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Treating Cancer by Mimicking Infection

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Treating Cancer by Mimicking Infection Author Manuscript Published OnlineFirst on May 23, 2019; DOI: 10.1158/1078-0432.CCR-18-1800 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Pathogen molecular pattern receptor agonists: treating cancer by mimicking infection Running Title: Pattern recognition receptors in immuno-oncology Mark Aleynick;1 Judit Svensson-Arvelund, PhD;1 Christopher R. Flowers, MD;2 Aurélien Marabelle, MD, PhD;3 Joshua D. Brody, MD.1,4,* 1Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA 2Winship Cancer Institute of Emory University, Emory University School of Medicine, Atlanta, GA 30307, USA 3Cancer Immunotherapy Program, Gustave Roussy, Villejuif 94800, France 4Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA *Correspondence: Joshua D. Brody [email protected]; 212-241-6756 Hess CSM Floor 5 Room 106 1470 Madison Avenue, New York, NY 10029 Disclosures: Mark Aleynick has no conflicts of interest to disclose. Judit Svensson-Arvelund has no conflicts of interest to disclose Christopher Flowers has served as a consultant for: Abbvie, AstraZeneca, Bayer, BeiGene, Celgene (unpaid), Denovo Biopharma, Genentech/Roche (unpaid), Gilead, OptumRx, Karyopharm, Pharmacyclics/ Janssen, Spectrum. Dr. Flowers has received research funding from: Abbvie, Acerta, BeiGene, Celgene, Gilead, Genentech/Roche, Janssen Pharmaceutical, Millennium/Takeda, Pharmacyclics, TG Therapeutics, Burroughs Wellcome Fund, Eastern Cooperative Oncology Group, National Cancer Institute, ORIEN/M2Gen, and the V Foundation. Aurélien Marabelle is the Principal Investigator of Clinical Trials from the following companies: Merck (MSD). Dr. Marabelle has served as a consultant for: Innate Pharma, Merck Serono, eTheRNA, Lytix pharma, Kyowa Kirin Pharma, Bayer, Novartis, BMS, Symphogen, Genmab, Amgen, Biothera, Nektar, GSK, Oncovir, Pfizer, Seattle Genetics, Flexus Bio, Roche/Genentech, OSE immunotherapeutics, Transgene, Gritstone, Merck (MSD), Cerenis, Protagen, Partner Therapeutics, Servier, Sanofi, Pierre Fabre, Molecular Partners, Roche, Pierre Fabre, Onxeo, EISAI, Bayer, Genticel, Rigontec, Daichii Sankyo, Imaxio, Sanofi, BioNTech, Corvus, GLG, Deerfield, Guidepoint Global, Edimark, System Analytics, imCheck, Sotio, Bioncotech, Pillar Partners, Boehringer Ingelheim. Dr. Marabelle has received research funding from Astrazeneca, BMS, Boehringer Ingelheim, Janssen Cilag, Merck, Novartis, Pfizer, Roche, Sanofi 1 Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on May 23, 2019; DOI: 10.1158/1078-0432.CCR-18-1800 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Joshua Brody has served as a consultant for: AstraZeneca, Bayer, Calithera, Celldex Therapeutics, Gilead, Merck, Pharmacyclics/ Janssen, Seattle Genetics, Teva. Dr. Brody has received research funding from: Acerta, Celgene, Gilead, Genentech/Roche, the Cancer Research Institute, and the Damon Runyon Cancer Research Foundation. Abstract Immunotherapies such as checkpoint blockade have achieved durable benefits for patients with advanced stage cancer and have changed treatment paradigms. However, these therapies rely on a patient’s own a priori primed tumor-specific T cells, limiting their efficacy to a subset of patients. Because checkpoint blockade is most effective in patients with inflamed or ‘hot’ tumors, a priority in the field is learning how to ‘turn cold tumors hot’. Inflammation is generally initiated by innate immune cells which receive signals through pattern recognition receptors (PRRs) – a diverse family of receptors that sense conserved molecular patterns on pathogens, alarming the immune system of an invading microbe. Their immunostimulatory properties can reprogram the immune suppressive tumor microenvironment and activate antigen presenting cells (APC) to present tumors antigens, driving de-novo tumor-specific T cell responses. These features, among others, make PRR-targeting therapies an attractive strategy in immuno- oncology. Here, we discuss mechanisms of PRR activation, highlighting ongoing clinical trials and recent pre-clinical advances focused on therapeutically targeting PRRs to treat cancer. Introduction The interplay between cancer and the immune system is a double edged sword; the inflammation that recruits and activates intratumoral immune cells can either eliminate cancer cells or drive tumor progression in a context dependent manner (1). PRRs are a key family of proteins involved in the inflammatory response. They are expressed on a wide variety of innate and adaptive immune cells as well as tumor cells, and recognize both foreign pathogen associated molecular patterns (PAMPs) and self-derived damage associated molecular patterns (DAMPs) resulting from injury or cell death (1–3). There are 5 families of PRRs: toll-like receptors (TLRs), nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), C-type lectin receptors (CLRs), RIG-I-like receptors (RLRs), and cytosolic DNA sensors (CDS) (2). Each PRR family possesses distinct immunomodulatory properties, making them attractive immunotherapeutic targets. Here, we discuss PRR mechanisms and clinical implications to provide a detailed overview of the role of PRRs in immuno-oncology. TLRs in Cancer Immunotherapy TLRs are the most widely studied PRR family, acknowledged in the 2011 Nobel Prize awarded to Drs. Steinman, Beutler, and Hoffman. There have been 10 TLRs identified in humans and 13 in mice (4); here we focus on the former. Structurally, TLRs are type I transmembrane proteins characterized by a ligand-binding N terminal ectodomain containing leucine-rich repeats, a single transmembrane domain, and a cytosolic Toll/IL-1R homology domain responsible for signal transduction (2). TLRs 1, 2, and 4-6 are located on the cell surface and recognize bacterial 2 Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on May 23, 2019; DOI: 10.1158/1078-0432.CCR-18-1800 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. membrane components such as lipids, proteins, lipoproteins (Fig. 1) (2,3), as well as several self- molecules, including extracellular matrix components, heat shock proteins (HSPs), and nuclear high-mobility group box 1 (HMGB1), often released as DAMPs from apoptotic or necrotic cells (1,3). Intracellular TLRs 3 and 7-9 are located within endosomes, and recognize viral and bacterial nucleic acids resulting from microbial replication or degradation upon entry into the cell (Fig. 1) (1–3). Their localization normally prevents intracellular TLRs from binding self nucleic acids. However, breakdown of this spatial separation may trigger autoimmune disease through recognition of self nucleic acids (3,5). Although TLR10 exists in humans, it has been difficult to study as it is non-functional in mice. Recent work suggests it may serve as a negative regulator of TLR signaling (6,7). TLRs dimerize upon binding their cognate ligand (Fig. 1), causing conformational changes that allow for the recruitment of adapter molecules (MyD88, TIRAP, TRIF, and TRAM), initiating signaling cascades that ultimately induce transcription of inflammatory mediators (2,3,8). As TLRs are highly expressed on antigen presenting cells (APCs), targeting TLRs can activate APCs and trigger adaptive immune responses; intratumorally, this may shift a tolerogenic tumor microenvironment (TME) to become immunogenic. However, because TLR signaling triggers inflammatory and cell survival mechanisms, and certain tumors express TLRs, TLR activation could instead be tumorigenic in certain settings (1,9). Both TLR7 and TLR8 signaling have been implicated in driving lung cancer cell survival and chemotherapy resistance mechanisms (10,11). TLR4 signaling in breast cancer both enhances chemotherapeutic resistance and promotes angiogenesis and lymphatic metastasis (12,13). Tumor cells may also secrete heat shock proteins and extracellular matrix factors as DAMPs, stimulating an immunosuppressive program in tumor associated macrophages (TAMs) to promote angiogenesis and metastasis (14,15). One recent study demonstrated that mice lacking TLR3/7/9 cleared implanted tumors through spontaneous induction of an adaptive anti-tumor response (16). Similar effects are observed with other PRR families; galectin-9 signaling through the CLR dectin-1 on TAMs is pro-tumorigenic in mouse models of pancreatic ductal adenocarcinoma, although signaling through this receptor in other cancers may have the opposite effect (17). While several of these reports implicate DAMPs in tumor initiation and progression through chronic inflammation, other studies demonstrate that DAMPs released from dying tumor cells are the hallmark of immunogenic cell death, activating APCs in the TME to present tumor antigen (9,18). Despite the nuanced role of PRR signaling in cancer, in many contexts, therapies targeting PRR pathways have the ability to overcome immunosuppression or drive a de novo anti-tumor response by activating APCs to enhance tumor antigen presentation (Fig. 2). For the remainder of this review, we will focus on clinical trials and pre-clinical studies utilizing PRRs in this setting. One of the few FDA approved TLR-targeting therapies in oncology is
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