Abstract SY26-02: Complex immune effects of inhibiting BRAF
Authors: Ribas Antoni 
Published: August 2015

Abstract
Antoni Ribas, M.D., Ph.D. Department of Medicine, Division of Hematology/Oncology; Department of Surgery; Department of Medical and Molecular Pharmacology, University of California Los Angeles (UCLA), and the Jonsson Comprehensive Cancer Center at UCLA, Los Angeles, CA.
Applying scientific knowledge about oncogenic signaling and the immunobiology from the laboratory to the clinic has fostered recent advances in the treatment of patients with metastatic melanoma and other cancers (1). The BRAFV600 mutation drives the growth of approximately 50% of melanomas, and targeted agents inhibiting oncogenic BRAF and/or MEK result in very high initial clinical responses, but relapse rates are also high. Activation of an immune response by releasing inhibitory checkpoints, such as CTLA4 or PD-1, can induce durable responses in a subset of patients with melanoma. Combining both modes of therapy has the goal of achieving high response rates with prolonged duration. The anticipation of benefits from such a combination are based on the clinically validated individual activity of both modes of therapy, the potentials for combining without limiting overlapping toxicities, the scientific rationale of potential benefits and the supportive evidence from preclinical models (2). Potential mechanisms of combinatorial activity are based on increased antigen expression and presentation to the immune system upon BRAF inhibition, the inhibition of immune suppressive factors by blocking oncogenic BRAF improving the infiltration of cytotoxic immune cells into the tumor microenviroment, and paradoxical activation of immune cells. The effects of paradoxical mitogen-activated protein kinase (MAPK) pathway activation by BRAF inhibitors in non-BRAF mutant cells needs to be taken into account, as it may lead to immune cell over-activation and unwanted toxicities (3). Therefore, the potential adverse effects of such combinations in terms of increased autoimmune toxicities and interference with the individual antitumor activities need to be considered when translating to the clinic.
Furthermore, the combinatorial approach of BRAF inhibitors with immunotherapy should also consider the reciprocal interaction from the immune system and its inflammatory effects on cancer cells. This means exploring how pro-inflammatory cytokines released by T cells or induced by intratumoral macrophages may be protecting melanoma cells from BRAF inhibition and driving them into a phenotype switch and neural crest dedifferentiation. It has been reported in a mouse model that acquired resistance to tumor immunotherapy can be mediated by TNFα produced by tumor infiltrating lymphocytes resulting in a melanoma de-differentiation detectable by the expression of the nerve growth factor receptor (NGFR, also known as CD271) (4). Similar inflammatory signaling-induced changes in melanoma have been described when using BRAF inhibitors, which may lead to decreased sensitivity to immunotherapy (5, 6). Understanding this reciprocal interaction between inflammation and inhibition of oncogenic BRAFV600 is of high importance to adequately test the hypothesis of combined immunotherapy and targeted therapy to treat patients with advanced melanoma.
Another avenue of the combination of targeted therapies with immunotherapy is using specific inhibitors for immune suppressive cells in the tumor microenviroment, which indirectly would improve the function of antitumor T cells. CSF-1 is a cytokine frequently produced by several cancers. CSF-1 increases the proliferation and differentiation of myeloid cells into immunosuppressive cells like M2-polarized macrophages and myeloid derived suppressor cells (MDSC) in the tumor. Inhibiting CSF-1R with small molecules decreases the immunosuppressive tumor microenvironment and improves the antitumor activity of T cell-based immunotherapy (7).
In conclusion, combination of targeted therapies such as BRAF inhibitors or CSF-1R inhibitors is a rational approach to improve tumor immunotherapy for melanoma.
References
1. McArthur GA, Ribas A. Targeting oncogenic drivers and the immune system in melanoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2013;31:499-506.
2. Hu-Lieskovan S, Robert L, Homet Moreno B, Ribas A. Combining Targeted Therapy With Immunotherapy in BRAF-Mutant Melanoma: Promise and Challenges. J Clin Oncol. 2014;32:2248-54.
3. Koya RC, Mok S, Otte N, Blacketor KJ, Comin-Anduix B, Tumeh PC, Minasyan A, Graham NA, Graeber TG, Chodon T, Ribas A. BRAF inhibitor vemurafenib improves the antitumor activity of adoptive cell immunotherapy. Cancer research. 2012;72:3928-37.
4. Landsberg J, Kohlmeyer J, Renn M, Bald T, Rogava M, Cron M, Fatho M, Lennerz V, Wolfel T, Holzel M, Tuting T. Melanomas resist T-cell therapy through inflammation-induced reversible dedifferentiation. Nature. 2012;490:412-6.
5. Muller J, Krijgsman O, Tsoi J, Robert L, Hugo W, Song C, Kong X, Possik PA, Cornelissen-Steijger PD, Foppen MH, Kemper K, Goding CR, McDermott U, Blank C, Haanen J, Graeber TG, Ribas A, Lo RS, Peeper DS. Low MITF/AXL ratio predicts early resistance to multiple targeted drugs in melanoma. Nat Commun. 2014;5:5712.
6. Konieczkowski DJ, Johannessen CM, Abudayyeh O, Kim JW, Cooper ZA, Piris A, Frederick DT, Barzily-Rokni M, Straussman R, Haq R, Fisher DE, Mesirov JP, Hahn WC, Flaherty KT, Wargo JA, Tamayo P, Garraway LA. A melanoma cell state distinction influences sensitivity to MAPK pathway inhibitors. Cancer Discov. 2014;4:816-27.
7. Mok S, Koya RC, Tsui C, Xu J, Robert L, Wu L, Graeber TG, West BL, Bollag G, Ribas A. Inhibition of CSF-1 receptor improves the antitumor efficacy of adoptive cell transfer immunotherapy. Cancer Res. 2014;74:153-61.
Citation Format: Antoni Ribas. Complex immune effects of inhibiting BRAF. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr SY26-02. doi:10.1158/1538-7445.AM2015-SY26-02