Concomitant Mycobacterium tuberculosis infection promotes lung tumor growth through enhancing Treg development

Zhou,Yan; Hu,Zhangguo; Cao,Shuhui; Yan,Bo; Qian,Jialin; Zhong,Hua

doi:10.3892/or.2017.5733

Concomitant Mycobacterium tuberculosis infection promotes lung tumor growth through enhancing Treg development

Authors:
- Yan Zhou
- Zhangguo Hu
- Shuhui Cao
- Bo Yan
- Jialin Qian
- Hua Zhong
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Affiliations: Department of Pulmonary Disease, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China, Department of Respiration Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China
Published online on: June 19, 2017 https://doi.org/10.3892/or.2017.5733
Pages: 685-692
Copyright: © Zhou et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Lung cancer is the most common malignancy in humans. An increased population of CD4+Foxp3+ regulatory T cells (Tregs) in the tumor-associated microenvironment plays an important role in cancer immune evasion. The exact role and the involved mechanisms of concomitant H37Rv infection in non-small cell lung cancer (NSCLC) development are still not clear. Here, we showed that H37Rv infection promoted NSCLC cell growth with a higher percentage of Tregs found in draining lymph nodes. We also determined in vitro that H37Rv infection induced macrophage maturation and PD-L1 expression, which promoted Treg proportion, with enhanced proliferation suppression function. Mechanism analysis revealed that AKT-mTORC1 signal was important for PD-L1 expression induced by H37Rv infection. Suppressing of AKT-mTORC1 signal by rapamycin or raptor deficiency showed decreased PD-L1 levels which further reduced Treg proportion in a co-culture system. Finally, tumor-bearing mice injected with H37Rv plus rapamycin enhance the immune response of lung cancer compared with injected with H37Rv alone. This study demonstrated that concomitant H37Rv infection promote NSCLC tumor immune eacape through enhancing Treg proportion.

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1	Paleiron N, Bylicki O, André M, Rivière E, Grassin F, Robinet G and Chouaïd C: Targeted therapy for localized non-small-cell lung cancer: A review. Onco Targets Ther. 9:4099–4104. 2016. View Article : Google Scholar : PubMed/NCBI
2	Whiteman DC and Wilson LF: The fractions of cancer attributable to modifiable factors: A global review. Cancer Epidemiol. 44:203–221. 2016. View Article : Google Scholar : PubMed/NCBI
3	Hamilton G, Rath B and Ulsperger E: A review of the role of surgery for small cell lung cancer and the potential prognostic value of enumeration of circulating tumor cells. Eur J Surg Oncol. 42:1296–1302. 2016. View Article : Google Scholar : PubMed/NCBI
4	Kuribayashi K, Funaguchi N and Nakano T: Chemotherapy for advanced non-small cell lung cancer with a focus on squamous cell carcinoma. J Cancer Res Ther. 12:528–534. 2016. View Article : Google Scholar : PubMed/NCBI
5	Giaj-Levra N, Ricchetti F and Alongi F: What is changing in radiotherapy for the treatment of locally advanced nonsmall cell lung cancer patients? A review. Cancer Invest. 34:80–93. 2016. View Article : Google Scholar : PubMed/NCBI
6	Chen L, He Z, Qin L, Li Q, Shi X, Zhao S, Chen L, Zhong N and Chen X: Antitumor effect of malaria parasite infection in a murine Lewis lung cancer model through induction of innate and adaptive immunity. PLoS One. 6:e244072011. View Article : Google Scholar : PubMed/NCBI
7	Kim JO, Jung SS, Kim SY, Kim TY, Shin DW, Lee JH and Lee YH: Inhibition of Lewis lung carcinoma growth by Toxoplasma gondii through induction of Th1 immune responses and inhibition of angiogenesis. J Korean Med Sci. 22:(Suppl). S38–S46. 2007. View Article : Google Scholar : PubMed/NCBI
8	Martínez A, Torello S and Kolter R: Sliding motility in mycobacteria. J Bacteriol. 181:7331–7338. 1999.PubMed/NCBI
9	Garg A, Barnes PF, Roy S, Quiroga MF, Wu S, García VE, Krutzik SR, Weis SE and Vankayalapati R: Mannose-capped lipoarabinomannan- and prostaglandin E2-dependent expansion of regulatory T cells in human Mycobacterium tuberculosis infection. Eur J Immunol. 38:459–469. 2008. View Article : Google Scholar : PubMed/NCBI
10	Gehring AJ, Rojas RE, Canaday DH, Lakey DL, Harding CV and Boom WH: The Mycobacterium tuberculosis 19-kilodalton lipoprotein inhibits gamma interferon-regulated HLA-DR and Fc gamma R1 on human macrophages through Toll-like receptor 2. Infect Immun. 71:4487–4497. 2003. View Article : Google Scholar : PubMed/NCBI
11	Liu H, Komai-Koma M, Xu D and Liew FY: Toll-like receptor 2 signaling modulates the functions of CD4⁺ CD25⁺ regulatory T cells. Proc Natl Acad Sci USA. 103:7048–7053. 2006. View Article : Google Scholar : PubMed/NCBI
12	Hirsch CS, Rojas R, Wu M and Toossi Z: Mycobacterium tuberculosis induces expansion of Foxp3 positive CD4 T-cells with a regulatory profile in tuberculin non-sensitized healthy subjects: Implications for effective immunization against TB. J Clin Cell Immunol. 7:72016. View Article : Google Scholar
13	He XY, Xiao L, Chen HB, Hao J, Li J, Wang YJ, He K, Gao Y and Shi BY: T regulatory cells and Th1/Th2 cytokines in peripheral blood from tuberculosis patients. Eur J Clin Microbiol Infect Dis. 29:643–650. 2010. View Article : Google Scholar : PubMed/NCBI
14	Kuo CH, Lo CY, Chung FT, Lee KY, Lin SM, Wang CH, Heh CC, Chen HC and Kuo HP: Concomitant active tuberculosis prolongs survival in non-small cell lung cancer: A study in a tuberculosis-endemic country. PLoS One. 7:e332262012. View Article : Google Scholar : PubMed/NCBI
15	Chen C, Liu Y, Liu Y and Zheng P: mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells. Sci Signal. 2:ra752009. View Article : Google Scholar : PubMed/NCBI
16	Zhou H, Wang Y, Lian Q, Yang B, Ma Y, Wu X, Sun S, Liu Y and Sun B: Differential IL-10 production by DCs determines the distinct adjuvant effects of LPS and PTX in EAE induction. Eur J Immunol. 44:1352–1362. 2014. View Article : Google Scholar : PubMed/NCBI
17	Xu C, Fillmore CM, Koyama S, Wu H, Zhao Y, Chen Z, Herter-Sprie GS, Akbay EA, Tchaicha JH, Altabef A, et al: Loss of Lkb1 and Pten leads to lung squamous cell carcinoma with elevated PD-L1 expression. Cancer Cell. 25:590–604. 2014. View Article : Google Scholar : PubMed/NCBI
18	Zamarron BF and Chen W: Dual roles of immune cells and their factors in cancer development and progression. Int J Biol Sci. 7:651–658. 2011. View Article : Google Scholar : PubMed/NCBI
19	Wieder T, Braumüller H, Kneilling M, Pichler B and Röcken M: T cell-mediated help against tumors. Cell Cycle. 7:2974–2977. 2008. View Article : Google Scholar : PubMed/NCBI
20	Sakaguchi S, Miyara M, Costantino CM and Hafler DA: FOXP3⁺ regulatory T cells in the human immune system. Nat Rev Immunol. 10:490–500. 2010. View Article : Google Scholar : PubMed/NCBI
21	Maynard CL, Hatton RD, Helms WS, Oliver JR, Stephensen CB and Weaver CT: Contrasting roles for all-trans retinoic acid in TGF-beta-mediated induction of Foxp3 and Il10 genes in developing regulatory T cells. J Exp Med. 206:343–357. 2009. View Article : Google Scholar : PubMed/NCBI
22	Roychoudhuri R, Eil RL and Restifo NP: The interplay of effector and regulatory T cells in cancer. Curr Opin Immunol. 33:101–111. 2015. View Article : Google Scholar : PubMed/NCBI
23	Yasumoto K, Hanagiri T and Takenoyama M: Lung cancer-associated tumor antigens and the present status of immunotherapy against non-small-cell lung cancer. Gen Thorac Cardiovasc Surg. 57:449–457. 2009. View Article : Google Scholar : PubMed/NCBI
24	Alexandroff AB, Jackson AM, O'Donnell MA and James K: BCG immunotherapy of bladder cancer: 20 years on. Lancet. 353:1689–1694. 1999. View Article : Google Scholar : PubMed/NCBI
25	Hibbs JB Jr, Lambert LH Jr and Remington JS: Resistance to murine tumors conferred by chronic infection with intracellular protozoa, Toxoplasma gondii and Besnoitia jellisoni. J Infect Dis. 124:587–592. 1971. View Article : Google Scholar : PubMed/NCBI
26	Grange JM, Bottasso O, Stanford CA and Stanford JL: The use of mycobacterial adjuvant-based agents for immunotherapy of cancer. Vaccine. 26:4984–4990. 2008. View Article : Google Scholar : PubMed/NCBI
27	Malmström PU, Wijkström H, Lundholm C, Wester K, Busch C and Norlén BJ: Swedish-Norwegian Bladder Cancer Study Group: 5-year followup of a randomized prospective study comparing mitomycin C and bacillus Calmette-Guerin in patients with superficial bladder carcinoma. J Urol. 161:1124–1127. 1999. View Article : Google Scholar : PubMed/NCBI
28	Stanford JL, Stanford CA, O'Brien ME and Grange JM: Successful immunotherapy with Mycobacterium vaccae in the treatment of adenocarcinoma of the lung. Eur J Cancer. 44:224–227. 2008. View Article : Google Scholar : PubMed/NCBI
29	Ordway D, Henao-Tamayo M, Harton M, Palanisamy G, Troudt J, Shanley C, Basaraba RJ and Orme IM: The hypervirulent Mycobacterium tuberculosis strain HN878 induces a potent TH1 response followed by rapid down-regulation. J Immunol. 179:522–531. 2007. View Article : Google Scholar : PubMed/NCBI
30	Scott-Browne JP, Shafiani S, Tucker-Heard G, Ishida-Tsubota K, Fontenot JD, Rudensky AY, Bevan MJ and Urdahl KB: Expansion and function of Foxp3-expressing T regulatory cells during tuberculosis. J Exp Med. 204:2159–2169. 2007. View Article : Google Scholar : PubMed/NCBI
31	Trinath J, Maddur MS, Kaveri SV, Balaji KN and Bayry J: Mycobacterium tuberculosis promotes regulatory T-cell expansion via induction of programmed death-1 ligand 1 (PD-L1, CD274) on dendritic cells. J Infect Dis. 205:694–696. 2012. View Article : Google Scholar : PubMed/NCBI
32	Periasamy S, Dhiman R, Barnes PF, Paidipally P, Tvinnereim A, Bandaru A, Valluri VL and Vankayalapati R: Programmed death 1 and cytokine inducible SH2-containing protein dependent expansion of regulatory T cells upon stimulation With Mycobacterium tuberculosis. J Infect Dis. 203:1256–1263. 2011. View Article : Google Scholar : PubMed/NCBI
33	Alvarez IB, Pasquinelli V, Jurado JO, Abbate E, Musella RM, de la Barrera SS and García VE: Role played by the programmed death-1-programmed death ligand pathway during innate immunity against Mycobacterium tuberculosis. J Infect Dis. 202:524–532. 2010. View Article : Google Scholar : PubMed/NCBI
34	Li L, Lao SH and Wu CY: Increased frequency of CD4(+)CD25(high) Treg cells inhibit BCG-specific induction of IFN-gamma by CD4(+) T cells from TB patients. Tuberculosis (Edinb). 87:526–534. 2007. View Article : Google Scholar : PubMed/NCBI
35	Francisco LM, Salinas VH, Brown KE, Vanguri VK, Freeman GJ, Kuchroo VK and Sharpe AH: PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med. 206:3015–3029. 2009. View Article : Google Scholar : PubMed/NCBI
36	Jiang X, Zhou J, Giobbie-Hurder A, Wargo J and Hodi FS: The activation of MAPK in melanoma cells resistant to BRAF inhibition promotes PD-L1 expression that is reversible by MEK and PI3K inhibition. Clin Cancer Res. 19:598–609. 2013. View Article : Google Scholar : PubMed/NCBI
37	Wang C, Yi T, Qin L, Maldonado RA, von Andrian UH, Kulkarni S, Tellides G and Pober JS: Rapamycin-treated human endothelial cells preferentially activate allogeneic regulatory T cells. J Clin Invest. 123:1677–1693. 2013. View Article : Google Scholar : PubMed/NCBI
38	Lastwika KJ, Wilson W III, Li QK, Norris J, Xu H, Ghazarian SR, Kitagawa H, Kawabata S, Taube JM, Yao S, et al: Control of PD-L1 expression by oncogenic activation of the AKT-mTOR pathway in non-small cell lung cancer. Cancer Res. 76:227–238. 2016. View Article : Google Scholar : PubMed/NCBI