访董晨：癌症疫苗 曙光乍现

编者按，2005年Th17概念提出，由于其表达的细胞因子和生物学功能、分化过程完全不同于Th1、Th2细胞，最初发现Th17在慢性感染和自体免疫疾病过程中发挥重要的作用，因此，一经发现Th17就引起了研究者们浓厚的兴趣。

　　

编者按，2005年Th17概念提出，由于其表达的细胞因子和生物学功能、分化过程完全不同于Th1、Th2细胞，且Th17在慢性感染和自体免疫疾病过程中发挥重要的作用，因此，一经发现Th17就引起了研究者们浓厚的兴趣。

 

最近，来自M.D Anderson Cancer Center的董晨教授实验室在2种癌症过程中发现了Th17的身影，更重要的是，Th17是参与抗癌过程重要细胞，这一新的发现为癌症细胞疗法甚至癌症疫苗的开发带来了新的契机。

 

 

这一新发现的成果最近发表在了免疫学权威期刊《Immunity》上。关于这一新的发现，生物通记者联系了董晨教授，了解了更多Th17的应用前景。

 

董晨教授实验室是最早发现Th17细胞特性的实验室之一。到目前为止，科学家们对Th17的了解还是不十分深入。现在掌握比较多的是Th17的发育特征，对Th17具体功能的了解尚十分有限。

 

据董晨教授介绍，其实，Th17首先是在肿瘤组织中被发现的，但对Th17的抗癌功效的研究却十分少。

 

Th17细胞能够分泌产生IL-17A、IL一 17F、IL-6以及肿瘤坏死因子α( tumor necrosis factor α，TNF-α)等， 其功能主要就体现在它分泌的这些细胞因子集体动员、 募集及活化中性粒细胞的能力上。Th17细胞产生的最重要的效应因子是IL-17， 其受体在体内广泛表达。虽然Th17细胞在自身免疫病中的病理性作用得到了证实， 但研究者们认为这并不是它们的主要的原始功能。当出现感染或炎症等严重伤害的早期，机体都需要中性粒细胞参与阻止组织坏死或者脓血症。而Th17细胞产生的IL-17能有效地介导中性粒细胞动员的兴奋过程，从而有效地介导了前炎症反应。

 

2006年Nature上发表的一篇文章（L ANQOWS KI JL，Z HANGX，WUI，e ta l . IL-23 promotes tumor incidence and growth[J]. Nature，2006,442(7101):461-465.）报道，IL-17、IL-23在人体肿瘤中得到大量的增生。也有研究小组发现IL-17可促进细胞因子分析促进Th1细胞和细胞毒性T细胞的活性而抑制肿瘤的生长。

 

董晨教授研究组研究发现在黑素瘤和纤维肉瘤中发现Th17细胞具有抗癌功效。他们发现Th17细胞可加强肿瘤组织中的炎症反应，激活肿瘤组织特异的细胞毒性T细胞发挥抗癌细胞功效。

 

白细胞介素17（interleukin-17A,简称IL-17A）缺陷的小鼠更易发生肺黑色素瘤（一种癌症）。如果，对小鼠采取T细胞疗法，用分泌IL-17A的T细胞治疗可有效阻止肿瘤的发生。更重要的，在IL-17A的辅助下，Th17细胞表现出比Th1细胞更强的治疗功效。

 

更让人意外的是，使用Th17细胞治疗可有效激活肿瘤特异性的CD8+T细胞，CD8+T细胞是抗肿瘤的必须细胞。Th17细胞能召集树突细胞进入肿瘤组织，并且能使得CD8α+树突细胞聚集到肿瘤组织中。

 

此外，Th17细胞激活肿瘤组织的趋化因子CCL20。总的来说，Th17细胞可有效促进肿瘤特异性的CD8+T细胞的活性。

 

当生物通记者问及Th17作为癌症细胞治疗技术和癌症疫苗时，董晨教授表示，Th17作为临床应用还有很长的路要走。我们需要分析更多Th17在其他肿瘤中的表现，并且更深入了解Th17对人类的功能。首先第一步，我认为，应该将Th17与细胞毒性T细胞结合起来进行治疗性研究，因为Th17细胞可促进细胞毒性T细胞发挥作用。

 

董晨教授表示，下一步他们将更深入了解Th17丰富的功能以及可塑性，并研究Th17与炎症的机制。

（生物通 张欢）

 

关于董晨教授

 

Name  Chen Dong, Ph.D.

Position Title                        Professor

EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, and include postdoctoral training

INSTITUTION AND LOCATION	DEGREE (if applicable)	YEAR(s)	FIELD OF STUDY
Wuhan University, Wuhan,China University of Alabama, Birmingham, AL Yale University, New Haven, CT	B.S. Ph.D. Postdoctoral fellowship	1989 1996 1997-2000	Cell Biology Cell and Molecular Biology Immunobiology

RESEARCH AND PROFESSIONAL EXPERIENCE:  Concluding with present position, list, in chronological order, previous employment, experience, and honors.  Include present membership on any Federal Government public advisory committee.  List, in chronological order, the title, all authors and completed references to all publications during the past three years and to representative earlier publications pertinent to this application.  If the list of publications in the last three years exceeds two pages, select the most pertinent publications.  DO NOT EXCEED TWO PAGES.

 

PROFESSIONAL EXPERIENCE:

1990-1996                                          Graduate Student, Department of Microbiology, University of Alabama at Birmingham,

                                    Mentor: Max D. Cooper, M.D.

1997-2000                     Postdoctoral Associate, Section of Immunobiology, Yale University School of Medicine

                                    New Haven, CT, Supervisor: Richard A. Flavell, Ph.D

2000-2004                     Assistant Professor, Department of Immunology, University of Washington School of Medicine, Seattle, WA

2004-2008                     Associate Professor (tenured), Department of Immunology, University of Texas MD Anderson Cancer Center

2008-                           Professor (tenured), Department of Immunology, University of Texas MD Anderson Cancer Center

2008-                           Director, Center for Inflammation and Cancer, MD Anderson Cancer Center

 

awards, Honors and Professional activities:

1999-2000                     Arthritis Foundation Postdoctoral Fellowship

2000 –2005                   Arthritis Investigator Award, Arthritis Foundation

2001                             Pfizer-Showell Travel Award, American Association of Immunologists

2002-2003                     Basil O’Connor Starter Investigator award, March of Dimes Foundation

2002                     Young Investigator Award (1^st Prize), International Cytokine Society

2003                             FOCIS 2003 Travel Award, Federation of Clinical Immunology Societies

2003-2008                     Contributing Faculty Member, Faculty of 1000 Biology, Immunology Faculty, Leukocyte Activation Section

2003-2009            Cancer Research Institute Investigator Award

2004-present         MD Anderson Cancer Center Research Trust Fellow

2004                             Milstein Young Investigator award, International Society of Interferon and Cytokine Research

2005                             Organizer, Symposium “Gene Regulation and Function in Health and Diseases”, New Haven, CT.

2006-2011                                          Editorial Board member, Journal of Biological Chemistry

2007-2010                                          American Lung Association Career Investigator Award

2007-2010                     MD Anderson Cancer Center Faculty Scholar Award in Research

2008-2013                     Leukemia and Lymphoma Society Scholar Award

2009                             Primary organizer and speaker, Keystone Symposium “TH17 cells in Health and Diseases”, Vancouver, Canada

2009                            American Association of Immunologists BD Biosciences Investigator Award for outstanding, early-career research contributions to the field of immunology

 

SELECTED PUBLICATIONS (from total 100):

1.       Dong, C.*, Yang, D. D.*, Wysk, M., Whitmarsh, A. J., Davis, R. J., and Flavell, R. A. Defective T cell differentiation in the absence of Jnk1. (1998) Science. 282: 2092-2095 (* contribute equally).

2.       Dong, C., Yang, D. D., Tournier, C., Whitmarsh, A. J., Xu, J., Davis, R. J., and Flavell, R. A. JNK is required for effector T cell function but not for T cell activation. (2000) Nature. 405: 91-94.

3.       Dong, C., Juedes, A. E., Temann, U.-A., Shresta, S., Allison, J. P., Ruddle, N. H. and Flavell, R. A. ICOS Costimulatory Receptor Is Essential for T-cell Activation and Function. (2001) Nature. 409:97-101.

4.       Dong, C., Davis, R. J. and Flavell, R. A. MAP kinases in the immune response (Review). (2002) Annual Review of Immunology. 20:55-72.

5.       Sun, M., Richards, S., Prasad, D. V. R., Mai, X. M., Rudensky, A. and Dong, C. Characterization of mouse and human B7-H3 genes. (2002) Journal of Immunology. 168:6294.

6.       Nurieva, R., Duong, J., Kishikawa, H., Dianzani, U., Rojo, J. M., Ho, I.-C., Flavell, R. A. and Dong, C. Transcriptional regulation of Th2 differentiation by ICOS. (2003) Immunity. 18:801-811.

7.       Prasad, D. V. R., Richards, S., Mai, X. M., and Dong, C. B7S1, a novel B7 family member that inhibits T cell activation. (2003) Immunity. 18:863-873.

8.       Dong, C. and Nurieva, R. Regulation of immune and autoimmune responses by ICOS. (Review). (2003) Journal of Autoimmunity. 21:255-260.

9.       Nurieva, R., Mai, X. M., Forbush, K., Ho, I.-C., Bevan, M. J. and Dong, C. B7h is required for T cell activation, differentiation and effector function. (2003) Proceedings of National Academy of Sciences. 100: 14163-14168.

10.   Prasad, D. V. R., Nguyen, T., Li, Z., Yang, Y., Duong, J., Wang, Y., and Dong, C. Murine B7-H3 is a negative regulator of T cells. (2004) Journal of Immunology. 173:2500-2506.

11.   Zhang, Y., Blattman, J., Kennedy, N., Duong, J., Nguyen, T., Wang, Y., Davis, R. J., Greenberg, P., Flavell, R. A. and Dong, C. Regulation of innate and adaptive immune responses by MKP5. (2004) Nature. 430:793-797.

12.   Park, H., Li, Z., Yang, X. O., Chang, S. H., Nurieva, R. I., Wang, Y.-H., Wang, Y., Hood, L., Zhu, Z., Tian, Q., Dong, C. A distinct lineage of TH cells regulates tissue inflammation by producing IL-17. (2005) Nature Immunology. 10: 1133-1142.

13.   Dong, C. Diversification of TH lineages- finding family roots for IL-17. (Perspectives). (2006) Nature Review Immunology. 6:329-333.

14.   Martin-Orozco, N. and Dong, C. New battlefields for costimulation. (Commentaries). (2006) Journal of Experimental Medicine. 203: 817-820.

15.     Nguyen, T., Liu, X., Zhang, Y., and Dong, C. BTNL2, a butyrophilin-like molecule that functions to inhibit T cell activation. (2006) Journal of Immunology. 176:7354–7360

16.   Nurieva, R.I. Thomas, S., Nguyen, T., Martin-Orozco, N., Wang, Y., Kaja, M.-K., Yu, X.-Z.,and Dong, C. T-cell immunity or tolerance is regulated by a combinatorial costimulation signal. (2006) EMBO Journal. 25, 2623–2633.

17.   Zhang, Y., Chung, Y. S., Bishop, C., Daugherty, B., Chute, H., Holst, P., Kurahara, C., Lott, F., Sun, N., Welcher, A., and Dong, C. Regulation of T cell activation and tolerance by PDL2. (2006) Proceedings of National Academy of Sciences. 103: 11695–11700.

18.     Martin-Orozco, N., Wang, Y.-H., Yagita, H. and Dong, C. Cutting Edge: PD-1-PD-L1 interaction is required for CD8+ T cell tolerance to tissue antigens. (2006) Journal of Immunology. 177: 8291–8295.

19.   Chang, S. H., Park, H., and Dong, C. Act1 is an immediate and essential signaling component of IL-17 receptor. (2006) Journal of Biological Chemistry. 281: 35603-35607.

20.   Akimzhanov, A., Yang, X. O. and Dong, C. Chromatin Remodeling at IL-17-IL-17F cytokine gene locus during inflammatory helper T cell differentiation. (2007) Journal of Biological Chemistry 282:5969-5972.

21.   Yang, Y., Liu, X., Nguyen, T., Bishop, C., Graf, D. and Dong, C. Characterization of B7S3 as a novel negative regulator of T cells. (2007) Journal of Immunology. 178: 3661–3667.

22.   Yang, X. O., Panopoulos, A. D., Nurieva, R., Chang, S. H., Wang, D., Watowich, S. S., and Dong, C. Stat3 regulates cytokine-mediated generation of inflammatory helper T cells. (2007) Journal of Biological Chemistry 282: 9358-9363.

23.   Nurieva, R.I, Chuvpilo, S., Wieder, E. D., Elkon, K. B., Locksley, R., Serfling, E. and Dong, C. A costimulation-initiated signaling pathway regulates NFATc1 transcription in T lymphocytes. (2007) Journal of Immunology. 179: 1096–1103.

24.   Angkasekwinai, P., Park, H., Wang, Y.-H., Wang, Y.-H., Chang, S. H., Corry, D. B., Liu, Y.-J., Zhu, Z. and Dong, C. IL-25 regulates the initiation of pro-allergic type 2 responses. (2007) Journal of Experimental Medicine. 204:1509-1517.

25.   Nurieva, R., Yang, X. O., Martinez, G., Zhang, Y., Panopoulos, A. D., Ma, L., Schluns, K., Tian, Q., Watowich, S. S., Jetten, A. M. and Dong, C. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. (2007) Nature. 448: 480-483.

26.   Martin-Orozco, N. and Dong, C. Inhibitory “co-stimulatory” molecules and anti-tumor immunity (Review). Seminars in Cancer Biology. (2007) Seminars in Cancer Biology. 17: 288–298.

27.   Chung, Y. S., Qin, H., Kang, C.-Y., Kim, S., Kwak, L. W., and Dong, C. An NKT cell-mediated autologous vaccine generates potent CD4⁺ T-cell-dependent anti-lymphoma immunity. (2007) Blood. 110:2013-2019.

28.   Pappu, B. and Dong, C. Unit 6.25 Measurement of interleukin 17. (2007) In: Current Protocols in Immunology. Coligan, J. E., Kruisbeek, A. M., Margulies, D. H., Shevach, E. M., Strober, W. Unlimited Learning Resources, LLC., 6.25.1-6.25.8.

29.   Yang, X. O., Pappu, B., Nurieva, R., Akimzhanov, A., Kang, H. S., Chung, Y., Ma, L., Panopoulos, A. D., Schluns, K., Watowich, S. S., Tian, Q., Jetten, A. M. and Dong, C. TH17 lineage differentiation programmed by orphan nuclear receptors RORa and RORg. (2008) Immunity. 28, 29–39.

30.   Chung, Y. S., Nurieva, R., Esashi, E., Wang, Y.-H., Zhou, D., Gapin, L., and Dong, C. A Critical Role of Costimulation During Intrathymic Development of Invariant NKT cells. (2008) Journal of Immunology. 180:2276-2783.

31.   Pappu, B. P., Angkasekwinai, P. and Dong, C. Regulatory mechanisms of helper T cell differentiation-New lessons learnt from interleukin 17 family cytokines (Review). (2008) Pharmacology & Therapeutics. 117:374–384.

32.   Dong, C. TH17 cells in development: an updated view of their molecular identity and genetic programming (Review). (2008) Nature Review Immunology. 8:337-348.

33.   Pappu, B. P., Borodovsky, A., Zheng, T., Yang, X., Wu, P., Dong, X., Weng, S., Browning, B., Scott, M., Ma, L., Tian, Q., Schneider, P., Flavell, R. A., Dong, C. * and Burkly, L. C. * TL1A-DR3 interaction regulates Th17 cell proliferation and Th17-mediated autoimmune disease.(2008) Journal of Experimental Medicine. 205:1049-1062. (* co-correspondent authors)

34.   Yang, X. O., Chang, S. H., Park, H., Nurieva, R., Wang, Y.-H., Zhu, Z. and Dong, C. Regulation of inflammatory responses by IL-17F. (2008) Journal of Experimental Medicine 205:1063-1075.

35.   Yang, X. O., Nurieva, R., Martinez, G. J., Chung, Y., Kang, H. S., Pappu, B. P., Shah, B., Chang, S. H., Schluns, K. S., Watowich, S. S., Feng, X., Jetten, A. M. and Dong, C. Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. (2008) Immunity. 29:44-56.

36.   Nurieva, R. I., Chung, Y., Hwang, D., Yang, X. O., Kang, H. S., Ma, L., Wang, Y.-H., Watowich, S. S., Jetten, A. M., Tian, Q. and Dong, C. Generation of follicular helper T cells is mediated by IL-21 but independent of TH1, TH2 or TH17 lineages. (2008) Immunity. 29:138-149.

37.   Dong, C. Regulation and pro-inflammatory function of interleukin 17 family cytokines. (Review) (2008) Immunological Reviews. 226:80-86.

38.   Martinez, G. J., Nurieva, R. I., Yang, X. O. and Dong, C. Regulation and function of pro-inflammatory TH17 cells. In: The Year in Immunology 2008. Rose, N. (2008) Annals of New York Academy of Sciences. 188-211.

39.   Yamazaki, T., Yang, X. O., Chung, Y., Fukunaga, A., Nurieva, R., Pappu, B., Martin-Orozco, N., Kang, H. S., Ma, L., Panopoulos, A. D., Craig, S., Watowich, S. S., Jetten, A. M., Tian, Q., and Dong, C. CCR6 regulates the migration of inflammatory and regulatory T cells. (2008) Journal of Immunology. 181:8391-8401.

40.   Nurieva, R. I. and Dong, C. Keeping Autoimmunity in Check: How to Control a Th17 Cell Controller. (Preview). (2008) Immunity. 29:841-843.

41.   Angkasekwinai, P. and Dong, C. IL-25, another promoter of allergy. (2009) In: Role or TH17 in inflammation and autoimmune disease. Ryffel, B. & di Padova, F. 69-83.

42.   Martin-Orozco, N., Chang, S. H., Chung, Y., Wang, Y.- H. and Dong, C. Th17 cells promote pancreatic inflammation but only induce diabetes efficiently in lymphopenic hosts after conversion into Th1 cells. (2009) European Journal of Immunology 39: 216–224.

43.   Chung, Y. and Dong, C. Don’t leave home without it: the IL-23 visa to T_H-17 cells. (News and Views) (2009) Nature Immunology. 10:236-238.

44.   Nurieva, R., Yang, X. O., Chung, Y. and Dong, C. Cutting Edge: In vitro generated TH17 cells maintain their cytokine expression program in normal but not lymphopenic hosts. (2009) Journal of Immunology. 182: 2565–2568.

45.   Dong, C. Mouse Th17 cells: current understanding on their generation and regulation. (Review). (2009) European Journal of Immunology. 39: 634–675.

46.   Chang, S. H. and Dong, C. IL-17F: regulation, signaling and function in inflammation (Review). (2009) Cytokine. 46:7-11.

47.   Liu , X., Alexiou, M., Martin-Orozco , N., Chung , Y., Nurieva , R., Ma , L., Tian, Q., Kollias, G., Lu, S., Graf, D. and Dong, C. Cutting Edge: A critical role of BTLA in peripheral T cell tolerance induction. (2009) Journal of Immunology. 182: 4516–4520.

48.   Chung, Y., Chang, S. H., Martinez, G. J., Yang, X. O., Nurieva, R., Kang, H. S., Ma, L., Watowich, S. S., Jetten, A., Tian, Q. and Dong, C. Critical regulation of early Th17 cell differentiation by IL-1 signaling. (2009) Immunity. 30, 576–587.

49.   Nurieva, R., Liu, X. and Dong, C. Yin-Yang of costimulation: crucial controls of immune tolerance and function. (Review). (2009) Immunological Reviews. 229: 88–100.

50.   Martin-Orozco, N. and Dong, C. IL-23/IL-17 axis of inflammation in cancer, a friend or foe? (Review) (2009) Current Opinion in Investigational Drugs. 10:543-549.

51.   Nurieva, R. I., Chung, Y., Martinez, G. J., Yang, X. O., Tanaka, S., Matskevitch, T. D., Wang, Y.-H. and Dong, C. Bcl6 mediates the development of T follicular helper cells. Science. In press.

 

SELECTED ONGOING Research Support.

1 U19 AI071130-01- Liu, YJ (PI)                                                           7/1/2006-6/30/2011          

Title: Texas Medical Center Asthma and Allergic Diseases Cooperative Research Center

National Institute of Health

Project 4. Regulation of TSLP by inflammatory TH cells- Dong, C. (Leader)                               

 

R01 AI054912-01-Dong, C. (P.I.)                                  1/1/07-12/31/11    

National Institute of Health                                           

Title: Immune Tolerance Mediated by negative Costimulatory Molecules

 

RO1 AR050772- Dong, C. (P.I.)                                                            9/1/03-8/31/12   

National Institute of Health                                                  

Title: Transcriptional regulation of inflammatory T cell differentiation.

 

SCOR grant- Kwak, L (PI)                                                                    10/1/2007-9/30/12     

Project 1- Dong, C. (Leader)                                                                                                    

Leukemia and Lymphoma Society                          

Title: Modulating the innate-adaptive immunity interface to boost lymphoid tumor vaccine responses

 

RO1 AI50761- Dong, C. (P.I.)                                                              12/01/2001 – 04/30/2011       

NIH                                                

Title: Signal Transduction and Cytokine Gene Regulation by Grail