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interplay beetween DC and tumor,When faced with invading microbes, the immune system must quickly launch an appropriate response to eliminate invaders and restore tissue integrity and homeostasis DCs, described for the first time by Steinman and Cohn (1973), are the master regulators of the immune response dictating tolerance or immunity (Steinman, 2011). Cancer antigens could be presented to T cells by DCs either at tumor sites or in draining lymph nodes (Fig. 1). Cancer antigens, soluble and particulate, are transported to lymph nodes via lymphatic vessels (Steinman, 2011). Soluble antigens are captured by lymph noderesident DCs while tissueresident DCs capture antigen at tumor sites; tissueresident DCs can present antigens either at the tumor site (Chiodoni et al., 1999) or they migrate through lymphatic vessels to present antigen in lymph nodes (Bonaccorsi et al., 2015; Steinman, 2011). DCs display protein antigens in the context of classical MHC class I and MHC class II molecules that allow selection and priming of rare antigenspecific T lymphocytes including CD8+ T cells, CD4+ T cells as introduced above (Trombetta and Mellman, 2005). They can also present lipid antigens in the context of nonclassical CD1 molecules that allow activation of NKT cells (Bendelac et al., 2007). The priming of new T cell repertoires might be critical for clinical success of therapeutic agents aiming to unleash antigenspecific CTLs. The diversity of T cell response is in part ensured by three features of DCs that control their ability to finetune the adaptive immune response: (1) DC maturation (Mellman and Steinman, 2001); (2) DC plasticity in response to environmental cues such as those linked with antigen capture, antigenindependent signals as cytokines and other cells in their environment (Mellman and Steinman, 2001); and (3) The existence of distinct DC subsets with specific functions (Banchereau and Steinman, 1998). Cancer cellderived signals are able to exploit these features, thus having a major impact on DC functionality in the tumor microenvironment (TEM) as discussed in more detail hereunder
ARTICLE IN PRESS Interplay between dendritic cells and cancer cells Jan Martinek, Te-Chia Wu, Diana Cadena, Jacques Banchereau*, Karolina Palucka* The Jackson Laboratory for Genomic Medicine, Farmington, CT, United States *Corresponding authors: e-mail address: jacques.banchereau@jax.org; karolina.palucka@jax.org Contents Introduction Dendritic cells in the immune response to cancer 2.1 Dendritic cell maturation as checkpoint of tolerance and immunity 2.2 Antigen capture and modulation of DC maturation 2.3 Dendritic cell subsets in cancer Dendritic cells dictate the outcome of immune response to cancer 3.1 DCs control anti-tumor immune response 3.2 The central role of type I IFN in tumor rejection 3.3 DCs in pro-tumor immunity and response to treatment 3.4 Chronic inflammation promotes immune escape via DCs Conclusions and future studies Acknowledgments References 12 15 15 16 17 20 22 25 25 Abstract Dendritic cells (DCs) orchestrate a repertoire of immune responses that bring about resistance to infection and tolerance to self Cancers can exploit DCs to evade immunity, but DCs also can generate resistance to cancer Owing to their capacity to capture, process, and present antigens to naïve T cells, thereby launching adaptive immunity, DCs are poised to play a critical role in cancer recognition and rejection As such, DCs represent a solution for the expansion and infiltration of T cells with tumor-rejecting properties Indeed, clinical responses to checkpoint blockade, such as anti-PD-1, are linked to the presence of T cell immunity to cancer-specific antigens However, only a fraction of patients has clinical benefit Unraveling the molecular pathways controlling DC-cancer interplay will therefore pave the way for identifying new targets for therapy that overcome limitations of current treatments and promote long-term cancer control International Review of Cell and Molecular Biology ISSN 1937-6448 https://doi.org/10.1016/bs.ircmb.2019.07.008 # 2019 Elsevier Inc All rights reserved ARTICLE IN PRESS Jan Martinek et al Introduction When faced with invading microbes, the immune system must quickly launch an appropriate response to eliminate invaders and restore tissue integrity and homeostasis Thereafter, the immune response must also rapidly subside to prevent unwanted tissue damage and to restore polyclonal T cell repertoire able to mount a new response to a different microbe (Paul, 2003) Thus, co-stimulatory and co-inhibitory pathways have co-evolved to control the extent of immune responses (Freeman et al., 2000; Krummel and Allison, 1995; Waterhouse et al., 1995) This led to the discovery of checkpoints such as programmed cell death (PD)-1, which control the effector function of T cells (Lesokhin et al., 2015; Sharma and Allison, 2015a) That in turn led to development of checkpoint inhibitors that could unleash T cell function and have already taken a significant place in cancer therapy (Sharma and Allison, 2015b; Topalian et al., 2015) Their clinical effect is at least partly associated with the presence of T cells specific to cancer-derived neo-antigens (Ags) (Le et al., 2017; Matsushita et al., 2012; Schumacher and Schreiber, 2015) Neo-Ags can be generated by a variety of means including genetic alterations in cancer cells (high mutation load, microsatellite instability and gene fusions) as well as epigenetic ( Jones et al., 2019) and post-translational regulation (Zarling et al., 2006) However, with a notable exception of malignant melanoma and Hodgkin’s disease, only a fraction of patients ($15%) responds clinically to this treatment modality (Haslam and Prasad, 2019) Treatment resistance (reviewed in Sharma et al., 2017) might be due in part to the low frequency of T cells specific to cancer neo-Ags, so-called “cold” tumors Conceptualization of the cancer-immunity cycle created a framework for the identification of barriers to effective cancer rejection (Chen and Mellman, 2013) and facilitated investigations into how to turn “cold” tumors with diminished T cell infiltrate into “hot” tumors Among others, provision of cancer Ag-specific T cells either via adoptive transfer (Fesnak et al., 2016; Rosenberg et al., 2008) or via their expansion in vivo (Palucka and Banchereau, 2014) represent ways of correcting the deficiency of T cell specific to cancer Ags Numerous T cell subsets contribute to and regulate the host response to cancer including: (1) CD4+ T cells with helper function, which is essential for establishing CD8+ T cell memory (Zhu and Paul, 2008) as well as generation of antibody response (Zhu and Paul, 2008); (2) CD4+ T cells with regulatory/suppressor function (Tregs), which represent a healthy homeostatic ARTICLE IN PRESS Interplay between dendritic cells and cancer cells mechanism but are amplified in cancer via numerous pathways to facilitate immune escape (Zhu and Paul, 2008); and (3) CD8+ T cells that can give rise to cytotoxic T lymphocytes (CTLs) able to reject tumors (Boon et al., 1994) Several cell types of the innate and adaptive immune system can contribute to the final fate of cancer cells and their rejection including innate effectors such as NK cells, neutrophils, and eosinophils, and adaptive effectors such as NKT cells, CD4+ T cells and antibodies (Abbas and Lichtman, 2003; Palucka and Coussens, 2016a) However, we will focus discussion on antigen-specific CD8+ T cells Desired criteria for anti-cancer CD8+ T cells include: (1) high T cell receptor (TCR) affinity (binding) and avidity (off-rate) for peptide major histocompatibility complexes (MHCs) expressed on cancer cells (Appay et al., 2008); (2) T cell trafficking into the tumor (e.g., expression of CXCR3) (Mullins et al., 2004) and persistence in the tumor site (e.g., CD103 (Le Floc’h et al., 2007) and CD49a (Sandoval et al., 2013)); (3) high expression of costimulatory molecules (e.g., CD137 (Wilcox et al., 2002)) or low expression of inhibitory molecules (e.g., PD-1 (Freeman et al., 2000)); and (4) high expression of effector molecules such as granzyme and perforin by T cells (Appay et al., 2008) Cancer cells cannot prime T cells by themselves due to usually low expression of MHC molecules and of costimulatory molecules and a high expression of inhibitory molecules and suppressive cytokines (Moussion and Mellman, 2018) Macrophages, despite being the most abundant myeloid cells in tumors, contribute minimally to priming of antigen-specific T cells because they are molecularly wired for tissue repair and antigen degradation rather than for antigen presentation (Ruffell and Coussens, 2015) In contrast, DCs have the remarkable capacity to capture antigens from their environment, migrate to draining lymph nodes and cross-present captured antigens on MHC class I for priming of CD8+ T cells and MHC class II for priming CD4+ T cells (Banchereau and Steinman, 1998; Steinman and Banchereau, 2007) Therefore, DCs are critical for generation of cancer antigen-specific T cells DCs are molecularly equipped to simultaneously deliver signals necessary for induction and expansion of antigen-specific T cells as they are able to: (1) present the cancer antigen peptides to both CD8+ and CD4+ T cells (cognate help); (2) deliver co-stimulatory signals to T cells via CD80, CD70 and 4-1BB, supporting T cell activation; and (3) deliver cytokine signals including interleukin (IL)-12, type I interferon (IFN) and IL-15 thereby supporting T cell expansion and polarization leading to secretion of type cytokines such as type II IFN (IFN-γ) (Banchereau and Steinman, 1998; Steinman and Banchereau, 2007) Here, we will review ARTICLE IN PRESS Jan Martinek et al the basics of DC biology in the context of their interactions with cancer cells, particularly how cancers hypnotize DCs to escape immune control by tilting the balance toward other myeloid cells (such as macrophages (Palucka and Coussens, 2016a) and myeloid derived suppressor cells (Marigo et al., 2008; Veglia et al., 2019)) to manipulate ensuing T cell responses and to escape immune control We will also discuss how the understanding of these interactions at the cellular and molecular level might offer novel therapeutic targets Dendritic cells in the immune response to cancer DCs, described for the first time by Steinman and Cohn (1973), are the master regulators of the immune response dictating tolerance or immunity (Steinman, 2011) Cancer antigens could be presented to T cells by DCs either at tumor sites or in draining lymph nodes (Fig 1) Cancer antigens, soluble and particulate, are transported to lymph nodes via lymphatic vessels (Steinman, 2011) Soluble antigens are captured by lymph node-resident DCs while tissue-resident DCs capture antigen at tumor sites; tissue-resident DCs can present antigens either at the tumor site (Chiodoni et al., 1999) or they migrate through lymphatic vessels to present antigen in lymph nodes (Bonaccorsi et al., 2015; Steinman, 2011) DCs display protein antigens in the context of classical MHC class I and MHC class II molecules that allow selection and priming of rare antigen-specific T lymphocytes including CD8+ T cells, CD4+ T cells as introduced above (Trombetta and Mellman, 2005) They can also present lipid antigens in the context of non-classical CD1 molecules that allow activation of NKT cells (Bendelac et al., 2007) The priming of new T cell repertoires might be critical for clinical success of therapeutic agents aiming to unleash antigenspecific CTLs The diversity of T cell response is in part ensured by three features of DCs that control their ability to fine-tune the adaptive immune response: (1) DC maturation (Mellman and Steinman, 2001); (2) DC plasticity in response to environmental cues such as those linked with antigen capture, antigen-independent signals as cytokines and other cells in their environment (Mellman and Steinman, 2001); and (3) The existence of distinct DC subsets with specific functions (Banchereau and Steinman, 1998) Cancer cell-derived signals are able to exploit these features, thus having a major impact on DC functionality in the tumor microenvironment (TEM) as discussed in more detail hereunder ARTICLE IN PRESS Interplay between dendritic cells and cancer cells Fig Dendritic cells control immune response to cancer The immune system is endowed with the ability to recognize a universe of diverse molecules called antigens, including cancer antigens, and to generate responses specific to the recognized antigens Lymphocytes (T, B, NK, and NKT cells) and their products are under the control of DCs DCs reside in peripheral tissues where they are poised to capture antigens Antigen-loaded migratory DCs travel from tissues through the afferent lymphatics into the draining lymph nodes There, they present processed protein and lipid Ags to T cells via both classical (MHC class I and class II) and non-classical (CD1 family) antigen presenting molecules The soluble antigens also reach the draining lymph nodes through lymphatics and conduits where they are captured, processed, and presented by lymph-node resident DCs Ag presentation by non-activated (immature) DCs leads to tolerance and/or development of Tregs Activated (mature), antigen-loaded DCs are geared towards the launching of antigen-specific immunity leading to the T cell proliferation and differentiation into helper and effector cells with unique functions and cytokine profiles DCs are also important in launching humoral immunity Thus, DCs are at the center of anti-cancer immunity 2.1 Dendritic cell maturation as checkpoint of tolerance and immunity One of DC vulnerabilities in the context of cancer is the direct link between their maturation and function as measured by the induction of T cell response (Steinman, 2011) To this end, in the steady state, non-activated (immature) DCs present antigens (including self-antigens) to T cells, thereby inducing tolerance either through T cell deletion or through differentiation of regulatory/suppressor T cells (Fig 1) These immature DCs can be ARTICLE IN PRESS Jan Martinek et al considered “immunological sensors,” alert for potentially dangerous microbes but also for the alterations of tissue homeostasis and sterile inflammation, and are capable of decoding and integrating such signals ( Janeway Jr and Medzhitov, 2002; Kawai and Akira, 2006; Pulendran et al., 2001) Immature DCs have special characteristics including: (1) expression of a specific set of damage sensing pathways (Banchereau et al., 2000; Steinman, 2011); (2) ability to efficiently capture Ags (Banchereau et al., 2000); (3) accumulation of MHC class II molecules in the late endosome-lysosomal compartment enabling loading of the peptide and assembly of peptide-MHC complexes that can then be transferred to cell surface (Steinman, 2011); and (4) low expression of costimulatory molecules (Steinman, 2011) These properties can be harnessed by cancers to generate Tregs rather than T cells able to reject tumors (Fehervari and Sakaguchi, 2004; Idoyaga et al., 2013; Melief, 2008; Tanchot et al., 2012; Yamazaki et al., 2006) For example, in a mouse model of melanoma the mere increase of DC infiltrate by their mobilization with FLT3L was not sufficient for tumor rejection even in the presence of PD-1 blockade (Salmon et al., 2016a) Yet, addition of DC activator such as TLR-3 ligand poly IC facilitated tumor regression (Salmon et al., 2016a) Mature Ag-loaded DCs can launch differentiation of Ag-specific T cells into effector cells (reviewed in Banchereau et al., 2000) (Fig 1) DC maturation is associated with: (1) down-regulation of Ag-capture activity (Trombetta and Mellman, 2005); (2) surface expression of CCR7 enabling migration of DCs into draining lymph nodes (Dieu-Nosjean et al., 1999; Forster et al., 1999); (3) translocation of peptide-MHC (pMHC) complexes to cell surface together with co-stimulatory molecules (Lanzavecchia and Sallusto, 2001); and (4) ability to secrete cytokines such as IL-12 (Veglia et al., 2019) and IL-15 (Waldmann and Tagaya, 1999) supporting T cell differentiation The ligation of the co-stimulatory receptor CD40 is an essential signal for the final differentiation into fully mature DCs (Banchereau et al., 1994) However, DC maturation alone does not result in a unique DC phenotype Instead, the different signals that are provided either directly or through the surrounding cells that respond to damage induce DCs to acquire distinct phenotypes that eventually contribute to different immune responses (Pulendran et al., 2001) (Fig 2) For example, γδ-T cells and NK cells release IFN-γ, mast cells release pre-formed IL-4 and tumor necrosis factor (TNF), plasmacytoid (p)DCs secrete IFN-α, stromal cells secrete IL-15 and thymic stromal lymphopoietin (TSLP) while neutrophils provide immunostimulatory DNA This plasticity in response to external signals ARTICLE IN PRESS Interplay between dendritic cells and cancer cells Cancer cell Dendritic cell Stromal cells NK cells Neutrophils pDCs Mast cells MDSCs Macrophages T regs CD8 T cells CD4 T cells Th2s Fig Interplay of dendritic cells and cancer: contribution of other cells DCs represent the link between the innate and adaptive immunity and as such they integrate signals from surrounding cells as well as are engaged in cross-talk with stromal cells other leukocytes and cancer cells Cancer cells and dendritic cells can impact each other indirectly by modulating intermediate cells, which is represented by the arrows in the figure This is driven by a variety of cell types, multiple surface bound and soluble factors too numerous to be represented here but several examples includes: secretion of stem cell factor (SCF) by numerous mouse and human cancer cell lines supported c-KIT expressing mast cells, which in turn secreted multiple cytokines such as IL-6, TNF-a VEGF, iNOS and CCL2, inducing tumor remodeling and altering DCs maturation/activation in TEM (Huang et al., 2008) Another example comes from TSLP production by cancer cells and stromal cells in breast and pancreatic cancers (De Monte et al., 2011; Kuan and Ziegler, 2018; Olkhanud et al., 2011b; Pedroza-Gonzalez et al., 2011b) TSLP drives DC maturation leading to expression among others of OX40-L, which enables priming of IL-4/IL-13 secreting Th2 T cells In turn, IL-4 and IL-13 modulate TEM by promoting development of suppressive macrophages producing EGF that supports cancer cell growth as well as directly impacting cancer cells by inhibition of apoptosis ITL7/BST2 mediated interaction between pDCs and cancer cells will suppress IFN-α and TNF-a production in pDCs (Cao et al., 2009), while cancer derived PGE2 and TGF-β synergistically leads to production of IL-6/IL-8 by pDCs (Bekeredjian-Ding et al., 2009) This in turn will have broad impact on both the innate (monocyte differentiation to macrophages and attraction of neutrophils) and adaptive (up regulation of OX40-L and ICOS-L on pDC upon maturation, resulting in T regulatory and Th2 T cells activation) immunity in TEM Last but not least, by secreting IL-12, DCs can directly support CD8+ CTL and NK cells (Mittal et al., 2017) In turn CD8+ T cells and NK cells will secrete IFN-y, which will stimulate CXCL9/10 production from DCs resulting in an influx of effector T cells to the tumor environment (Mikucki et al., 2015) Additionally, NK cells can produce FLT3L, a growth factor promoting pre-DCs differentiation and DCs survival (Barry et al., 2018) ARTICLE IN PRESS Jan Martinek et al represents another vulnerability that can be exploited by cancers to escape immune-mediated elimination Whereas some of the mechanisms dictating DC maturation are differentially regulated in distinct DC subsets, many of the principles are shared 2.2 Antigen capture and modulation of DC maturation DCs are scarce in tumor tissues when compared to other myeloid cells such as macrophages and must therefore compete for both Ag capture and T cell access Ag capture is a critical step controlling the acquisition and subsequent presentation of cancer Ags (Durand and Segura, 2015; Mellman and Steinman, 2001; Trombetta and Mellman, 2005) and is often linked with modulation of DC maturation (Fig 3) Acquisition of cancer Ags can be mediated via several pathways including phagocytosis (Guermonprez and Amigorena, 2005); receptor mediated endocytosis (as, for example, with the lectin Clec9A (Schreibelt et al., 2012)); capture of IgG-Ags immune complexes (Liu et al., 2006; Nimmerjahn and Ravetch, 2006; Rovere et al., 1998); pinocytosis enabling capture of soluble molecules (de Baey and Lanzavecchia, 2000); nibbling enabling capture of cell membrane fragments from live cells (Harshyne et al., 2003); capture of extracellular vesicles (Muller et al., 2016; Wolfers et al., 2001a); and capture of pre-formed peptides (cross-dressing) (Wakim and Bevan, 2011) Hereunder, we will expand on some of these mechanisms to illustrate the potential vulnerabilities that can be exploited by cancer cells to escape immune elimination 2.2.1 Phagocytosis Phagocytosis is an active process of ingestion of particulate Ags that is essential for: (1) the clearance of apoptotic bodies from dying cells; and (2) for the efficient uptake of pathogens and Ags from dying infected and/or cancer cells (Aderem and Underhill, 1999; Platt et al., 1998) When captured by macrophages, apoptotic bodies are degraded ( Jutras and Desjardins, 2005) However, when captured by DCs, their antigenic material can be cross-presented to T cells to elicit Ag-specific CD4+ (Inaba et al., 1998) and CD8+ T cell responses (Albert et al., 1998a; Berard et al., 2000a) Studies pioneered by Zitvogel and Kroemer labs demonstrated the links between phagocytosis and so-called immunogenic cell death in response to chemotherapy (Obeid et al., 2007) The critical mechanism involves the recognition of calreticulin translocated to the surface of apoptotic bodies from cancer cells and its availability for recognition by receptors on DCs ARTICLE IN PRESS Interplay between dendritic cells and cancer cells IL-10, CCL4, CCL2, CXCL1, CXCL5, PGE2, ATP, Arginase, TSLP,TGF-β, HMGB1 TIM-3 Phosphatidylserine TGF- R Activated TGFIntegrins E-cadherin EpCAM CD44 LFA-1 ICAM-1 Fc Receptor IL-1β, IL-6, IL-8, IL-15, IL-10, IFN-α, TNF-α DNA MHC-I Vesicles/ Exosomes RNA MHC-II Cancer antigen Dexosome Apoptotic bodies Endocytosis Fusion STING RIG-1 TLRs Fc Receptors CR1/CR2/CR3 SIRP DEC205, CD207, CD206, CD209, DCIR, AXL, TIM-3 Phagocytosis Fig Interplay of dendritic cells and cancer: direct interactions (A) Interactions between DCs and intact cancer cells driven by secreted and surface molecules: Here we illustrate with few examples surface bound receptors and ligands, as well as also secreted chemokine, cytokines, and metabolites involved in the interplay between DCs and intact cancer cells In addition to molecular pathways discussed in the text and other legends, cancer cells can secrete CCL2 and CCL20, attracting CCR2+ tumor promoting monocytes and macrophages but also tolerogenic immature DCs (Nagarsheth et al., 2017) IL-6 and IL-8 (CXCL8) secreted by DCs have been shown to support tumor growth, survival and invasiveness in multiple types of cancer (Ara et al., 2009; Araki et al., 2007; Yao et al., 2007) Through the secretion of IL-10, TGF-β and other factors, cancer cells induce T cell Ig and mucin domain (TIM-3) up regulation (Continued) ARTICLE IN PRESS 10 Jan Martinek et al (Obeid et al., 2007) This discovery showed that cancer cell apoptosis could efficiently activate an immune response if the correct combination of “eatme” signals is present on the surface of dying cells However, the putative DC calreticulin receptors that are important for the sensing of immunogenic cell death remain to be uncovered (Martins et al., 2010) Another important mechanism of cancer cell phagocytosis is mediated by CD47-SIRPα interactions (Chao et al., 2010; Jaiswal et al., 2009; Majeti et al., 2009) and has been recently shown to contribute to immune escape by delivering a “don’t’-eat-me” signal Indeed, CD47, a "don’t eat me" signal for phagocytic cells including DCs, is overexpressed on cancer cells as compared to matched adjacent normal (nontumor) tissue (Chao et al., 2010; Jaiswal et al., 2009; Majeti et al., 2009) In vitro, blockade of CD47 signaling using monoclonal antibodies enabled phagocytosis of cancer cells that were otherwise protected (Willingham et al., 2012) Furthermore, this pathway plays a role in DC maturation as SIRP-α engagement by CD47-Fc leads to immature DC phenotype, decreased cytokine production, and low IFN-γ production by T cells after priming linked with an impaired development of a T helper (Th)1 response (Hagnerud et al., 2006; Latour et al., 2001) The CD47-SIRPα axis appears to also dictate the fate of captured DNA as blocking the interaction of SIRPα with CD47 preferentially increased the sensing of captured DNA in DCs but not in macrophages (Xu et al., 2017) Fig 3—Cont’d by DCs TIM-3 senses danger signals such as tumor derived nucleic acid it can also sense phosphatidylserine (PS) PS serves as an “eat me” signal and is exported to the outer membrane layer under oxidative stress to facilitate phagocytosis (Birge et al., 2016) Cancer derived HMGB1 can interact with TIM-3 and inhibit its function (Chiba et al., 2012) ICs can be internalized by DCs and deliver Ags for presentation to T cells (Amigorena et al., 1992; Geissmann et al., 2001) (B) Release and capture of cancer antigen Here we illustrate how intact and dying cancer cells release cancer antigens for capture by DCs We show examples related to extracellular vesicles and apoptotic bodies derived from cancer cells and pathways through which DCs can capture them Cancer cells can produce extracellular vesicles by “blebbing” of the cell membrane and encapsulating parts of the cytosol or by formation of exosomes from the multivesicular endosome These vesicles contain genetic material, cancer antigens as well as immunosuppressive proteins such as PD-L1 and Fas-L (Bobrie and Thery, 2013; Sansone et al., 2017; Schuler et al., 2014; Wolfers et al., 2001b) Nucleic acids, contained within extracellular vesicles and apoptotic bodies can trigger intracellular danger associated receptors/pathways such as TLRs, STING and RIG-I in DCs ICAM-1 positive vesicles can be endocytosed after binding to DC surface via LFA-1 interaction (Chiba et al., 2012), they can also fuse with DCs membrane via fusion molecules such as flotillin or GTPases (Subra et al., 2010) ARTICLE IN PRESS 23 Interplay between dendritic cells and cancer cells A B C D E F Fig DCs role in the Yin and Yang circle of cancer immune response The Yang side of the tumor immune response: Images illustrate different stages of anti-cancer immune response leading to cancer rejection (A) the capture of cancer antigen by tumor infiltrating DCs (Cytokeratin (CK) in green and CD11c+ DCs in red) (B) Activated DCs provide co-stimulatory signal to T cells (CD3+ T cells (green) are in close contact with CD11c+ (not shown) DCs expressing the co-stimulatory molecule CD86 (red)) This process can take place at the draining lymph node or, as shown here, at the tumor site with cancer cells stained for CK (blue) (C) after Ag presentation along with adequate co-stimulation, Ag-specific T cells will kill cancer cells via the action of granzymes and perforin (cytotoxic CD3+ (not shown) CD8+ (red) T cell, killing a target cancer cell (blue) by perforin (green) secretion The Yin side of the tumor immune response: Images depicting how cancer cells can corrupt DCs, reprogramming them into launching an immune response that will support cancer growth and progression (D) Cancer cells can produce factors that will corrupt DC maturation (CK+ cancer cells (blue) present surface bound TGF-β (red) to DCs, which induces them to secrete IL-1β (green)) (E) Corrupted DCs, will secrete factors with an impact on the whole TME This is shown in E where CD11c+ DCs (green) produce and secrete IL-1β in proximity but also directly onto CK+ cancer cells (blue) (F) Corrupted immune system will then support cancer progression (CK+ cancer cells (blue), based on their KI67 staining (green), are highly proliferating despite being in close proximity with tumor infiltrating CD11c+ DCs (red)) the steady state and upon cancer challenge Thus, progress will come from basic studies and deep analysis of patient tissues linked with causative studies in pre-clinical models Next generation immunotherapies will be based on cycles of interventions designed to boost and modulate ARTICLE IN PRESS 24 Jan Martinek et al anti-cancer immunity Eventually all patients will be treated with checkpoint inhibitors, either directly or after interventions targeting inflammation, by vaccination to boost T cell repertoires, or by adoptive T cell transfer The majority of patients will subsequently develop acquired resistance followed by immune escape; this will lead to the next cycle of treatments incorporating multi-modal biomarkers Despite rapid progress in the field, much remains to be discovered and defined in terms of biomarkers The cancer-immunity cycle represents a framework enabling uncovering of mechanisms operative at each step We must fully understand the rules of T cell priming in vivo in humans and develop strategies for directing T cells to tumors Last but not least, the role of Tregs, so well established in murine cancer, will need to be redefined in humans Recent studies place one DC subset, cDC1, at the center of regulation of cancer immunity How then other DC subsets contribute to and modulate anti-cancer immunity and by what mechanisms? Are the mechanisms regulating DC-T cell interactions at the tumor shared with those operating in the draining lymph node? The studies on modulation of DCs in lymph nodes draining tumors have only begun (Binnewies et al., 2019) and this line of investigation is likely to enhance our understanding of how the new T cell repertoire can be primed in the context of cancer environment Metabolic regulation of DCs creates another layer of control by the TEM that will need to be explored (Sinclair et al., 2017; Wculek et al., 2019) Another important question is how the differences in the phenotype of human DC subsets between individuals and tissues (Alcantara-Hernandez et al., 2017) impact the launching of anticancer immunity and response to check point inhibitors By analogy to its role in autoimmune diseases, host genetic variation is likely to have a significant contribution to DC-cancer interactions (Hafler and Jager, 2005; Ye et al., 2014) Genome-wide association studies (GWAS) have identified more than three hundred susceptibility loci predisposed to the development of autoimmune diseases These studies of patients affected by severe autoimmune or immunodeficiency syndromes have led to the discovery of several causative variants (Gutierrez-Arcelus et al., 2016) Polymorphisms of Human Leukocyte Antigen (HLA) molecules have been associated with development of virally-induced tumors such as head and neck, cervical, and nasopharyngeal cancers (Brodin et al., 2015; Brodin and Davis, 2017; Mangino et al., 2017) Resolving all this will keep busy for a while! ARTICLE IN PRESS Interplay between dendritic cells and cancer cells 25 Acknowledgments We thank patients and healthy donors for participation in our studies; our current and former lab members and collaborators; Dr Taneli Helenius for editing the manuscript, the JAX creative services and the Imaging sciences services at the Jackson Laboratory for expert assistance with this publication Due to space limitations we could cite only selected papers Supported by The Jackson Laboratory; R01 CA219880 (KP); U01 AI124297 (JB); and P30CA034196 (Research reported in this publication was partially supported by the National Cancer Institute of the National Institutes of Health under Award Number P30CA034196 The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health) References Abbas, A.K., Lichtman, A.H., 2003 Cellular and molecular immunology, fifth ed Saunders, Philadelphia, p 562 Aderem, A., Underhill, D.M., 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