MEK inhibition suppresses B regulatory cells and augments anti-tumor immunity

Autoři: Mark Yarchoan aff001;  Aditya A. Mohan aff001;  Lauren Dennison aff001;  Teena Vithayathil aff001;  Amanda Ruggieri aff002;  Gregory B. Lesinski aff002;  Todd D. Armstrong aff001;  Nilofer S. Azad aff001;  Elizabeth M. Jaffee aff001
Působiště autorů: Bloomberg–Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America aff001;  Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, United States of America aff002
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article


Mitogen-activated protein kinase (MAPK) kinase (MEK) is an integral component of the RAS pathway and a therapeutic target in RAS-driven cancers. Although tumor responses to MEK inhibition are rarely durable, MEK inhibitors have shown substantial activity and durable tumor regressions when combined with systemic immunotherapies in preclinical models of RAS-driven tumors. MEK inhibitors have been shown to potentiate anti-tumor T cell immunity, but little is known about the effects of MEK inhibition on other immune subsets, including B cells. We show here that treatment with a MEK inhibitor reduces B regulatory cells (Bregs) in vitro, and reduces the number of Bregs in tumor draining lymph nodes in a colorectal cancer model in vivo. MEK inhibition does not impede anti-tumor humoral immunity, and B cells contribute meaningfully to anti-tumor immunity in the context of MEK inhibitor therapy. Treatment with a MEK inhibitor is associated with improved T cell infiltration and an enhanced response to anti-PD1 immunotherapy. Together these data indicate that MEK inhibition may reduce Bregs while sparing anti-tumor B cell function, resulting in enhanced anti-tumor immunity.

Klíčová slova:

B cells – Cancer immunotherapy – Cancer treatment – Cytotoxic T cells – Immune response – Lymph nodes – MAPK signaling cascades – T cells


1. Diaz-Flores E, Shannon K. Targeting oncogenic Ras. Genes Dev. Cold Spring Harbor Laboratory Press; 2007;21: 1989–92. doi: 10.1101/gad.1587907 17699748

2. Dudley DT, Pang L, Decker SJ, Bridges AJ, Saltiel AR. A synthetic inhibitor of the mitogen-activated protein kinase cascade. Proc Natl Acad Sci U S A. National Academy of Sciences; 1995;92: 7686–9. doi: 10.1073/pnas.92.17.7686 7644477

3. Caunt CJ, Sale MJ, Smith PD, Cook SJ. MEK1 and MEK2 inhibitors and cancer therapy: the long and winding road. Nat Rev Cancer. Nature Publishing Group; 2015;15: 577–592. doi: 10.1038/nrc4000 26399658

4. Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, et al. Improved Overall Survival in Melanoma with Combined Dabrafenib and Trametinib. N Engl J Med. Massachusetts Medical Society; 2015;372: 30–39. doi: 10.1056/NEJMoa1412690 25399551

5. Larkin J, Ascierto PA, Dréno B, Atkinson V, Liszkay G, Maio M, et al. Combined Vemurafenib and Cobimetinib in BRAF -Mutated Melanoma. N Engl J Med. Massachusetts Medical Society; 2014;371: 1867–1876. doi: 10.1056/NEJMoa1408868 25265494

6. Gotwals P, Cameron S, Cipolletta D, Cremasco V, Crystal A, Hewes B, et al. Prospects for combining targeted and conventional cancer therapy with immunotherapy. Nat Rev Cancer. Nature Publishing Group; 2017;17: 286–301. doi: 10.1038/nrc.2017.17 28338065

7. McArthur GA, Ribas A. Targeting Oncogenic Drivers and the Immune System in Melanoma. J Clin Oncol. 2013;31: 499–506. doi: 10.1200/JCO.2012.45.5568 23248252

8. Liu L, Mayes PA, Eastman S, Shi H, Yadavilli S, Zhang T, et al. The BRAF and MEK Inhibitors Dabrafenib and Trametinib: Effects on Immune Function and in Combination with Immunomodulatory Antibodies Targeting PD-1, PD-L1, and CTLA-4. Clin Cancer Res. American Association for Cancer Research; 2015;21: 1639–51. doi: 10.1158/1078-0432.CCR-14-2339 25589619

9. Ebert PJR, Cheung J, Yang Y, McNamara E, Hong R, Moskalenko M, et al. MAP Kinase Inhibition Promotes T Cell and Anti-tumor Activity in Combination with PD-L1 Checkpoint Blockade. Immunity. Elsevier; 2016;44: 609–621. doi: 10.1016/j.immuni.2016.01.024 26944201

10. Deken MA, Gadiot J, Jordanova ES, Lacroix R, van Gool M, Kroon P, et al. Targeting the MAPK and PI3K pathways in combination with PD1 blockade in melanoma. Oncoimmunology. Taylor & Francis; 2016;5: e1238557. doi: 10.1080/2162402X.2016.1238557 28123875

11. Frederick DT, Piris A, Cogdill AP, Cooper ZA, Lezcano C, Ferrone CR, et al. BRAF Inhibition Is Associated with Enhanced Melanoma Antigen Expression and a More Favorable Tumor Microenvironment in Patients with Metastatic Melanoma. Clin Cancer Res. 2013;19: 1225–1231. doi: 10.1158/1078-0432.CCR-12-1630 23307859

12. Rosser EC, Mauri C. Regulatory B Cells: Origin, Phenotype, and Function. Immunity. Cell Press; 2015;42: 607–612. doi: 10.1016/j.immuni.2015.04.005 25902480

13. Ganti SN, Albershardt TC, Iritani BM, Ruddell A. Regulatory B cells preferentially accumulate in tumor-draining lymph nodes and promote tumor growth. Sci Rep. Nature Publishing Group; 2015;5: 12255. doi: 10.1038/srep12255 26193241

14. Richards JD, Davé SH, Chou CH, Mamchak AA, DeFranco AL. Inhibition of the MEK/ERK signaling pathway blocks a subset of B cell responses to antigen. J Immunol. 2001;166: 3855–64. doi: 10.4049/jimmunol.166.6.3855 11238629

15. Hoeflich KP, Merchant M, Orr C, Chan J, Den Otter D, Berry L, et al. Intermittent Administration of MEK Inhibitor GDC-0973 plus PI3K Inhibitor GDC-0941 Triggers Robust Apoptosis and Tumor Growth Inhibition. Cancer Res. 2012;72: 210–219. doi: 10.1158/0008-5472.CAN-11-1515 22084396

16. Castle JC, Loewer M, Boegel S, de Graaf J, Bender C, Tadmor AD, et al. Immunomic, genomic and transcriptomic characterization of CT26 colorectal carcinoma. BMC Genomics. BioMed Central; 2014;15: 190. doi: 10.1186/1471-2164-15-190 24621249

17. Kobayashi T, Hamaguchi Y, Hasegawa M, Fujimoto M, Takehara K, Matsushita T. B Cells Promote Tumor Immunity against B16F10 Melanoma. Am J Pathol. Elsevier; 2014;184: 3120–3129. doi: 10.1016/j.ajpath.2014.07.003 25173132

18. Singh K, Deshpande P, Pryshchep S, Colmegna I, Liarski V, Weyand CM, et al. ERK-Dependent T Cell Receptor Threshold Calibration in Rheumatoid Arthritis. J Immunol. 2009;183: 8258–8267. doi: 10.4049/jimmunol.0901784 20007589

19. Thiel MJ, Schaefer CJ, Lesch ME, Mobley JL, Dudley DT, Tecle H, et al. Central role of the MEK/ERK MAP kinase pathway in a mouse model of rheumatoid arthritis: Potential proinflammatory mechanisms. Arthritis Rheum. 2007;56: 3347–3357. doi: 10.1002/art.22869 17907188

20. Shindo T, Kim TK, Benjamin CL, Wieder ED, Levy RB, Komanduri K V. MEK inhibitors selectively suppress alloreactivity and graft-versus-host disease in a memory stage-dependent manner. Blood. 2013;121: 4617–4626. doi: 10.1182/blood-2012-12-476218 23575444

21. D’Souza WN, Chang C-F, Fischer AM, Li M, Hedrick SM. The Erk2 MAPK regulates CD8 T cell proliferation and survival. J Immunol. 2008;181: 7617–29. doi: 10.4049/jimmunol.181.11.7617 19017950

22. Murphy AG, Zheng L. Small molecule drugs with immunomodulatory effects in cancer. Hum Vaccin Immunother. Taylor & Francis; 2015;11: 2463–2468. doi: 10.1080/21645515.2015.1057363 26110550

Článek vyšel v časopise


2019 Číslo 10
Nejčtenější tento týden