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Unraveling the Role of the Immune System in BRAF–MEK Inhibitor Responses Keiran S.M

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Unraveling the Role of the Immune System in BRAF–MEK Inhibitor Responses Keiran S.M VIEWS IN THE SPOTLIGHT Two Worlds Collide: Unraveling the Role of the Immune System in BRAF–MEK Inhibitor Responses Keiran S.M. Smalley Summary: Although BRAF–MEK inhibition can enhance the immune recognition of melanoma cells, the mechanisms that underlie this remain poorly defi ned. In this issue of Cancer Discovery , Erkes and colleagues present new data showing that BRAF–MEK inhibition activates pyroptosis in melanoma cells through gasdermin E cleavage, leading to T-cell infi ltration and improved therapy responses in vivo . See related article by Erkes et al., p. 254 (9). Melanoma is the deadliest form of skin cancer. Over the levels of the T-cell stimulatory molecules CD80, CD83, and past 9 years, signifi cant progress has been made in the devel- CD86. In transgenic mouse melanoma models of BRAF - opment of therapies that can deliver long-term responses mutant melanoma, inhibition of BRAF improved the ratio to patients with advanced disease. Among these, targeted of CD8 + T cells to MDSCs in the tumor. There were initial therapies such as the BRAF–MEK inhibitor combination are concerns that the BRAF–MEK inhibitor combination might associated with a 5-year overall survival of approximately lead to immunosuppression, particularly as MEK is required 33%, and the immune checkpoint inhibitors (ICI; such as for T-cell activation. Interestingly, this did not seem to be anti–PD-1 therapy) have been shown to be effective in >30% the case, and although MEK inhibition was found to impair of patients ( 1, 2 ). One major question for the melanoma fi eld naïve T-cell priming, it paradoxically increased the numbers is how best to combine targeted therapy and immunotherapy of tumor-associated T cells, in part by suppressing the apop- so that response durations can be maximized and off-target tosis that followed chronic T-cell receptor (TCR) stimulation effects are minimized. ( 5 ). The potential for the MEK–BRAF inhibitor combination BRAF inhibitors and the BRAF–MEK inhibitor combina- to synergize with immune checkpoint blockade was dem- tion were initially developed as tumor-intrinsic therapies that onstrated in mouse melanoma models, with the antitumor target the uncontrolled cell growth of melanoma cells driven effects observed being associated with decreased tissue-asso- by mutant BRAF . It is now becoming clear that oncogenic ciated macrophage (TAM) and Treg accumulation, improved BRAF can also modulate the ability of the immune system to IFNγ release, and enhanced antigen presentation ( 6 ). recognize melanoma cells. Acquisition of a BRAF mutation Acquisition of BRAF inhibitor resistance is associated with leads to constitutive signaling through the MAPK pathway, a reduced immune response. In an analysis of pre- and post- which in turn contributes to immune escape through the BRAF inhibitor–treated melanoma patient samples, numbers recruitment of regulatory T cells (Treg), decreased antigen of tumor-infi ltrating CD8+ T cells declined, and the propor- presentation (via downregulation of MHC class I), and the tion of suppressive immune cells including MDSCs, Tregs, and inhibition of IFNγ, IL2, and TNFα release ( 3 ). As would be TAMs increased, as the individuals failed therapy. These obser- expected, inhibition of BRAF in BRAF -mutant melanoma vations paved the way for immunotherapy/targeted therapy cells reverses these processes and can restore tumor–immune combinations to be evaluated clinically. Initial attempts to recognition ( 4 ). In preclinical studies, it was found that BRAF develop targeted therapy/immunotherapy combinations (par- inhibition led to increased CD40L expression and IFNγ release ticularly with ipilimumab) were not successful due to severe from CD4 + T cells, reduced accumulation of myeloid-derived toxicity. More success has been experienced by combining suppressor cells (MDSC) and Tregs, and decreased levels of BRAF–MEK inhibitors with anti–PD-1, with some improve- multiple cytokines including IL1, IL6, and IL10 ( 3 ). In cocul- ments in response being noted ( 7, 8 ). Mechanistically this ture studies of melanoma cells and dendritic cells (DC), BRAF combination was associated with enhanced CD8 + T-cell accu- inhibition restored IL12 and TNFα expression and increased mulation and the increased expression of MHC I and II. As with ipilimumab, the targeted therapy/anti–PD-1 combination was associated with serious off-target effects (58% grade 3–5 toxicity). At this time, a rational mechanistic basis for combin- The Department of Tumor Biology and the Department of Cutaneous ing immunotherapy and targeted therapy is still lacking. Oncology, The Moffi tt Cancer Center & Research Institute, Tampa, Florida. In this issue of Cancer Discovery, Erkes and colleagues Corresponding Author: Keiran S.M. Smalley, Moffi tt Cancer Center, 12902 report on a new mechanism by which the immune system Magnolia Drive, Tampa, FL 33612. Phone: 813-745-8725; Fax: 813-449- contributes to the BRAF–MEK inhibitor response in vivo 8260; E-mail: keiran.smalley@moffi tt.org ( 9 ). For their studies, the authors chose to forego the usual Cancer Discov 2020;10:176–8. BRAF -mutant human melanoma cell lines and instead used doi: 10.1158/2159-8290.CD-19-1441 murine BRAF -mutant melanoma cell lines that had been sub- © 2020 American Association for Cancer Research. jected to multiple rounds of UV irradiation to increase their 176 | CANCER DISCOVERY FEBRUARY 2020 AACRJournals.org Downloaded from cancerdiscovery.aacrjournals.org on September 23, 2021. © 2020 American Association for Cancer Research. VIEWS A No BRAF–MEK inhibitor form of cell death in the melanoma cells, and stimulated an immune response. MDSCs Melanoma cells Multiple forms of programmed cell death are known to exist, including apoptosis, necroptosis, ferroptosis, NETo- sis, parthanosis, and pyroptosis. Among these, pyroptosis (which is derived from the Greek word for fire, “pyro”) is Macrophages linked to pathogen infection and involves the release of proinflammatory cytokines. Classic pyroptosis is depend- ent upon the caspase-1–mediated cleavage of gasdermin D (GSDMD), whose N-terminal portion assembles into cell membrane–spanning pores that mediate cytokine release and lytic cell death. Previous work by the authors demon- strated a role for caspase-3–mediated cleavage of gasdermin B In the presence of BRAF–MEK inhibitor E (GSDME) in pyroptotic cell death, providing a poten- BRAF–MEKi tial link between BRAF inhibitor–induced apoptosis and pyroptosis-associated immune stimulation (10). Silencing of Gsdme in the melanoma cells through CRISPR knock- HMGB1 down was shown to reduce both pyroptotic cell death and Melanoma cells immune cell accumulation in BRAF–MEK inhibitor–treated GSDME tumors, but curiously did not alter the dynamics of the initial antitumor response. Although these data appeared Dendritic cells conflicting, it was found that theGsdme -silenced tumors were more likely to recur following cessation of therapy, demonstrating a role for pyroptosis in the immune regula- MHC tion of residual disease. The apparent lack of effect of Gsdme T cells silencing upon the initial antitumor responses seen by Erkes and colleagues suggested the involvement of additional immune-mediated effects of BRAF–MEK inhibition that Figure 1. Scheme showing the effects of BRAF–MEK inhibitor therapy were pyroptosis-independent (9). on pyroptosis induction and T-cell recruitment. A, Prior to therapy, the The pyroptotic response was blunted following the acqui- mouse melanoma had larger numbers of MDSCs and TAMs. B, Following sition of BRAF–MEK inhibitor resistance, an effect associ- BRAF–MEK inhibitor treatment, there is a switch to a more active immune environment characterized by DC activation and T-cell recruitment. One ated with reduced caspase-3 activity, GDSME cleavage, and of the major drivers of this response is cleavage of gasdermin E (GSDME) HMGB1 release. This decrease in pyroptosis following acqui- leading to the release of immune-stimulatory molecules including HMGB1, sition of BRAF–MEK inhibitor resistance was also associated which then increases antigen presentation and T-cell recruitment. with reduced levels of T-cell accumulation in the tumor, fur- ther supporting the link between pyroptosis and a continued immunogenicity. These cell lines have the capacity to respond antitumor immune response. As the final part of their study, to both immunotherapy and targeted therapy in vivo, and can the authors asked whether there was any therapeutic benefit be grown efficiently in immunocompetent mice. The authors to restoring pyroptosis in BRAF–MEK inhibitor–resistant began by making the striking observation that BRAF–MEK tumors. A number of clinically relevant drugs including inhibitor responses in vivo were significantly longer in dura- CDK4/6 inhibitors, BET inhibitors, ERK inhibitors, and tion when the melanoma cell lines were grown in immuno- chemotherapeutic agents were evaluated for their ability to competent mice compared with the immunocompromised induce pyroptosis. Among these, the chemotherapy drug mice (9). In the immunocompetent mice, BRAF–MEK inhi- etoposide was found to induce pyroptosis, and some improve- bition was associated with a vigorous immune response ment in mouse survival was observed when this drug was characterized by increased infiltration of CD4+ and CD8+ used as a salvage therapy (9). The authors did not determine T cells and reduced levels of MDSCs and TAMs (Fig. 1). This whether etoposide restored T-cell infiltration to the resistant immune response was critical
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