ABSTRACT
Circadian rhythms of approximately 24 h have emerged as important modulators of the immune system. These oscillations are important for mounting short-term, innate immune responses, but surprisingly also long-term, adaptive immune responses. Recent data indicate that they play a central role in antitumor immunity, in both mice and humans. In this review, we discuss the evolving literature on circadian antitumor immune responses and the underlying mechanisms that control them. We further provide an overview of circadian treatment regimens-chrono-immunotherapies-that harness time-of-day differences in immunity for optimal efficacy. Our aim is to provide an overview for researchers and clinicians alike, for a better understanding of the circadian immune system and how to best harness it for chronotherapeutic interventions. This knowledge is important for a better understanding of immune responses per se and could revolutionize the way we approach the treatment of cancer and a range of other diseases, ultimately improving clinical practice.
Subject(s)
Circadian Rhythm , Neoplasms , Humans , Circadian Rhythm/immunology , Animals , Neoplasms/immunology , Neoplasms/therapy , Immunotherapy/methods , Immunity, Innate , Adaptive ImmunityABSTRACT
Lymphocytes spanning the entire innate-adaptive spectrum can stably reside in tissues and constitute an integral component of the local defense network against immunological challenges. In tight interactions with the epithelium and endothelium, tissue-resident lymphocytes sense antigens and alarmins elicited by infectious microbes and abiotic stresses at barrier sites and mount effector responses to restore tissue homeostasis. Of note, such a host cell-directed immune defense system has been recently demonstrated to surveil epithelial cell transformation and carcinoma development, as well as cancer cell metastasis at selected distant organs, and thus represents a primordial cancer immune defense module. Here we review how distinct lineages of tissue-resident innate lymphoid cells, innate-like T cells, and adaptive T cells participate in a form of multilayered cancer immunity in murine models and patients, and how their convergent effector programs may be targeted through both shared and private regulatory pathways for cancer immunotherapy.
Subject(s)
Immunity, Innate , Neoplasms , Humans , Animals , Neoplasms/immunology , Neoplasms/therapy , Lymphocytes/immunology , Lymphocytes/metabolism , Tumor Microenvironment/immunology , Adaptive Immunity , Immunotherapy/methodsABSTRACT
Immune checkpoint blockade (ICB) induces a remarkable and durable response in a subset of cancer patients. However, most patients exhibit either primary or acquired resistance to ICB. This resistance arises from a complex interplay of diverse dynamic mechanisms within the tumor microenvironment (TME). These mechanisms include genetic, epigenetic, and metabolic alterations that prevent T cell trafficking to the tumor site, induce immune cell dysfunction, interfere with antigen presentation, drive heightened expression of coinhibitory molecules, and promote tumor survival after immune attack. The TME worsens ICB resistance through the formation of immunosuppressive networks via immune inhibition, regulatory metabolites, and abnormal resource consumption. Finally, patient lifestyle factors, including obesity and microbiome composition, influence ICB resistance. Understanding the heterogeneity of cellular, molecular, and environmental factors contributing to ICB resistance is crucial to develop targeted therapeutic interventions that enhance the clinical response. This comprehensive overview highlights key mechanisms of ICB resistance that may be clinically translatable.
Subject(s)
Drug Resistance, Neoplasm , Immune Checkpoint Inhibitors , Immunotherapy , Neoplasms , Tumor Microenvironment , Humans , Tumor Microenvironment/immunology , Neoplasms/immunology , Neoplasms/therapy , Neoplasms/metabolism , Neoplasms/etiology , Drug Resistance, Neoplasm/immunology , Animals , Immunotherapy/methods , Immune Checkpoint Inhibitors/therapeutic use , Immune Checkpoint Inhibitors/pharmacology , Epigenesis, GeneticABSTRACT
Ten-eleven translocation (TET) proteins are iron-dependent and α-ketoglutarate-dependent dioxygenases that sequentially oxidize the methyl group of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). All three epigenetic modifications are intermediates in DNA demethylation. TET proteins are recruited by transcription factors and by RNA polymerase II to modify 5mC at enhancers and gene bodies, thereby regulating gene expression during development, cell lineage specification, and cell activation. It is not yet clear, however, how the established biochemical activities of TET enzymes in oxidizing 5mC and mediating DNA demethylation relate to the known association of TET deficiency with inflammation, clonal hematopoiesis, and cancer. There are hints that the ability of TET deficiency to promote cell proliferation in a signal-dependent manner may be harnessed for cancer immunotherapy. In this review, we draw upon recent findings in cells of the immune system to illustrate established as well as emerging ideas of how TET proteins influence cellular function.
Subject(s)
DNA Demethylation , Dioxygenases , Immunotherapy , Inflammation , Neoplasms , Humans , Neoplasms/therapy , Neoplasms/immunology , Neoplasms/etiology , Neoplasms/metabolism , Animals , Inflammation/metabolism , Inflammation/immunology , Immunotherapy/methods , Dioxygenases/metabolism , Immune System/metabolism , Immune System/immunology , Epigenesis, Genetic , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins/genetics , DNA Methylation , DNA-Binding Proteins/metabolism , DNA-Binding Proteins/genetics , Mixed Function Oxygenases/metabolism , Mixed Function Oxygenases/geneticsABSTRACT
Exhausted CD8 T (Tex) cells are a distinct cell lineage that arise during chronic infections and cancers in animal models and humans. Tex cells are characterized by progressive loss of effector functions, high and sustained inhibitory receptor expression, metabolic dysregulation, poor memory recall and homeostatic self-renewal, and distinct transcriptional and epigenetic programs. The ability to reinvigorate Tex cells through inhibitory receptor blockade, such as αPD-1, highlights the therapeutic potential of targeting this population. Emerging insights into the mechanisms of exhaustion are informing immunotherapies for cancer and chronic infections. However, like other immune cells, Tex cells are heterogeneous and include progenitor and terminal subsets with unique characteristics and responses to checkpoint blockade. Here, we review our current understanding of Tex cell biology, including the developmental paths, transcriptional and epigenetic features, and cell intrinsic and extrinsic factors contributing to exhaustion and how this knowledge may inform therapeutic targeting of Tex cells in chronic infections, autoimmunity, and cancer.
Subject(s)
Costimulatory and Inhibitory T-Cell Receptors/metabolism , Immunotherapy/methods , Neoplasms/immunology , Programmed Cell Death 1 Receptor/metabolism , T-Lymphocytes/physiology , Virus Diseases/immunology , Animals , Cellular Senescence , Chronic Disease , Clonal Anergy , Epigenesis, Genetic , Humans , Neoplasms/therapy , Virus Diseases/therapyABSTRACT
IgG antibodies mediate a diversity of immune functions by coupling of antigen specificity through the Fab domain to signal transduction via Fc-Fc receptor interactions. Indeed, balanced IgG signaling through type I and type II Fc receptors is required for the control of proinflammatory, anti-inflammatory, and immunomodulatory processes. In this review, we discuss the mechanisms that govern IgG-Fc receptor interactions, highlighting the diversity of Fc receptor-mediated effector functions that regulate immunity and inflammation as well as determine susceptibility to infection and autoimmunity and responsiveness to antibody-based therapeutics and vaccines.
Subject(s)
Antibodies/therapeutic use , Autoimmune Diseases/immunology , Immunoglobulin G/metabolism , Immunotherapy/methods , Infections/immunology , Receptors, Fc/metabolism , Animals , Autoimmune Diseases/therapy , Disease Susceptibility , Humans , Immunity, Humoral , Infections/therapy , Inflammation , Signal TransductionABSTRACT
Commensal microorganisms (the microbiota) live on all the surface barriers of our body and are particularly abundant and diverse in the distal gut. The microbiota and its larger host represent a metaorganism in which the cross talk between microbes and host cells is necessary for health, survival, and regulation of physiological functions locally, at the barrier level, and systemically. The ancestral molecular and cellular mechanisms stemming from the earliest interactions between prokaryotes and eukaryotes have evolved to mediate microbe-dependent host physiology and tissue homeostasis, including innate and adaptive resistance to infections and tissue repair. Mostly because of its effects on metabolism, cellular proliferation, inflammation, and immunity, the microbiota regulates cancer at the level of predisposing conditions, initiation, genetic instability, susceptibility to host immune response, progression, comorbidity, and response to therapy. Here, we review the mechanisms underlying the interaction of the microbiota with cancer and the evidence suggesting that the microbiota could be targeted to improve therapy while attenuating adverse reactions.
Subject(s)
Immunity, Innate , Immunotherapy/methods , Intestinal Mucosa/immunology , Microbiota/immunology , Neoplasms/immunology , Adaptive Immunity , Animals , Antineoplastic Agents/therapeutic use , Carcinogenesis , Humans , Inflammation , Neoplasms/microbiology , Neoplasms/therapy , Wound HealingABSTRACT
Common gamma receptor-dependent cytokines and their JAK/STAT pathways play pivotal roles in T cell immunity. Abnormal activation of this system was pervasive in diverse T cell malignancies assessed by pSTAT3/pSTAT5 phosphorylation. Activating mutations were described in some but not all cases. JAK1 and STAT3 were required for proliferation and survival of these T cell lines whether or not JAKs or STATs were mutated. Activating JAK and STAT mutations were not sufficient to initiate leukemic cell proliferation but rather only augmented signals from upstream in the cytokine pathway. Activation required the full pathway, including cytokine receptors acting as scaffolds and docking sites for required downstream JAK/STAT proteins. JAK kinase inhibitors have depressed leukemic T cell line proliferation. The insight that JAK/STAT system activation is pervasive in T cell malignancies suggests novel therapeutic approaches that include antibodies to common gamma cytokines, inhibitors of cytokine-receptor interactions, and JAK kinase inhibitors that may revolutionize therapy for T cell malignancies.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Enzyme Inhibitors/therapeutic use , Immunotherapy/methods , Janus Kinases/metabolism , Lymphoma, T-Cell/immunology , STAT Transcription Factors/metabolism , Animals , Antineoplastic Agents/therapeutic use , Carcinogenesis , Cytokines/immunology , Cytokines/metabolism , Humans , Interleukin Receptor Common gamma Subunit/metabolism , Lymphoma, T-Cell/therapy , Receptors, Cytokine/antagonists & inhibitors , Signal TransductionABSTRACT
Numerous studies have evaluated the gut microbiome as a biomarker for predicting cancer immunotherapy, but the heterogeneity among different studies has hindered its applications. In this issue of Cell, Derosa et al. report a biomarker based on the ecological topology of the gut microbiota that can predict immunotherapy efficacy effectively.
Subject(s)
Gastrointestinal Microbiome , Immunotherapy , Neoplasms , Periodicals as Topic , Humans , Biomarkers/metabolism , Biomarkers, Tumor/metabolism , Gastrointestinal Microbiome/immunology , Immunotherapy/methods , Neoplasms/therapy , Neoplasms/immunologyABSTRACT
Immunosenescence poses a significant challenge to tumor immunotherapy in elderly individuals. In this issue of Cell, Zhivaki et al. elucidate that dendritic cells "hyperactivated" by specific adjuvants elicit TH1-skewed CD4+ T cell responses in a manner contingent on the NLRP3 inflammasome, which can eliminate tumors in aged mice.
Subject(s)
Dendritic Cells , Animals , Dendritic Cells/immunology , Mice , Neoplasms/immunology , Neoplasms/therapy , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Inflammasomes/metabolism , Inflammasomes/immunology , Immunotherapy/methods , CD4-Positive T-Lymphocytes/immunology , Humans , Aging/immunology , Th1 Cells/immunology , ImmunosenescenceABSTRACT
Defective host defenses later in life are associated with changes in immune cell activities, suggesting that age-specific considerations are needed in immunotherapy approaches. In this study, we found that PD-1 and CTLA4-based cancer immunotherapies are unable to eradicate tumors in elderly mice. This defect in anti-tumor activity correlated with two known age-associated immune defects: diminished abundance of systemic naive CD8+ T cells and weak migratory activities of dendritic cells (DCs). We identified a vaccine adjuvant, referred to as a DC hyperactivator, which corrects DC migratory defects in the elderly. Vaccines containing tumor antigens and DC hyperactivators induced T helper type 1 (TH1) CD4+ T cells with cytolytic activity that drive anti-tumor immunity in elderly mice. When administered early in life, DC hyperactivators were the only adjuvant identified that elicited anti-tumor CD4+ T cells that persisted into old age. These results raise the possibility of correcting age-associated immune defects through DC manipulation.
Subject(s)
CD4-Positive T-Lymphocytes , Dendritic Cells , Mice, Inbred C57BL , Dendritic Cells/immunology , Animals , CD4-Positive T-Lymphocytes/immunology , Mice , Aging/immunology , CD8-Positive T-Lymphocytes/immunology , Immunotherapy/methods , Cancer Vaccines/immunology , Female , Neoplasms/immunology , Neoplasms/therapy , Programmed Cell Death 1 Receptor/metabolism , CTLA-4 Antigen/metabolism , Cell Movement , Antigens, Neoplasm/immunologyABSTRACT
The quality and quantity of tumor-infiltrating lymphocytes, particularly CD8+ T cells, are important parameters for the control of tumor growth and response to immunotherapy. Here, we show in murine and human cancers that these parameters exhibit circadian oscillations, driven by both the endogenous circadian clock of leukocytes and rhythmic leukocyte infiltration, which depends on the circadian clock of endothelial cells in the tumor microenvironment. To harness these rhythms therapeutically, we demonstrate that efficacy of chimeric antigen receptor T cell therapy and immune checkpoint blockade can be improved by adjusting the time of treatment during the day. Furthermore, time-of-day-dependent T cell signatures in murine tumor models predict overall survival in patients with melanoma and correlate with response to anti-PD-1 therapy. Our data demonstrate the functional significance of circadian dynamics in the tumor microenvironment and suggest the importance of leveraging these features for improving future clinical trial design and patient care.
Subject(s)
CD8-Positive T-Lymphocytes , Immunotherapy , Lymphocytes, Tumor-Infiltrating , Mice, Inbred C57BL , Tumor Microenvironment , Animals , Humans , Mice , CD8-Positive T-Lymphocytes/immunology , Cell Line, Tumor , Circadian Clocks , Circadian Rhythm , Endothelial Cells/immunology , Immune Checkpoint Inhibitors/therapeutic use , Immune Checkpoint Inhibitors/pharmacology , Immunotherapy/methods , Lymphocytes, Tumor-Infiltrating/immunology , Melanoma/immunology , Melanoma/therapy , Melanoma/pathology , Tumor Microenvironment/immunologyABSTRACT
The gut microbiota influences the clinical responses of cancer patients to immunecheckpoint inhibitors (ICIs). However, there is no consensus definition of detrimental dysbiosis. Based on metagenomics (MG) sequencing of 245 non-small cell lung cancer (NSCLC) patient feces, we constructed species-level co-abundance networks that were clustered into species-interacting groups (SIGs) correlating with overall survival. Thirty-seven and forty-five MG species (MGSs) were associated with resistance (SIG1) and response (SIG2) to ICIs, respectively. When combined with the quantification of Akkermansia species, this procedure allowed a person-based calculation of a topological score (TOPOSCORE) that was validated in an additional 254 NSCLC patients and in 216 genitourinary cancer patients. Finally, this TOPOSCORE was translated into a 21-bacterial probe set-based qPCR scoring that was validated in a prospective cohort of NSCLC patients as well as in colorectal and melanoma patients. This approach could represent a dynamic diagnosis tool for intestinal dysbiosis to guide personalized microbiota-centered interventions.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Gastrointestinal Microbiome , Immunotherapy , Lung Neoplasms , Neoplasms , Female , Humans , Male , Akkermansia , Carcinoma, Non-Small-Cell Lung/microbiology , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/immunology , Dysbiosis/microbiology , Feces/microbiology , Gastrointestinal Microbiome/drug effects , Immune Checkpoint Inhibitors/therapeutic use , Immune Checkpoint Inhibitors/pharmacology , Immunotherapy/methods , Lung Neoplasms/microbiology , Lung Neoplasms/drug therapy , Metagenomics/methods , Neoplasms/microbiology , Treatment OutcomeABSTRACT
Cancer immunotherapy remains limited by poor antigenicity and a regulatory tumor microenvironment (TME). Here, we create "onion-like" multi-lamellar RNA lipid particle aggregates (LPAs) to substantially enhance the payload packaging and immunogenicity of tumor mRNA antigens. Unlike current mRNA vaccine designs that rely on payload packaging into nanoparticle cores for Toll-like receptor engagement in immune cells, systemically administered RNA-LPAs activate RIG-I in stromal cells, eliciting massive cytokine/chemokine response and dendritic cell/lymphocyte trafficking that provokes cancer immunogenicity and mediates rejection of both early- and late-stage murine tumor models. In client-owned canines with terminal gliomas, RNA-LPAs improved survivorship and reprogrammed the TME, which became "hot" within days of a single infusion. In a first-in-human trial, RNA-LPAs elicited rapid cytokine/chemokine release, immune activation/trafficking, tissue-confirmed pseudoprogression, and glioma-specific immune responses in glioblastoma patients. These data support RNA-LPAs as a new technology that simultaneously reprograms the TME while eliciting rapid and enduring cancer immunotherapy.
Subject(s)
Immunotherapy , Lipids , RNA , Tumor Microenvironment , Animals , Dogs , Female , Humans , Mice , Antigens, Neoplasm/immunology , Brain Neoplasms/therapy , Brain Neoplasms/immunology , Cancer Vaccines/immunology , Cancer Vaccines/therapeutic use , Cell Line, Tumor , Cytokines/metabolism , Dendritic Cells/immunology , Dendritic Cells/metabolism , Glioblastoma/therapy , Glioblastoma/immunology , Glioma/therapy , Glioma/immunology , Immunotherapy/methods , Mice, Inbred C57BL , Neoplasms/therapy , Neoplasms/immunology , RNA/chemistry , RNA/therapeutic use , RNA, Messenger/metabolism , RNA, Messenger/genetics , Lipids/chemistryABSTRACT
Fewer than 200 proteins are targeted by cancer drugs approved by the Food and Drug Administration (FDA). We integrate Clinical Proteomic Tumor Analysis Consortium (CPTAC) proteogenomics data from 1,043 patients across 10 cancer types with additional public datasets to identify potential therapeutic targets. Pan-cancer analysis of 2,863 druggable proteins reveals a wide abundance range and identifies biological factors that affect mRNA-protein correlation. Integration of proteomic data from tumors and genetic screen data from cell lines identifies protein overexpression- or hyperactivation-driven druggable dependencies, enabling accurate predictions of effective drug targets. Proteogenomic identification of synthetic lethality provides a strategy to target tumor suppressor gene loss. Combining proteogenomic analysis and MHC binding prediction prioritizes mutant KRAS peptides as promising public neoantigens. Computational identification of shared tumor-associated antigens followed by experimental confirmation nominates peptides as immunotherapy targets. These analyses, summarized at https://targets.linkedomics.org, form a comprehensive landscape of protein and peptide targets for companion diagnostics, drug repurposing, and therapy development.
Subject(s)
Neoplasms , Proteogenomics , Humans , Proteogenomics/methods , Neoplasms/genetics , Neoplasms/drug therapy , Neoplasms/therapy , Neoplasms/metabolism , Molecular Targeted Therapy , Immunotherapy/methods , Antigens, Neoplasm/metabolism , Antigens, Neoplasm/genetics , Cell Line, Tumor , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/pharmacology , Peptides/metabolism , Proteomics , Proto-Oncogene Proteins p21(ras)/genetics , Proto-Oncogene Proteins p21(ras)/metabolismABSTRACT
T cell responses display two key characteristics. First, a small population of epitope-specific naive T cells expands by several orders of magnitude. Second, the T cells within this proliferating population take on diverse functional and phenotypic properties that determine their ability to exert effector functions and contribute to T cell memory. Recent technological advances in lineage tracing allow us for the first time to study these processes in vivo at single-cell resolution. Here, we summarize resulting data demonstrating that although epitope-specific T cell responses are reproducibly similar at the population level, expansion potential and diversification patterns of the offspring derived from individual T cells are highly variable during both primary and recall immune responses. In spite of this stochastic response variation, individual memory T cells can serve as adult stem cells that provide robust regeneration of an epitope-specific tissue through population averaging. We discuss the relevance of these findings for T cell memory formation and clinical immunotherapy.
Subject(s)
Adult Stem Cells/immunology , Cell Differentiation , Immunotherapy/methods , Single-Cell Analysis/methods , T-Lymphocytes/immunology , Animals , Biodiversity , Cell Lineage , Cell Proliferation , Cultural Diversity , Epitopes, T-Lymphocyte/immunology , Epitopes, T-Lymphocyte/metabolism , Humans , Immunologic Memory , Lymphocyte ActivationABSTRACT
The immune system is capable of recognizing tumors and eliminates many early malignant cells. However, tumors evolve to evade immune attack, and the tumor microenvironment is immunosuppressive. Immune responses are regulated by a number of immunological checkpoints that promote protective immunity and maintain tolerance. T cell coinhibitory pathways restrict the strength and duration of immune responses, thereby limiting immune-mediated tissue damage, controlling resolution of inflammation, and maintaining tolerance to prevent autoimmunity. Tumors exploit these coinhibitory pathways to evade immune eradication. Blockade of the PD-1 and CTLA-4 checkpoints is proving to be an effective and durable cancer immunotherapy in a subset of patients with a variety of tumor types, and additional combinations are further improving response rates. In this review we discuss the immunoregulatory functions of coinhibitory pathways and their translation to effective immunotherapies for cancer.
Subject(s)
Antibodies, Monoclonal/therapeutic use , B7-H1 Antigen/immunology , CTLA-4 Antigen/immunology , Immunotherapy/methods , Neoplasms/therapy , Programmed Cell Death 1 Receptor/immunology , T-Lymphocytes/immunology , Animals , Humans , Immunotherapy/trends , Lymphocyte Activation/drug effects , Neoplasms/immunology , Tumor Escape , Tumor MicroenvironmentABSTRACT
CD8+ T cell responses are critical for anti-tumor immunity. While extensively profiled in the tumor microenvironment, recent studies in mice identified responses in lymph nodes (LNs) as essential; however, the role of LNs in human cancer patients remains unknown. We examined CD8+ T cells in human head and neck squamous cell carcinomas, regional LNs, and blood using mass cytometry, single-cell genomics, and multiplexed ion beam imaging. We identified progenitor exhausted CD8+ T cells (Tpex) that were abundant in uninvolved LN and clonally related to terminally exhausted cells in the tumor. After anti-PD-L1 immunotherapy, Tpex in uninvolved LNs reduced in frequency but localized near dendritic cells and proliferating intermediate-exhausted CD8+ T cells (Tex-int), consistent with activation and differentiation. LN responses coincided with increased circulating Tex-int. In metastatic LNs, these response hallmarks were impaired, with immunosuppressive cellular niches. Our results identify important roles for LNs in anti-tumor immune responses in humans.
Subject(s)
CD8-Positive T-Lymphocytes , Neoplasms , Humans , Animals , Mice , Lymph Nodes , Neoplasms/therapy , Neoplasms/pathology , Immunotherapy/methods , Tumor MicroenvironmentABSTRACT
Ion channels and transporters mediate the transport of charged ions across hydrophobic lipid membranes. In immune cells, divalent cations such as calcium, magnesium, and zinc have important roles as second messengers to regulate intracellular signaling pathways. By contrast, monovalent cations such as sodium and potassium mainly regulate the membrane potential, which indirectly controls the influx of calcium and immune cell signaling. Studies investigating human patients with mutations in ion channels and transporters, analysis of gene-targeted mice, or pharmacological experiments with ion channel inhibitors have revealed important roles of ionic signals in lymphocyte development and in innate and adaptive immune responses. We here review the mechanisms underlying the function of ion channels and transporters in lymphocytes and innate immune cells and discuss their roles in lymphocyte development, adaptive and innate immune responses, and autoimmunity, as well as recent efforts to develop pharmacological inhibitors of ion channels for immunomodulatory therapy.
Subject(s)
Adaptive Immunity/physiology , Immunity, Innate/physiology , Ion Channels/metabolism , Animals , Calcium Channels/genetics , Calcium Channels/metabolism , Cation Transport Proteins/genetics , Cation Transport Proteins/metabolism , Humans , Hypersensitivity/genetics , Hypersensitivity/immunology , Hypersensitivity/metabolism , Immunologic Deficiency Syndromes/drug therapy , Immunologic Deficiency Syndromes/genetics , Immunologic Deficiency Syndromes/immunology , Immunologic Deficiency Syndromes/metabolism , Immunotherapy/methods , Ion Channels/genetics , Lymphocytes/cytology , Lymphocytes/immunology , Lymphocytes/metabolism , Mast Cells/immunology , Mast Cells/metabolism , Molecular Targeted Therapy , Mutation , Signal TransductionABSTRACT
Therapeutic cancer vaccines are designed to increase tumor-specific T cell immunity. However, suppressive mechanisms within the tumor microenvironment (TME) may limit T cell function. Here, we assessed how the route of vaccination alters intratumoral myeloid cells. Using a self-assembling nanoparticle vaccine that links tumor antigen peptides to a Toll-like receptor 7/8 agonist (SNP-7/8a), we treated tumor-bearing mice subcutaneously (SNP-SC) or intravenously (SNP-IV). Both routes generated antigen-specific CD8+ T cells that infiltrated tumors. However, only SNP-IV mediated tumor regression, dependent on systemic type I interferon at the time of boost. Single-cell RNA-sequencing revealed that intratumoral monocytes expressing an immunoregulatory gene signature (Chil3, Anxa2, Wfdc17) were reduced after SNP-IV boost. In humans, the Chil3+ monocyte gene signature is enriched in CD16- monocytes and associated with worse outcomes. Our results show that the generation of tumor-specific CD8+ T cells combined with remodeling of the TME is a promising approach for tumor immunotherapy.