Inhibiting the Tgfβ Signaling Pathway Enhances Immune Checkpoint Blockade

294 Editorial One checkpoint may hide another: inhibiting the TGFβ signaling pathway enhances immune checkpoint blockade Aditi Gupta, Sadna Budhu, Taha Merghoub Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Parker Institute for Cancer Immunotherapy at Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA Correspondence to: Taha Merghoub. Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Parker Institute for Cancer Immunotherapy at Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Email: [email protected]. Comment on: Tauriello DVF, Palomo-Ponce S, Stork D, et al. TGFbeta drives immune evasion in genetically reconstituted colon cancer metastasis. Nature 2018;554:538-43. Submitted Nov 13, 2018. Accepted for publication Jan 06, 2019. doi: 10.21037/hbsn.2019.01.10 View this article at: http://dx.doi.org/10.21037/hbsn.2019.01.10 Tumors employ several mechanisms to evade recognition its activation (4). Aside from its role in cancer, TGFβ plays by the immune system. Among these are epigenetic a critical role in controlling aberrant immune responses changes such as loss of the antigen presenting machinery against self, such as in autoimmune diseases. (e.g., HLA-A,B,C) that cause tumors to become invisible Since the FDA approval of Ipilimumab in 2011 and to the immune system. They can employ mechanisms Pembrolizumab in 2014, immunotherapy has moved to suppress the immune response through the enzyme to the forefront of cancer care. While we have seen indoleamine dioxygenase (IDO) and the inhibitory receptor promising success of these agents as monotherapies, it is programmed death ligand 1 (PD-L1). Both tumor cells increasingly evident that the combination of these agents and the surrounding stroma can be the source of such (e.g., Ipilumumab and Nivolumab) together or with other molecules. Tumors can recruit suppressive immune cells conventional therapies [e.g., chemotherapy and radiation [regulatory T cells (Tregs), myeloid derived suppressor cells therapy (RT)] and novel immunotherapy targets will (MDSCs)] that inhibit T cell responses to tumors mainly provide greater clinical benefit. However, rational design by secreting anti-inflammatory cytokines (1,2). TGFβ of combination therapy is necessary to enhance the efficacy is the most well characterized of these cytokines. TGFβ of these immunotherapies. When it comes to targeting is a pleotropic cytokine that is important in regulating specific molecules with immunotherapy, it is imperative immune responses. It is found in many cancer types and is to understand the spatial and temporal expression associated with poor clinical outcome (3). Depending on of these molecules in the tumor microenvironment. the context of the microenvironment, TGFβ can suppress Secreted factors such as TGFβ can be made by tumor the immune system by inducing Tregs, and inhibiting cells, stromal fibroblasts and immune infiltrates. It is CD4+ and CD8+ T cell effector functions such as their important to determine which cells predominantly express activation or cytolytic activity. There are three isoforms of the target molecule. Another level of complexity comes TGFβ in humans and mice (TGFβ1, TGFβ2 and TGFβ3) from the fact that not all cancer types contain the same that have high homology with each other. Numerous cells components of the microenvironment. Furthermore, the make and secrete the inactive latent form of TGFβ into timing and doses of agents to be combined will need to be the extracellular space; however, only a few cells within the optimized. Some combinations have already been shown tumor microenvironment (TME) contain the machinery (αv to be counterproductive due to inefficient timing (5). It is integrins, proteases, GARP etc.) to convert it to its active imperative to understand the biology of the immune system form. It appears that the suppressive functions of TGFβ are and the TME in order to design rational hypothesis-driven mediated not only by its synthesis but also by the extent of preclinical and clinical trials of combination therapy. © HepatoBiliary Surgery and Nutrition. All rights reserved. HepatoBiliary Surg Nutr 2019;8(3):289-294 | http://dx.doi.org/10.21037/hbsn.2019.01.10 290 Gupta et al. TGFβ inhibition enhances immune checkpoint blockade A No Treatment B TGFβ Inhibition + anti-PD-L1 Legend CD8+ T cell Fibroblast Tumor cell TGFβ1 TGFβ2 TGFβ3 Granzyme B Figure 1 TGFβ inhibition promotes T cell infiltration. Schematic depicting the role of TGFβ in (A) promoting T cell exclusion through formation of a stromal barrier and (B) enhanced T cell infiltration and activation by combining TGFβ inhibition with checkpoint blockade. Two studies by Mariathasan et al. (6) and Tauriello fibroblasts (CAFs) were the main source of TGFβ in mouse et al. (7) in Nature highlighted how understanding the and human CRC samples. Treatment with galunisertib, a mechanisms behind the failure of immune checkpoint TGFBR1-specific inhibitor, reduced primary tumors and blockade in urothelial and colorectal cancer (CRC) can metastatic disease burden. The addition of anti-PD-L1 aid in developing treatment to overcome resistance to with galunisertib eradicated most overt metastatic disease immunotherapies. It is now recognized that immune and prolonged overall survival for more than a year after checkpoint blockade works best in tumors that are treatment. Activation of both CD4+ and CD8+ T cells was heavily infiltrated by T cells or “hot” tumors. Conversely, observed with galunisertib treatment. A complementary immunotherapies are less effective in tumors that either lack study by Mariathasan et al. evaluated biomarkers of clinical T cells, referred to as “immune desert” or “cold” tumors, responses to the anti-PD-L1 antibody, atezolizumab, in or in tumors that exclude T cells. Mariathasan et al. and patients with metastatic urothelial cancer. Transcriptomic Tauriello et al. showed that the presence of TGFβ in the evaluation revealed that clinical response was associated stroma of tumors leads to exclusion of T cell infiltration with a CD8+ effector T cell phenotype and high tumor into tumors by trapping them in the periphery. Concurrent mutation burden, but TGFβ signaling in fibroblasts was blockade of TGFβ signaling and PD-L1 in these immune associated with poor response and survival (3). This finding excluded tumors lead to greater anti-tumor effects by was particularly relevant for the T cell excluded subtype of turning an immune excluded tumor into an inflamed “hot” metastatic urothelial cancer, where a pan-fibroblast TGFβ tumor (Figure 1). In addition, it appears that CD8+ T cells response signature (F-TBRS) was significantly associated were necessary for the anti-tumor efficacy as both studies with non-responders. show enhanced CD8+ T cell activation. Both studies above (Tauriello et al. and Mariathasan Tauriello et al., modeled microsatellite-stable (MSS) et al.) suggest that targeting the TME through inhibition human CRC using genetically engineered mice (designated of TGFβ signaling may be a means to enhance checkpoint LAKTP), which developed carcinomas that displayed a blockade immunotherapy across several cancer types. In TME with high levels of stromal TGFβ activity conferring both cases, the authors showed that the source of TGFβ poor prognoses (3,8). In this model, cancer associated is primarily derived from CAFs, which express high levels © HepatoBiliary Surgery and Nutrition. All rights reserved. HepatoBiliary Surg Nutr 2019;8(3):289-294 | http://dx.doi.org/10.21037/hbsn.2019.01.10 HepatoBiliary Surgery and Nutrition, Vol 8, No 3 June 2019 291 of TGFβ1 and TGFβ3. To date, most preclinical studies is a small molecule inhibitor of TGFβRI and is the most involving the TGFβ pathway use tumor models that are developed TGFβ receptor kinase inhibitor (10,11). Lastly, enriched in stromal components such as CAFs. However, M7824 is a fusion protein composed of the extracellular the role and source of TGFβ in stroma-poor tumors, such as domain of human TGFβRII, acting as a TGFβ trap, melanoma, remains to be investigated. It will be interesting connected to the C-terminus of human anti-PD-L1 (13). So in the future to determine whether TGFβ blockade will only far, the most advanced inhibitors in the clinic target TGFβ benefit patients whose tumors are enriched with CAFs. In signaling directly or block all three isoforms of TGFβ. Given addition, TGFβ has been shown to have profound effects on the homeostatic roles of TGFβ, including proliferation, suppressing both adaptive and innate immune cells. Most differentiation, and migration, inhibition of all 3 isoforms may studies on TGFβ focus on its immunosuppressive role on be detrimental to normal physiology in treated individuals. CD4+ and CD8+ T cells (9). These two studies demonstrated In fact, there has been side effects and toxicities associated that TGFβ inhibition enhanced CD4+ and CD8+ T cell with TGFβ inhibitors in the past; therefore, selective activation and differentiation, especially when combined inhibition of one isoform rather than pan-TGFβ blockade with PD-L1 blockade. However, the authors did not explore may lead to adequate tumor control while reducing off target the effects of TGFβ inhibition on innate immune cells. It effects. Currently, isoform specific inhibitors of TGFβ1 is well known that TGFβ can promote immunosuppressive and TGFβ3 are undergoing clinical development (14). macrophages and tolerogenic dendritic cells (9). It would be Table 1 summarizes the

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