L, Otano I, Alvarez M, Ochoa MC, Belsue V, de Andrea C, Rodriguez-Ruiz ME, Perez-Gracia JL, Marquez-Rodas I, et al. (2019) Prophylactic TNF blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapy. Nature 569: 428–432. 10.1038/s41586-019-1162-y
- Perruccio K, Bonifazi P, Topini F, Tosti A, Bozza S, Aloisi T, Carotti A, Aversa F, Martelli MF, Romani L, et al. (2010) Thymosin alpha1 to harness immunity to pathogens after haploidentical hematopoietic transplantation. Ann N Y Acad Sci 1194: 153–161. 10.1111/j.1749-6632.2010.05486.x
- Porter RJ, Andrews C, Brice DP, Durum SK, McLean MH (2018) Can we target endogenous anti-inflammatory responses as a therapeutic strategy for inflammatory bowel disease?. Inflamm Bowel Dis 24: 2123–2134. 10.1093/ibd/izy230
- Ritter B, Greten FR (2019) Modulating inflammation for cancer therapy. J Exp Med 216: 1234–1243. 10.1084/jem.20181739
- Romani L, Bistoni F, Gaziano R, Bozza S, Montagnoli C, Perruccio K, Pitzurra L, Bellocchio S, Velardi A, Rasi G, et al. (2004) Thymosin alpha 1 activates dendritic cells for antifungal Th1 resistance through toll-like receptor signaling. Blood 103: 4232–4239. 10.1182/blood-2003-11-4036
- Romani L, Bistoni F, Perruccio K, Montagnoli C, Gaziano R, Bozza S, Bonifazi P, Bistoni G, Rasi G, Velardi A, et al. (2006) Thymosin alpha1 activates dendritic cell tryptophan catabolism and establishes a regulatory environment for balance of inflammation and tolerance. Blood 108: 2265–2274. 10.1182/blood-2006-02-004762
- Romani L, Moretti S, Fallarino F, Bozza S, Ruggeri L, Casagrande A, Aversa F, Bistoni F, Velardi A, Garaci E (2012) Jack of all trades: Thymosin alpha1 and its pleiotropy. Ann N Y Acad Sci 1269: 1–6. 10.1111/j.1749-6632.2012.06716.x
- Romani L, Oikonomou V, Moretti S, Iannitti RG, D’Adamo MC, Villella VR, Pariano M, Sforna L, Borghi M, Bellet MM, et al. (2017) Thymosin alpha1 represents a potential potent single-molecule-based therapy for cystic fibrosis. Nat Med 23: 590–600. 10.1038/nm.4305
- Samaan MA, Pavlidis P, Papa S, Powell N, Irving PM (2018) Gastrointestinal toxicity of immune checkpoint inhibitors: From mechanisms to management. Nat Rev Gastroenterol Hepatol 15: 222–234. 10.1038/nrgastro.2018.14
- Sharma MD, Baban B, Chandler P, Hou DY, Singh N, Yagita H, Azuma M, Blazar BR, Mellor AL, Munn DH (2007) Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase. J Clin Invest 117: 2570–2582. 10.1172/JCI31911
- Shon WJ, Lee YK, Shin JH, Choi EY, Shin DM (2015) Severity of DSS-induced colitis is reduced in Ido1-deficient mice with down-regulation of TLR-MyD88-NF-kB transcriptional networks. Sci Rep 5: 17305 10.1038/srep17305
- Som A, Mandaliya R, Alsaadi D, Farshidpour M, Charabaty A, Malhotra N, Mattar MC (2019) Immune checkpoint inhibitor-induced colitis: A comprehensive review. World J Clin Cases 7: 405–418. 10.12998/wjcc.v7.i4.405
- Spranger S, Dai D, Horton B, Gajewski TF (2017) Tumor-residing Batf3 dendritic cells are required for effector T cell trafficking and adoptive T cell therapy. Cancer Cell 31: 711–723.e4. 10.1016/j.ccell.2017.04.003
- Szeto GL, Finley SD (2019) Integrative approaches to cancer immunotherapy. Trends Cancer 5: 400–410. 10.1016/j.trecan.2019.05.010
- Thomas RM, Wang L, Chen C, Hancock WW, Wells AD (2019) Foxp3 cooperates with Ikaros to control the suppressive function of regulatory T cells. J Immunol 202: 69.23.
- Wang F, Yin Q, Chen L, Davis MM (2018) Bifidobacterium can mitigate intestinal immunopathology in the context of CTLA-4 blockade. Proc Natl Acad Sci U S A 115: 157–161. 10.1073/pnas.1712901115
- Wang T, Zheng N, Luo Q, Jiang L, He B, Yuan X, Shen L (2019) Probiotics Lactobacillus reuteri abrogates immune checkpoint blockade-associated colitis by inhibiting group 3 innate lymphoid cells. Front Immunol 10: 1235 10.3389/fimmu.2019.01235
- Wirtz S, Popp V, Kindermann M, Gerlach K, Weigmann B, Fichtner-Feigl S, Neurath MF (2017) Chemically induced mouse models of acute and chronic intestinal inflammation. Nat Protoc 12: 1295–1309. 10.1038/nprot.2017.044
- Xu Y, Zhan Y, Lew AM, Naik SH, Kershaw MH (2007) Differential development of murine dendritic cells by GM-CSF versus Flt3 ligand has implications for inflammation and trafficking. J Immunol 179: 7577–7584. 10.4049/jimmunol.179.11.7577
- Yao Q, Doan LX, Zhang R, Bharadwaj U, Li M, Chen C (2007) Thymosin-alpha1 modulates dendritic cell differentiation and functional maturation from human peripheral blood CD14+ monocytes. Immunol Lett 110: 110–120. 10.1016/j.imlet.2007.04.007
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