Skip to main content

Advertisement

SpringerLink
Log in

Influences of BRAF Inhibitors on the Immune Microenvironment and the Rationale for Combined Molecular and Immune Targeted Therapy

  • Melanoma (RJ Sullivan, Section Editor)
  • Published:
Current Oncology Reports Aims and scope Submit manuscript

Abstract

The identification of key driver mutations in melanoma has led to the development of targeted therapies aimed at BRAF and MEK, but responses are often limited in duration. There is growing evidence that MAPK pathway activation impairs antitumor immunity and that targeting this pathway may enhance responses to immunotherapies. There is also evidence that immune mechanisms of resistance to targeted therapy exist, providing the rationale for combining targeted therapy with immunotherapy. Preclinical studies have demonstrated synergy in combining these strategies, and combination clinical trials are ongoing. It is, however, becoming clear that additional translational studies are needed to better understand toxicity, proper timing, and sequence of therapy, as well as the utility of multidrug regimens and effects of other targeted agents on antitumor immunity. Insights gained through translational research in preclinical models and clinical studies will provide mechanistic insight into therapeutic response and resistance and help devise rational strategies to enhance therapeutic responses.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as • Of importance •• Of major importance

  1. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949–54.

    Article  CAS  PubMed  Google Scholar 

  2. Sosman JA, Kim KB, Schuchter L, et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med. 2012;366:707–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Singh M, Lin J, Hocker TL, Tsao H. Genetics of melanoma tumorigenesis. Br J Dermatol. 2008;158:15–21.

    Article  CAS  PubMed  Google Scholar 

  4. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380:358–65.

    Article  CAS  PubMed  Google Scholar 

  6. Larkin J, Ascierto PA, Dreno B, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014;371:1867–76.

    Article  PubMed  Google Scholar 

  7. Long GV, Stroyakovskiy D, Gogas H, et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet. 2015;386:444–51.

    Article  CAS  PubMed  Google Scholar 

  8. Carvajal RD, Sosman JA, Quevedo JF, et al. Effect of selumetinib vs chemotherapy on progression-free survival in uveal melanoma: a randomized clinical trial. JAMA. 2014;311:2397–405.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Long GV, Fung C, Menzies AM, et al. Increased MAPK reactivation in early resistance to dabrafenib/trametinib combination therapy of BRAF-mutant metastatic melanoma. Nat Commun. 2014;5:5694.

    Article  CAS  PubMed  Google Scholar 

  10. Kwong LN, Boland GM, Frederick DT, et al. Co-clinical assessment identifies patterns of BRAF inhibitor resistance in melanoma. J Clin Invest. 2015;125:1459–70.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367:1694–703.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367:107–14.

    Article  CAS  PubMed  Google Scholar 

  13. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Schadendorf D, Hodi FS, Robert C, et al. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J Clin Oncol. 2015;33:1889–94.

    Article  CAS  PubMed  Google Scholar 

  16. Prieto PA, Yang JC, Sherry RM, et al. CTLA-4 blockade with ipilimumab: long-term follow-up of 177 patients with metastatic melanoma. Clin Cancer Res. 2012;18:2039–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ribas A, Puzanov I, Dummer R, et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015;16:908–18.

    Article  CAS  PubMed  Google Scholar 

  18. Robert C, Schachter J, Long GV, et al. Pembrolizumab versus Ipilimumab in advanced melanoma. N Engl J Med. 2015;372:2521–32.

    Article  CAS  PubMed  Google Scholar 

  19. Topalian SL, Sznol M, McDermott DF, et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol. 2014;32:1020–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013;369:134–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Larkin J, Hodi FS, Wolchok JD. Combined nivolumab and ipilimumab or Monotherapy in untreated melanoma. N Engl J Med. 2015;373:1270–1.

    Article  PubMed  Google Scholar 

  22. Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372:2006–17.

    Article  PubMed  Google Scholar 

  23. Boni A, Cogdill AP, Dang P, et al. Selective BRAFV600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function. Cancer Res. 2010;70:5213–9.

    Article  CAS  PubMed  Google Scholar 

  24. Frederick DT, Piris A, Cogdill AP, 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;19:1225–31. BRAF/MAPK inhibition causes a more favorable immune microenvironment due to increased melanoma differentiation antigen expression as well as decrease in immunosuppressive cytokines. Also noted, however, in this translational human tissue based study is an increase in exhaustion markers PD-1, PD-L1, and TIM-3. The favorable changes are seen within 10-14 days and lost by several weeks after treatment.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Cooper ZA, Frederick DT, Ahmed Z, Wargo JA. Combining checkpoint inhibitors and BRAF-targeted agents against metastatic melanoma. Oncoimmunology. 2013;2:e24320.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Cooper ZA, Juneja VR, Sage PT, et al. Response to BRAF inhibition in melanoma is enhanced when combined with immune checkpoint blockade. Cancer Immunol Res. 2014;2:643–54. In vivo mouse model demonstrates that BRAF inhibition enhances number and function of intratumoral T cells and that following BRAF inhibition by checkpoint inhibition leads to improved tumor control and survival.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Dobreva ZG, Miteva LD, Stanilova SA. The inhibition of JNK and p38 MAPKs downregulates IL-10 and differentially affects c-Jun gene expression in human monocytes. Immunopharmacol Immunotoxicol. 2009;31:195–201.

    Article  CAS  PubMed  Google Scholar 

  28. Liu C, Peng W, Xu C, et al. BRAF inhibition increases tumor infiltration by T cells and enhances the antitumor activity of adoptive immunotherapy in mice. Clin Cancer Res. 2013;19:393–403.

    Article  CAS  PubMed  Google Scholar 

  29. Jiang X, Zhou J, Giobbie-Hurder A, et al. 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. 2013;19:598–609. BRAF inhibitor resistance is mediated by immune microenvironment with upregulation of PD-L1 on tumor cells.

    Article  CAS  PubMed  Google Scholar 

  30. Schilling B, Paschen A. Immunological consequences of selective BRAF inhibitors in malignant melanoma: Neutralization of myeloid-derived suppressor cells. Oncoimmunology. 2013;2:e25218.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Ho PC, Meeth KM, Tsui YC, et al. Immune-based antitumor effects of BRAF inhibitors rely on signaling by CD40L and IFNgamma. Cancer Res. 2014;74:3205–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Khalili JS, Liu S, Rodriguez-Cruz TG, et al. Oncogenic BRAF(V600E) promotes stromal cell-mediated immunosuppression via induction of interleukin-1 in melanoma. Clin Cancer Res. 2012;18:5329–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Sumimoto H, Imabayashi F, Iwata T, Kawakami Y. The BRAF-MAPK signaling pathway is essential for cancer-immune evasion in human melanoma cells. J Exp Med. 2006;203:1651–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Li M, Knight DA, Synder LA, et al. A role for CCL2 in both tumor progression and immunosurveillance. Oncoimmunology. 2013;2:e25474.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Knight DA, Ngiow SF, Li M, et al. Host immunity contributes to the anti-melanoma activity of BRAF inhibitors. J Clin Invest. 2013;123:1371–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Vergani E, Di Guardo L, Dugo M, et al. Overcoming melanoma resistance to vemurafenib by targeting CCL2-induced miR-34a, miR-100 and miR-125b. Oncotarget. 2016;7:4428–41.

  37. Wang T, Xiao M, Ge Y, et al. BRAF inhibition stimulates melanoma-associated macrophages to drive tumor growth. Clin Cancer Res. 2015;21:1652–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Mantovani A, Sozzani S, Locati M, et al. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 2002;23:549–55.

    Article  CAS  PubMed  Google Scholar 

  39. Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 2008;8:958–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Smith MP, Sanchez-Laorden B, O’Brien K, et al. The immune microenvironment confers resistance to MAPK pathway inhibitors through macrophage-derived TNFalpha. Cancer Discov. 2014;4:1214–29. Macrophages increase in number in response to BRAF inhibition and present a mechanism of resistance, described in this paper to be mediated by TNF-α.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Bradley SD, Chen Z, Melendez B, et al. BRAFV600E Co-opts a conserved MHC class i internalization pathway to diminish antigen presentation and CD8+ T-cell recognition of melanoma. Cancer Immunol Res. 2015;3:602–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Callahan MK, Masters G, Pratilas CA, et al. Paradoxical activation of T cells via augmented ERK signaling mediated by a RAF inhibitor. Cancer Immunol Res. 2014;2:70–9. BRAF inhibition directly activates T cells through pardoxical MAPK activation.

    Article  CAS  PubMed  Google Scholar 

  43. Wilmott JS, Long GV, Howle JR, et al. Selective BRAF inhibitors induce marked T-cell infiltration into human metastatic melanoma. Clin Cancer Res. 2012;18:1386–94.

    Article  CAS  PubMed  Google Scholar 

  44. Cooper ZA, Frederick DT, Juneja VR, et al. BRAF inhibition is associated with increased clonality in tumor-infiltrating lymphocytes. Oncoimmunology. 2013;2:e26615.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Ott PA, Henry T, Baranda SJ, et al. Inhibition of both BRAF and MEK in BRAF(V600E) mutant melanoma restores compromised dendritic cell (DC) function while having differential direct effects on DC properties. Cancer Immunol Immunother. 2013;62:811–22. BRAF mutated cells suppress DC function which is reversed with BRAF/MEK inhibition.

    Article  CAS  PubMed  Google Scholar 

  46. Vella LJ, Andrews MC, Pasam A, et al. The kinase inhibitors dabrafenib and trametinib affect isolated immune cell populations. Oncoimmunology. 2014;3:e946367.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Vella LJ, Pasam A, Dimopoulos N, et al. MEK inhibition, alone or in combination with BRAF inhibition, affects multiple functions of isolated normal human lymphocytes and dendritic cells. Cancer Immunol Res. 2014;2:351–60.

    Article  CAS  PubMed  Google Scholar 

  48. Ferrari de Andrade L, Ngiow SF, Stannard K, et al. Natural killer cells are essential for the ability of BRAF inhibitors to control BRAFV600E-mutant metastatic melanoma. Cancer Res. 2014;74:7298–308. NK cells are a mediator of BRAF inhibitor response and present a possible target in designing future combination therapies.

    Article  CAS  PubMed  Google Scholar 

  49. Sottile R, Pangigadde PN, Tan T, et al. HLA class I downregulation is associated with enhanced NK-cell killing of melanoma cells with acquired drug resistance to BRAF inhibitors. Eur J Immunol. 2016;46:409–19.

    Article  CAS  PubMed  Google Scholar 

  50. Koya RC, Mok S, Otte N, et al. BRAF inhibitor vemurafenib improves the antitumor activity of adoptive cell immunotherapy. Cancer Res. 2012;72:3928–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Hooijkaas A, Gadiot J, Morrow M, et al. Selective BRAF inhibition decreases tumor-resident lymphocyte frequencies in a mouse model of human melanoma. Oncoimmunology. 2012;1:609–17.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Liu L, Mayes PA, Eastman S, 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. 2015;21:1639–51.

    Article  CAS  PubMed  Google Scholar 

  53. Puzanov I. Combining targeted and immunotherapy: BRAF inhibitor dabrafenib (D) +/- the MEK inhibitor trametinib (T) in combination with ipilimumab (Ipi) for V600E/K mutation-positive unresectable or metastatic melanoma (MM). J Transl Med. 2015;13 Suppl 1:K8.

    Article  PubMed Central  Google Scholar 

  54. Ribas A, Hodi FS, Callahan M, et al. Hepatotoxicity with combination of vemurafenib and ipilimumab. N Engl J Med. 2013;368:1365–6. The first phase 1 trial to report tolerability of combination targeted and checkpoint blockade showed unexpected grade 3 hepatotoxicity and highlighted the need for closer monitoring in combination clinical trials. Trial was closed early due to 7/12 patients developing grade 3 hepatotoxicity to combination vemurafenib and ipilimumab.

    Article  CAS  PubMed  Google Scholar 

  55. Ribas A, Butler M, Lutsky J, Lawrence DP, Robert C, et al. Phase I study combining anti-PD-L1 (MEDI4736) with BRAF (dabrafenib) and/or MEK (trametinib) inhibitors in advanced melanoma. J Clin Oncol. 2015;33:abstr 3003. This phase 1 clinical trial is first study to demonstrate tolerability and efficacy with combination of MAPK targeted therapy and immunotherapy against PD-1/PD-L1 axis. High response rates and disease control rates were seen with combination BRAF and MEK inhibition along with anti-PD-L1 antibody with preliminary evidence of durable response.

    Article  Google Scholar 

  56. Amin A LD, Salama AK, Koon HB, et al. A single-arm, open-label, phase II study to evaluate the safety of vemurafenib (VEM) followed by ipilimumab (IPI) in BRAF V600-mutated metastatic melanoma (MM). J Clin Oncol 2015; 33 (suppl; abstr 9032).

  57. Wargo JA, Lawrence DP, Cooper ZA, Frederick DT, et al. A phase II study of combined therapy with vemurafenib (vem) and high-dose interleukin-2 (aldesleukin; HD IL-2) in patients with metastatic melanoma. J Clin Oncol. 2015;33, e20074.

    Google Scholar 

  58. Puzanov I, Callahan MK, Linette GP. Phase 1 study of the BRAF inhibitor dabrafenib (D) with or without the MEK inhibitor trametinib (T) in combination with ipilimumab (Ipi) for V600E/K mutation-positive unresectable or metastatic melanoma (MM). J Clin Oncol. 2014;32(suppl; abstr 2511):5s.

    Google Scholar 

  59. Ackerman A, Klein O, McDermott DF, et al. Outcomes of patients with metastatic melanoma treated with immunotherapy prior to or after BRAF inhibitors. Cancer. 2014;120:1695–701. This retrospective study of 274 metastatic melanoma patients treated with sequential BRAF targeted and immunotherapy suggests that treating with immunotherapy at time of BRAF inhibitor resistance is unlikely to be of clinical benefit.

    Article  CAS  PubMed  Google Scholar 

  60. Das Thakur M, Salangsang F, Landman AS, et al. Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance. Nature. 2013;494:251–5.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, 1400 Holcombe Blvd, Unit 463, Houston, TX, 77030, USA

    Sangeetha M. Reddy

  2. Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA

    Alexandre Reuben

  3. Department of Surgical Oncology, Genomic Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA

    Jennifer A. Wargo

Authors
  1. Sangeetha M. Reddy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alexandre Reuben
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jennifer A. Wargo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jennifer A. Wargo.

Ethics declarations

Conflict of Interest

Sangeetha M. Reddy declares that she has no conflict of interest.

Alexandre Reuben declares that he has no conflict of interest.

Jennifer A. Wargo has received honoraria from Dava Oncology and has served on advisory boards for GlaxoSmithKline and Roche/Genentech.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Melanoma

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Reddy, S.M., Reuben, A. & Wargo, J.A. Influences of BRAF Inhibitors on the Immune Microenvironment and the Rationale for Combined Molecular and Immune Targeted Therapy. Curr Oncol Rep 18, 42 (2016). https://doi.org/10.1007/s11912-016-0531-z

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11912-016-0531-z

Keywords

Search

Navigation