P38 MAPK-inhibited dendritic cells induce superior antitumour immune responses and overcome regulatory T-cell-mediated immunosuppression

Nature Communications

Volumn 5, Issue , 2014, Pages

  Lu, Yong ^a   Zhang, Mingjun ^a   Wang, Siqing ^b   Hong, Bangxing ^a   Wang, Zhiqiang ^c   Li, Haiyan ^a   Zheng, Yuhuan ^a   Yang, Jing ^c   Davis, Richard E ^c   Qian, Jianfei ^a   Hou, Jian ^d   Yi, Qing ^a  

^a LERNER RESEARCH INSTITUTE   (United States)

^b JILIN UNIVERSITY   (China)

^c UNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER   (United States)

^d SECOND MILITARY MEDICAL UNIVERSITY   (China)

Author keywords

[No Author keywords available]

Indexed keywords

4 (4 FLUOROPHENYL) 2 (4 HYDROXYPHENYL) 5 (4 PYRIDYL)IMIDAZOLE; 4 (4 FLUOROPHENYL) 2 (4 METHYLSULFINYLPHENYL) 5 (4 PYRIDYL)IMIDAZOLE; MITOGEN ACTIVATED PROTEIN KINASE 14; OX40 LIGAND; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA; PROTEIN P50; SMALL INTERFERING RNA; MITOGEN ACTIVATED PROTEIN KINASE P38;

CANCER; DISEASE TREATMENT; GENE EXPRESSION; IMMUNE RESPONSE; IMMUNITY; INHIBITION; PUBLIC HEALTH; TUMOR;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANTITUMOR GENE; ARTICLE; CANCER IMMUNOTHERAPY; CELL DIFFERENTIATION; CONTROLLED STUDY; DENDRITIC CELL; EFFECTOR CELL; ENZYME INHIBITION; GENE EXPRESSION; HUMAN; HUMAN CELL; IMMUNE RESPONSE; IMMUNOSUPPRESSIVE TREATMENT; MALE; MOUSE; NONHUMAN; PROTEIN PROTEIN INTERACTION; REGULATORY T LYMPHOCYTE; UPREGULATION; ANIMAL; C57BL MOUSE; CELLULAR IMMUNITY; CYTOLOGY; DOWN REGULATION; FEMALE; GENETICS; IMMUNOLOGICAL TOLERANCE; IMMUNOLOGY; KNOCKOUT MOUSE; NEOPLASM; PATHOPHYSIOLOGY; TUMOR CELL LINE;

ANIMALS; CELL DIFFERENTIATION; CELL LINE, TUMOR; DENDRITIC CELLS; DOWN-REGULATION; FEMALE; HUMANS; IMMUNE TOLERANCE; IMMUNITY, CELLULAR; MALE; MICE, INBRED C57BL; MICE, KNOCKOUT; NEOPLASMS; P38 MITOGEN-ACTIVATED PROTEIN KINASES; T-LYMPHOCYTES, REGULATORY;

EID: 84903447014     PISSN: None     EISSN: 20411723     Source Type: Journal    
DOI: 10.1038/ncomms5229     Document Type: Article

References (53)

1. Kalinski, P., Muthuswamy, R. & Urban, J. Dendritic cells in cancer immunotherapy: vaccines and combination immunotherapies. Expert Rev. Vaccines 12, 285-295 (2013).
2. Heiro, Y. i. D. & Appel, S. Current status and future perspectives of dendritic cell-based cancer immunotherapy. Scand. J. Immunol. 78, 167-171 (2013).
3. Zou, W. Regulatory T cells, tumour immunity and immunotherapy. Nat. Rev. Immunol. 6, 295-307 (2006).
4. Menetrier-Caux, C., Gobert, M. & Caux, C. Differences in tumor regulatory T-cell localization and activation status impact patient outcome. Cancer Res. 69, 7895-7898 (2009).
5. Zou, W. Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat. Rev. Cancer 5, 263-274 (2005). (Pubitemid 40488632)
6. Feng, L. L. & Wang, X. Targeting Foxp3 - regulatory T cells-related immunosuppression for cancer immunotherapy. Chin. Med. J. (Engl) 123, 3334-3342 (2010).
7. Byrne, W. L., Mills, K. H., Lederer, J. A. & O'Sullivan, G. C. Targeting regulatory T cells in cancer. Cancer Res. 71, 6915-6920 (2011).
8. Shimizu, J., Yamazaki, S., Takahashi, T., Ishida, Y. & Sakaguchi, S. Stimulation of CD25(-)CD4(-) regulatory T cells through GITR breaks immunological self-tolerance. Nat. Immunol. 3, 135-142 (2002). (Pubitemid 34141443)
9. Piconese, S., Valzasina, B. & Colombo, M. P. OX40 triggering blocks suppression by regulatory T cells and facilitates tumor rejection. J. Exp. Med. 205, 825-839 (2008). (Pubitemid 351549881)
10. Valzasina, B., Piconese, S., Guiducci, C. & Colombo, M. P. Tumor-induced expansion of regulatory T cells by conversion of CD4 -CD25-lymphocytes is thymus and proliferation independent. Cancer Res. 66, 4488-4495 (2006).
11. Ramirez-Montagut, T. et al. Glucocorticoid-induced TNF receptor family related gene activation overcomes tolerance/ignorance to melanoma differentiation antigens and enhances antitumor immunity. J. Immunol. 176, 6434-6442 (2006). (Pubitemid 43787825)
12. Cohen, A. D. et al. Agonist anti-GITR antibody enhances vaccine-induced CD8(-) T-cell responses and tumor immunity. Cancer Res. 66, 4904-4912 (2006).
13. Attia, P. et al. Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4. J. Clin. Oncol. 23, 6043-6053 (2005).
14. Xie, J. et al. Novel and detrimental effects of lipopolysaccharide on in vitro generation of immature dendritic cells: involvement of mitogen-activated protein kinase p38. J. Immunol. 171, 4792-4800 (2003). (Pubitemid 37310599)
15. Wang, S. et al. Optimizing immunotherapy in multiple myeloma: restoring the function of patients' monocyte-derived dendritic cells by inhibiting p38 or activating MEK/ERK MAPK and neutralizing interleukin-6 in progenitor cells. Blood 108, 4071-4077 (2006). (Pubitemid 44913277)
16. Wang, S. et al. Tumor evasion of the immune system: inhibiting p38 MAPK signaling restores the function of dendritic cells in multiple myeloma. Blood 107, 2432-2439 (2006). (Pubitemid 43345564)
17. Oosterhoff, D. et al. Tumor-mediated inhibition of human dendritic cell differentiation and function is consistently counteracted by combined p38 MAPK and STAT3 inhibition. Oncoimmunology 1, 649-658 (2012).
18. Cirone, M. et al. Dendritic cell differentiation blocked by primary effusion lymphoma-released factors is partially restored by inhibition of P38 MAPK. Int. J. Immunopathol. Pharmacol. 23, 1079-1086 (2010).
19. Lee, J. C. et al. A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature 372, 739-746 (1994).
20. Tabuchi, K. et al. Cochlear protection from acoustic injury by inhibitors of p38 mitogen-activated protein kinase and sequestosome 1 stress protein. Neuroscience 166, 665-670 (2010).
21. Croft, M. Control of immunity by the TNFR-related molecule OX40 (CD134). Annu. Rev. Immunol. 28, 57-78 (2010).
22. Takeda, I. et al. Distinct roles for the OX40-OX40 ligand interaction in regulatory and nonregulatory T cells. J. Immunol. 172, 3580-3589 (2004). (Pubitemid 38337939)
23. Daynes, R. A. & Jones, D. C. Emerging roles of PPARs in inflammation and immunity. Nat. Rev. Immunol. 2, 748-759 (2002). (Pubitemid 37328715)
24. Watts, T. H. TNF/TNFR family members in costimulation of T cell responses. Annu. Rev. Immunol. 23, 23-68 (2005). (Pubitemid 40563164)
25. Jensen, S. M. et al. Signaling through OX40 enhances antitumor immunity. Semin. Oncol. 37, 524-532 (2010).
26. So, T. & Croft, M. Cutting edge: OX40 inhibits TGF-beta-and antigen-driven conversion of naive CD4 T cells into CD25-Foxp3- T cells. J. Immunol. 179, 1427-1430 (2007).
27. Xu, L. et al. Positive and negative transcriptional regulation of the Foxp3 gene is mediated by access and binding of the Smad3 protein to enhancer I. Immunity 33, 313-325 (2010).
28. Trempolec, N., Dave-Coll, N. & Nebreda, A. R. SnapShot: p38 MAPK signaling. Cell 152, 656-656e1 (2013).
29. Wu, Z., Bucher, N. L. & Farmer, S. R. Induction of peroxisome proliferator-activated receptor gamma during the conversion of 3T3 fibroblasts into adipocytes is mediated by C/EBPbeta, C/EBPdelta, and glucocorticoids. Mol. Cell. Biol. 16, 4128-4136 (1996). (Pubitemid 26251212)
30. Szatmari, I., Rajnavolgyi, E. & Nagy, L. PPARgamma, a lipid-activated transcription factor as a regulator of dendritic cell function. Ann. NY Acad. Sci. 1088, 207-218 (2006). (Pubitemid 47092034)
31. He, J. et al. p38 MAPK in myeloma cells regulates osteoclast and osteoblast activity and induces bone destruction. Cancer Res. 72, 6393-6402 (2012).
32. Song, X. T. et al. A20 is an antigen presentation attenuator, and its inhibition overcomes regulatory T cell-mediated suppression. Nat. Med. 14, 258-265 (2008).
33. Evel-Kabler, K., Song, X. T., Aldrich, M., Huang, X. F. & Chen, S. Y. SOCS1 restricts dendritic cells' ability to break self tolerance and induce antitumor immunity by regulating IL-12 production and signaling. J. Clin. Invest. 116, 90-100 (2006). (Pubitemid 43121794)
34. Prasad, S. J. et al. Dendritic cells loaded with stressed tumor cells elicit long-lasting protective tumor immunity in mice depleted of CD4-CD25 - regulatory T cells. J. Immunol. 174, 90-98 (2005). (Pubitemid 40007395)
35. Arrighi, J. F., Rebsamen, M., Rousset, F., Kindler, V. & Hauser, C. A critical role for p38 mitogen-activated protein kinase in the maturation of human blood-derived dendritic cells induced by lipopolysaccharide, TNF-alpha, and contact sensitizers. J. Immunol. 166, 3837-3845 (2001). (Pubitemid 32224909)
36. Yu, Q., Kovacs, C., Yue, F. Y. & Ostrowski, M. A. The role of the p38 mitogen-activated protein kinase, extracellular signal-regulated kinase, and phosphoinositide-3-OH kinase signal transduction pathways in CD40 ligand-induced dendritic cell activation and expansion of virus-specific CD8 - T cell memory responses. J. Immunol. 172, 6047-6056 (2004). (Pubitemid 38621206)
37. Villadangos, J. A. & Schnorrer, P. Intrinsic and cooperative antigen-presenting functions of dendritic-cell subsets in vivo. Nat. Rev. Immunol. 7, 543-555 (2007). (Pubitemid 46987783)
38. Szatmari, I. et al. PPARgamma regulates the function of human dendritic cells primarily by altering lipid metabolism. Blood 110, 3271-3280 (2007). (Pubitemid 350106320)
39. Kock, G. et al. Regulation of dectin-1-mediated dendritic cell activation by peroxisome proliferator-activated receptor-gamma ligand troglitazone. Blood 117, 3569-3574 (2011).
40. Zitvogel, L., Tesniere, A. & Kroemer, G. Cancer despite immunosurveillance: immunoselection and immunosubversion. Nat. Rev. Immunol. 6, 715-727 (2006). (Pubitemid 44453458)
41. Jarnicki, A. G. et al. Attenuating regulatory T cell induction by TLR agonists through inhibition of p38 MAPK signaling in dendritic cells enhances their efficacy as vaccine adjuvants and cancer immunotherapeutics. J. Immunol. 180, 3797-3806 (2008).
42. Zhao, F. et al. Activation of p38 mitogen-activated protein kinase drives dendritic cells to become tolerogenic in ret transgenic mice spontaneously developing melanoma. Clin. Cancer Res. 15, 4382-4390 (2009).
43. Yang, Z., Zhang, X., Darrah, P. A. & Mosser, D. M. The regulation of Th1 responses by the p38 MAPK. J. Immunol. 185, 6205-6213 (2010).
44. Franks, H. A. et al. Novel function for the p38-MK2 signaling pathway in circulating CD1c - (BDCA-1 -) myeloid dendritic cells from healthy donors and advanced cancer patients; inhibition of p38 enhances IL-12 whilst suppressing IL-10. Int. J. Cancer 134, 575-586 (2014).
45. Kuhnol, C., Herbarth, M., Foll, J., Staege, M. S. & Kramm, C. CD137 stimulation and p38 MAPK inhibition improve reactivity in an in vitro model of glioblastoma immunotherapy. Cancer Immunol. Immunother. 62, 1797-1809 (2013).
46. Vu, M. D. et al. OX40 costimulation turns off Foxp3- Tregs. Blood 110, 2501-2510 (2007).
47. Gough, M. J. & Weinberg, A. D. OX40 (CD134) and OX40L. Adv. Exp. Med. Biol. 647, 94-107 (2009).
48. Zaini, J. et al. OX40 ligand expressed by DCs costimulates NKT and CD4 - Th cell antitumor immunity in mice. J. Clin. Invest. 117, 3330-3338 (2007). (Pubitemid 350096989)
49. Moran, A. E., Kovacsovics-Bankowski, M. & Weinberg, A. D. The TNFRs OX40, 4-1BB, and CD40 as targets for cancer immunotherapy. Curr. Opin. Immunol. 25, 230-237 (2013).
50. Hong, S. et al. Optimizing dendritic cell vaccine for immunotherapy in multiple myeloma: tumour lysates are more potent tumour antigens than idiotype protein to promote anti-tumour immunity. Clin. Exp. Immunol. 170, 167-177 (2012).
51. Legler, D. F., Krause, P., Scandella, E., Singer, E. & Groettrup, M. Prostaglandin E2 is generally required for human dendritic cell migration and exerts its effect via EP2 and EP4 receptors. J. Immunol. 176, 966-973 (2006). (Pubitemid 43099695)
52. Xie, J. et al. Critical roles of Raf/MEK/ERK and PI3K/AKT signaling and inactivation of p38 MAP kinase in the differentiation and survival of monocyte-derived immature dendritic cells. Exp. Hematol. 33, 564-572 (2005). (Pubitemid 40592173)
53. Keller, A. M., Schildknecht, A., Xiao, Y., van den Broek, M. & Borst, J. Expression of costimulatory ligand CD70 on steady-state dendritic cells breaks CD8 - T cell tolerance and permits effective immunity. Immunity 29, 934-946 (2008).