Several mechanisms for negative regulation of the STING pathway have been described, such as elimination of accumulated DNA by DNases 77 and post-translational modification of proteins in the pathway after stimulation Recent work has indicated another level of regulation, which is dual stimulation of two innate immune pathways by the same ligand having opposing functional consequences. This result indicates that cross-talk between different innate immune pathways can potentially lead to unexpected outcomes and offers new opportunities to target and modulate immune responses.
The complexity of intercellular interactions in the tumor microenvironment could impact the regulation of innate immune sensing pathways during the evolution of the tumor-host interaction. Many pathways appear to be capable of sensing tumor-derived factors in specific settings, but likely have varying downstream effects depending on the cellular context and the nature of the stimulus received.
Therefore, whether tumors support productive inflammation likely depends not only on tumor-intrinsic release of PRR ligands, but also the state of stromal cells that sense them. NK cells have been reported to contribute to tumor control in some settings 82 , but in established B16 tumors NK cells also have been shown to have regulatory function resulting in immune suppression, in part through PD-L1 expression It also has been described that NKT cells can be either anti-tumor or tumor-promoting Until recently, little information has been available regarding innate lymphoid cell populations and anti-tumor immunity.
However, a recent report in which a polyoma middle-T antigen transgenic mouse model was used to study early breast cancer development revealed that the earliest host cells accumulating in the tumor microenvironment are innate lymphoid-like cells that contribute to tumor control Overall, additional work will be needed to interrogate the functional contributions of these additional innate immune cell subsets in human cancers and also in the context of immunotherapy response versus resistance.
Another host factor that appears to impact innate immune cell activation is the composition of the commensal microbiota. The most diverse and dense microbiota resides in the gastrointestinal tract, mainly in the colon, contributing qualitatively and quantitatively to intestinal homeostasis Intestinal commensals provide structural and biological functions including nutrient digestion and drug metabolism.
Importantly, commensals have evolved closely with their hosts in a symbiotic relationship, and this interaction also shapes the immune system. Interestingly, recent studies demonstrate that gut commensals have an important impact on systemic anti-tumor immune responses. This difference correlated with the rate of tumor growth in the two cohorts of mice Interestingly, cohousing of mice was sufficient to eliminate the difference in phenotype.
Moreover, transfer of fecal material from JAX mice which had superior anti-tumor immunity to TAC mice had a therapeutic effect, increasing tumor antigen-specific T cell frequencies and slowing tumor growth in TAC mice.
Administration of a cocktail of Bifidobacterium strains to tumor-bearing TAC mice replicated the benefit of the fecal transplant from JAX mice, and synergized with anti-PD-L1 mAb for maximal therapeutic benefit.
Gene expression profiling of these DCs revealed evidence for a modest pre-activation of DCs when Bifidobacterium was present, arguing for an innate immune mechanism for this improved immune activation effect In agreement, germ-free or antibiotic-treated mice, which completely lack or have a compromised commensal microbiota, showed defective innate immunity during viral infection 92 , Furthermore, in the tumor context, germ-free mice and antibiotic-treated mice were resistant to anti-CTLA-4 therapy Oral transfer of B.
Apart from checkpoint blockade therapy, the therapeutic effects of chemotherapy with oxaliplatin or of anti-ILR plus CpG were facilitated by gut microbes 95 , In these contexts, the therapeutic effect mediated by the microbiota relied on the production of cytokines by myeloid cells 95 , or translocation of bacteria to peripheral organs, which increased Th17 cells involved in the anti-tumor response Overall, these seminal studies demonstrate how different commensals affect the basal state of endogenous innate immune cells and could favor anti-tumor responses, as well as affect the therapeutic effect of immunotherapies and conventional anti-cancer treatment.
Gene expression profiling of the tumor microenvironment has revealed the presence of T cell transcripts, chemokines, and a type I IFN gene signature in a major subset of human cancers 9 , 23 , 98 , This T cell-inflamed tumor microenvironment gene signature has been associated with clinical response to therapeutic vaccines, the anti-CTLA-4 mAb, and more recently anti-PD-1 mAb , Based on the hypothesis that one source of inter-patient heterogeneity lies in the constellation of somatic changes in the tumor cells themselves, the T cell-inflamed tumor microenvironment gene signature has been analyzed in parallel with exome sequencing of the same tumors in a subset of metastatic melanomas represented in the cancer genome atlas TCGA.
Because of the central function of Batf3 DCs in the initiation of anti-tumor immune responses in transplantable tumor models, a mechanism was pursued around this DC subset. Batf3 is also associated with a type I IFN gene signature Based on the notion that recruitment and activation of Batf3 DCs is likely a cornerstone to initiate a de novo immune response against tumors, several novel therapeutic interventions can be envisioned.
The most obvious strategy to consider is direct injection of activated Batf3 DCs into the tumor microenvironment. Injection of these DCs directly into the tumor microenvironment restored T cell priming, effector T cell recruitment, and caused partial tumor shrinkage, which was amplified with co-administration of anti-CTLA-4 and anti-PD-L1 mAbs In a related strategy, systemic administration of Flt3L to increase Batf3 DCs in the tumor microenvironment, combined with intratumoral injection of poly I:C had a similar effect These are approaches that are immediately testable in the clinic with available reagents.
DMXAA showed a similarly potent therapeutic effect in other transplantable mouse models of prostate cancer, breast cancer, and sarcoma.
In addition, mice that completely rejected tumors were protected against a rechallenge with the same tumor cell line, implying the generation of an immunological memory One major approach involves rational modifications of cyclic dinucleotides CDNs to improve efficiency, which led to the development of synthetic dithio-mixed linkage CDNs A phase 1 clinical trial of ADU-S in patients with cutaneously accessible solid tumors and lymphomas has been initiated Other innate immune pathway activators are being tested in the clinic as single agents or in combination with other therapies, with the aim to boost anti-tumor T cell responses , , Preclinical data have indicated that the efficacy of stereotactic radiation of tumors, which as part of its mechanism of action boosts anti-tumor immune responses, largely depends on the host STING pathway Clinical trials have been initiated combining stereotactic radiation with anti-PD-1 mAb in an attempt to convert non-T cell-inflamed tumors into T cell-inflamed tumors, which may synergize with checkpoint blockade immunotherapy.
Finally, as the molecular mechanisms in the tumor cells continue to be identified that are ultimately causal for T cell exclusion, new targeted therapies can be envisioned to block those pathways and enable endogenous immune responses to proceed.
Our current estimate is that this pathway is associated with T cell exclusion in at least 20 additional cancer types Recent work has pointed toward several additional tumor-intrinsic oncogene pathways that are associated with immune exclusion and are also ripe for targeting.
As an exhaustive analysis of additional molecular pathways is collated through analysis of TCGA and other ongoing prospective genomic studies of samples in the context of immunotherapy clinical trials, it is expected that a prioritized list of candidate drug targets will emerge.
Innate immune activation plays a critical role in the spontaneous adaptive immune response against cancer. Recent work has implicated the STING pathway of cytosolic DNA sensing as a major pathway involved in this process, which is associated with T cell infiltration and the ability to respond to checkpoint blockade immunotherapy. Thus, one might envision combination therapies in the future, establishing a T cell-inflamed tumor microenvironment phenotype with innate immune activators and then blocking negative regulation with agents such as anti-PD-1 mAb.
Future work should integrate a more detailed evaluation of additional innate-like cells in the tumor microenvironment, in the context of immunotherapy response and therapeutic efficacy. The remaining authors declare no conflict of interest.
The three Es of cancer immunoediting. Annu Rev Immunol ; 22 — Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell ; — Immune infiltration in human tumors: a prognostic factor that should not be ignored. Oncogene ; 29 — Histopathologic-based prognostic factors of colorectal cancers are associated with the state of the local immune reaction.
J Clin Oncol ; 29 — Tumor-infiltrating lymphocyte grade is an independent predictor of sentinel lymph node status and survival in patients with cutaneous melanoma. J Clin Oncol ; 30 — Article Google Scholar. Immune infiltrates are prognostic factors in localized gastrointestinal stromal tumors.
Cancer Res ; 73 — Prognostic significance of tumor-infiltrating T cells in ovarian cancer: a meta-analysis. Gynecol Oncol ; — Gene signature in melanoma associated with clinical activity: a potential clue to unlock cancer immunotherapy. Cancer J ; 16 — A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma. J Transl Med ; 9 In situ cytotoxic and memory T cells predict outcome in patients with early-stage colorectal cancer.
J Clin Oncol ; 27 — Towards the introduction of the 'Immunoscore' in the classification of malignant tumours. J Pathol ; — Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood ; — Effector function of human tumor-specific CD8 T cells in melanoma lesions: a state of local functional tolerance.
Cancer Res ; 64 — PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature ; — Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med ; — Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab.
J Clin Oncol ; 32 — Pembrolizumab for the treatment of non-small-cell lung cancer. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. Nivolumab versus everolimus in advanced renal-cell carcinoma.
PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. Cancer Res ; 69 — Non-redundant requirement for CXCR3 signalling during tumoricidal T-cell trafficking across tumour vascular checkpoints.
Nat Commun ; 6 The receptor of the type I interferon family. Curr Top Microbiol Immunol ; — Injection of mice with antibody to interferon enhances the growth of transplantable murine tumors.
J Exp Med ; — Interferon and cell division. Interferon-resistant L cells: characteristics and origin. J Natl Cancer Inst ; 52 — Molecular mechanisms of action of interferons in the Friend virus-induced leukemia cell system. Haematologica ; 72 — Gresser I, Bourali C. Antitumor effects of interferon preparations in mice. J Natl Cancer Inst ; 45 — A critical function for type I interferons in cancer immunoediting. Nat Immunol ; 6 — Type I interferon is selectively required by dendritic cells for immune rejection of tumors.
J Immunol ; — Immunol Rev ; — Science ; — Novel insights into the relationships between dendritic cell subsets in human and mouse revealed by genome-wide expression profiling. Genome Biol ; 9 :R Identification of a dendritic cell receptor that couples sensing of necrosis to immunity.
Immunity ; 35 — Immunity ; 41 — Immunity ; 44 — Visualization of immediate immune responses to pioneer metastatic cells in the lung. Tumor masses support naive T cell infiltration, activation, and differentiation into effectors. Effector lymphocyte-induced lymph node-like vasculature enables naive T-cell entry into tumours and enhanced anti-tumour immunity. Matzinger P. An innate sense of danger.
Ann NY Acad Sci ; — STING activation of tumor endothelial cells initiates spontaneous and therapeutic antitumor immunity. The role of the purinergic P2X7 receptor in inflammation. J Inflamm ; 4 Oncogene ; 34 — ILBP is regulated by the inflammasome and modulates tumorigenesis in the intestine. MyDmediated signaling prevents development of adenocarcinomas of the colon: role of interleukin Cancer Immunol Res ; 2 — Mol Cell ; 51 — Science ; :aaa Cell intrinsic immunity spreads to bystander cells via the intercellular transfer of cGAMP.
Carcinoma-astrocyte gap junctions promote brain metastasis by cGAMP transfer. Nat Commun ; 5 Cancer Res ; 76 — Release of chromatin protein HMGB1 by necrotic cells triggers inflammation.
Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med ; 13 — Nat Immunol ; 13 — Mutually exclusive redox forms of HMGB1 promote cell recruitment or proinflammatory cytokine release. Redox modification of cysteine residues regulates the cytokine activity of high mobility group box-1 HMGB1. Mol Med ; 18 — Pivotal advance: analysis of proinflammatory activity of highly purified eukaryotic recombinant HMGB1 amphoterin.
J Leukoc Biol ; 81 — CD a potent suppressor of antitumor immune responses. Trends Immunol ; 33 — MicroRNAs bind to toll-like receptors to induce prometastatic inflammatory response. Nat Genet ; 38 — More recently, several exciting new interleukins have been characterized that have considerable promise for future immunotherapy.
This review provides an overview of the antitumor effects of relatively new interleukins as potential therapeutic agents applicable for cancer immunotherapy. They are released by many cells produced in large amounts, cytokines may enter 1 Intractable Disease Research in addition to those of the immune system. University, Shinjuku, e. Although cyte—macrophage colony-stimulating factor cytokines are structurally diverse, they share sev- GM-CSF are related structurally, and their eral properties, including pleiotropism, that is, genes are also closely linked in the genome.
IL, , and the same functional effects. The pleiotropic have very unique structural characteristics that ability allows a cytokine to mediate diverse bio- they are heterodimeric molecules, whose subunit logic effects, but it greatly limits the therapeutic is sometimes shared by another cytokine.
Owing to the redun- be devised. Tumor cells induce weak immune responses compensate. Most cytokines act close to where because they usually lack costimulators and do they are produced, either on the same cell that not express class I and II MHC molecules, so secretes the cytokine in autocrine action, or on a they do not activate helper T cells and cytotoxic nearby cell in paracrine action.
Cytokines often T lymphocytes CTLs. However, cell-mediated Interleukins cont. To localize the cytokine effects to where they allergic asthma allergic asthma are needed, tumor cells can be transfected with cytokine genes.
When tumors transfected with a cytokine gene are injected into host, the tumors are rejected or begin to grow and then regress. Different cytokines may dependent blockade of IL production Induction of early Th1 differentiation by stimulate antitumor immunity by different Increases monocyte viable cell number Mast cells and Th2 cells Costimulation, promotes Th2 cytokine mechanisms. GM-CSF is also a macrophage-activating factor and pro- motes the differentiation bone marrow cells and Langerhans cells into mature dendritic cells DCs.
In clini- Table 1. T lymphocytes and is responsible for T-cell clonal expansion after antigen recognition. IL-2 exerts an antitumor effect via the well as protective memory. The coordination of proliferation of NK cells, lymphokine-activated these responses is achieved through a network of killer LAK cells and CTLs based on the ability cytokines.
Cytokines induce maturation within to expand subpopulations of T cells that bear IL-2 these lineages and control effector function, and receptors. Early studies of high-dose bolus sched- then to turn off these responses when control of ules of IL-2 in the mids showed promising the pathogen is achieved. STAT: Signal transducer and activator of transcription.
These regimens were reported to produce response rates complete response and one partial response were observed that are associated with advanced cancer. Phase I study and survival comparable with those reported for high-dose IL-2 with much less toxicity.
Duration of response was superior in patients who received the high-dose intravenous IL-2 compared with Effect study those who received the low-dose intravenous IL There were no differences in overall sur- vival. Among the patients con- High dose iv. More recently, the Cytokine Low dose iv. Median response was greater in high- Patients dose arm although survival was not. However, for patients with bone or liver metastases or a pri- n 40 30 22 28 33 25 24 71 mary tumor in place, survival was superior with high-dose IL Metastatic renal Resectable solid prostate cancer IL-2 is thus effective in renal cancer and cell carcinoma Different solid melanoma immunotherapy, whereas its use melanoma Metastatic Metastatic carcinoma carcinoma hormone- refractory Renal cell Renal cell appears paradoxical in view of its primary role Tumor tumors tumors in immune regulation [17].
In contrast to IL-2, which immunity [21]. IL has an important role effector T-cell proliferation and maturation, but in cancer vaccine and adoptive T-cell regimens. In addition, IL cancer immunotherapy. Thus, IL homeostatic expansion of naive cells during has a potential to be used as a vaccine adjuvant to lymphopenia [22,23]. In mice, IL-7 treatment induces for DC-based vaccines by intratumoral injection dramatic expansions in peripheral T-cell num- or systemic therapy for cancer.
Moreover, trans- bers without obvious toxicity [23,24]. There appears to be a preferential for induction of antitumor immunity [35].
IL has pleiotropic ligand-dependent T-cell antitumor reactivity actions, from augmenting the proliferation of in Lewis lung cancer [28]. IL is also a T-cell T cells and driving the differentiation of B cells growth factor and vaccine adjuvant [29,30] , but into memory cells and terminally differenti- IL-7 and IL work at different phases of ated plasma cells to augmenting the activity of T-cell activation.
Both alter T-cell homeostasis NK cells [36—38]. IL-7 acts on cannot support the proliferation of activated resting T cells and preferentially expands naive Treg cells in vitro. Since IL has lower tox- T cells, leading to increased repertoire diversity. Thus, experimental data in murine tumor models indi- IL-7 can be used as immunorestorative T-cell cate that in vivo administration of IL gene- growth factor for naive T cells, especially in transduced cells, recombinant IL, or IL future science group www.
Depending on the experimen- body, which recognizes a receptor of the death- tal model, IL activates predominantly NK or inducing ligand TRAIL, and displays potent anti- T-cell-dependent responses.
Several other mono- cer cells have been injected subcutaneously clonal antibodies targeted at tumor-associated into syngeneic mice [40—43]. Cells responsive to the combi- tumor effects in tumor-bearing syngeneic hosts, nation of IL-6 and sIL-6R, but not to IL-6 alone, through CD8-dependent or NK-dependent include hemopoietic progenitor cells, endothelial mechanisms.
IL in conjunction with IL cells and neuronal cells [57—59]. Regulates Generates Th1 Generates Th17 Induces both Treg inflammatory responses responses pro- and anti- function responses, inflammatory hematopoiesis and responses acute-phase responses Figure 2.
These cytokines coordinately regulate T-helper cell differentiation and play critical roles in the development of immunity. IL acti- and adaptive immunities [64,65]. IL is an [72—75]. IL stabilizes them and maintains essential cytokine for the differentiation of Th1 their Th17 phenotype [76]. IL is consists of cells, which is required for the generation of type an IL prelated protein p28 and an IL 1 cell-mediated immunity and establishment of prelated protein, Epstein—Barr virus EBV - antitumor immunity [64,66].
IL prelated protein p19 to form IL [67]. In addition, the immune antitumor effects of IL in most, if not all, suppression-dominated microenvironment in tumor studies [84]. Murine CT26 leukemias and lymphomas. Production of IL and B16F1 tumor cell lines transduced with the at the tumor site by neoplastic cells engineered murine IL gene in a retroviral vector show to release IL by appropriate expression vec- potent antitumor and antimetastatic effects tors induces the rejection of neoplastic cells by similar to those of IL [,].
Improved and remain tumor free for the entire day antitumor effects have been shown when IL observation period []. However, the antitumor was administered with other cytokines such as responses induced by IL and IL are differ- IL-2 and IL or with neoplastic cells expressing ent, ILmediated tumor suppression is only costimulatory molecules [85,86]. Analysis of the evident at later time points after tumor inocula- immune mechanisms activated by IL in these tion, while IL induced tumor suppression is preclinical models suggests the role of several obvious in an earlier time frame [].
In the with memory phenotype. Interestingly, ILp19 of IL []. The fact that NK cell depletion and IL12p40, but not ILp35, are found to do not affect either the growth rate of IL be overexpressed in the majority of human can- transduced cells or the percentage of tumor-free cers.
Thus, the endogenous IL expression animals suggests that NK cells are not needed promotes tumor incidence and growth, while for the antitumor activity of IL at least in the application of IL at the excessive amount CT26 tumor model []. Moreover, viral vector-encoding single-chain sc mouse WSX-1 can also deliver inhibitory signals to limit IL produces a protective effect on intracranial the magnitude and duration of type I-mediated tumor-bearing mice [].
IL inhibits Th17 differentiation roles of IL in inducing antitumor immune and IL production, resulting in suppression responses in vivo, the endogenous IL expres- of the development of experimental autoim- sion has been reported to promote tumor inci- mune encephalomyelitis [].
IL also induces dence and growth []. Similar activity of IL against a murine tumor model of NK cell-dependent antitumor effects of IL colon carcinoma colon 26 C26 [].
C26 tumor are seen using human esophageal carcinoma cells cells, which are transduced with the linked scIL Eca [] and murine hepatocellular carci- cDNA exhibit a minimal tumor growth in vivo, noma MM45T.
Li []. Moreover, IL also and all mice inoculated with these tumor cells sur- offers a powerful immunotherapeutic maneuver vive with a complete tumor remission. Recovered mice from the cooperatively elicit ADCC activity []. This is in contrast to static activities. B16FIL cells exert anti- that of IL, which is achieved when the Th1- tumor activity against subcutaneous tumor and type response is fully promoted in the presence also experimental pulmonary metastasis even of endogenously expressed IL [].
In NOD-SCID mice, during the IL treatment, any apparent adverse these activities are decreased, but are still fairly effects such as splenomegaly and liver injury with well retained, suggesting that different mecha- elevated serum glutamic-oxaloacetic transaminase nisms other than the immune response are also and glutamic-pyruvic transaminase activities and involved in the exertion of these activities [].
Similar T-cell-dependent antitumor metastases, but also clearly inhibit angiogen- effects are also observed using TBJ neuroblas- esis by dorsal air sac method and IL exhib- toma, which is engineered to overexpress scIL its dose-dependent inhibition of angiogenesis TBJ-IL [,], and colon 26 transduced with on chick embryo chorioallantoic membrane. MIG []. The antitumor wild-type WSX-1 []. Downregulation of IL, respectively.
Moreover, several human melanoma cells ILvaccinated mice do not. In addition, IL inhib- tumor. MDA cells, and suppresses an early onset of bone metastasis []. Thus, IL may be useful clinically factor []. These biological activities indicate gene-7, MDA-7, encodes a protein that contains that IL may be a useful cytokine for immuno- an IL signature motif shared by other mem- therapy of cancer.
Indeed, IL was found to bers of the IL family of cytokines [,]. It tumors more slowly than control cells [85].
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