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Despite significant advances in the field of cancer immunotherapy, the majority of patients still do not benefit from treatment and must rely on traditional therapies. Dendritic cells have long been a focus of cancer immunotherapy due to their role in inducing protective adaptive immunity, but cancer vaccines have shown limited efficacy in the past. With the advent of immune checkpoint blockade and the ability to identify patient-specific neoantigens, new vaccines, and combinatorial therapies are being evaluated in the clinic. Dendritic cells are also emerging as critical regulators of the immune response within tumors. Understanding how to augment the function of these intratumoral dendritic cells could offer new approaches to enhance immunotherapy, in addition to improving the cytotoxic and targeted therapies that are partially dependent upon a robust immune response for their efficacy. Here we will discuss the role of specific dendritic cell subsets in regulating the anti-tumor immune response, as well as the current status of dendritic cell-based immunotherapies, in order to provide an overview for future lines of research and clinical trials.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and has the highest rate of recurrence 1 . The predominant standard of care for advanced TNBC is systemic chemotherapy with or without immunotherapy; however, responses are typically short lived 1 , 2 . Thus, there is an urgent need to develop more effective treatments. Components of the PI3K pathway represent plausible therapeutic targets; more than 70% of TNBCs have alterations in PIK3CA, AKT1 or PTEN 3 – 6 . However, in contrast to hormone-receptor-positive tumours, it is still unclear whether or how triple-negative disease will respond to PI3K pathway inhibitors 7 . Here we describe a promising AKT-inhibitor-based therapeutic combination for TNBC. Specifically, we show that AKT inhibitors synergize with agents that suppress the histone methyltransferase EZH2 and promote robust tumour regression in multiple TNBC models in vivo. AKT and EZH2 inhibitors exert these effects by first cooperatively driving basal-like TNBC cells into a more differentiated, luminal-like state, which cannot be effectively induced by either agent alone. Once TNBCs are differentiated, these agents kill them by hijacking signals that normally drive mammary gland involution. Using a machine learning approach, we developed a classifier that can be used to predict sensitivity. Together, these findings identify a promising therapeutic strategy for this highly aggressive tumour type and illustrate how deregulated epigenetic enzymes can insulate tumours from oncogenic vulnerabilities. These studies also reveal how developmental tissue-specific cell death pathways may be co-opted for therapeutic benefit. AKT inhibitors synergize with agents that suppress the histone methyltransferase EZH2 and promote robust tumour regression in multiple triple-negative breast cancer models in vivo by triggering an involution-like process.

While screening and early detection have reduced mortality from prostate cancer, castration-resistant disease (CRPC) is still incurable. Here, we report that combined EZH2/HDAC inhibitors potently kill CRPCs and cause dramatic tumor regression in aggressive human and mouse CRPC models. Notably, EZH2 and HDAC both transmit transcriptional repressive signals: regulating histone H3 methylation and histone deacetylation, respectively. Accordingly, we show that suppression of both EZH2 and HDAC are required to derepress/induce a subset of EZH2 targets, by promoting the sequential demethylation and acetylation of histone H3. Moreover, we find that the induction of one of these targets, ATF3 , which is a broad stress response gene, is critical for the therapeutic response. Importantly, in human tumors, low ATF3 levels are associated with decreased survival. Moreover, EZH2 - and ATF3- mediated transcriptional programs inversely correlate and are most highly/lowly expressed in advanced disease. Together, these studies identify a promising therapeutic strategy for CRPC and suggest that these two major epigenetic regulators buffer prostate cancers from a lethal response to cellular stresses, thereby conferring a tractable therapeutic vulnerability.

Little is known regarding how the interactions of stem cells with the immune system regulate their plasticity. A study now describes a mechanism by which normal breast and cancer stem cells utilize miR-199a to downregulate the corepressor LCOR and minimize responses to type I interferon.

While screening and early detection have reduced mortality from prostate cancer, castration-resistant disease (CRPC) is still incurable. Here, we report that combined EZH2/HDAC inhibitors potently kill CRPCs and cause dramatic tumor regression in aggressive human and mouse CRPC models. Notably, EZH2 and HDAC both transmit transcriptional repressive signals: regulating histone H3 methylation and histone deacetylation, respectively. Accordingly, we show that suppression of both EZH2 and HDAC are required to derepress/induce a subset of EZH2 targets, by promoting the sequential demethylation and acetylation of histone H3. Moreover, we find that the induction of one of these targets, ATF3, which is a broad stress response gene, is critical for the therapeutic response. Importantly, in human tumors, low ATF3 levels are associated with decreased survival. Moreover, EZH2- and ATF3-mediated transcriptional programs inversely correlate and are most highly/lowly expressed in advanced disease. Together, these studies identify a promising therapeutic strategy for CRPC and suggest that these two major epigenetic regulators buffer prostate cancers from a lethal response to cellular stresses, thereby conferring a tractable therapeutic vulnerability. Epigenetic, transcriptional, and functional studies show that two major epigenetic regulators (EZH2 and HDAC) buffer advanced prostate cancer from lethal stress responses, revealing a promising combination therapy for castration-resistant disease.

Intratumoral CD103+ dendritic cells (cDC1) are required for anti-tumor immune responses. In tumors that are poorly responsive to immunotherapeutic approaches targeting T cells, targeting cDC1 represents an alternative approach that may be useful in improving patient response rates. As such, it is critical to understand cDC1 function within tumors, and what may be preventing optimal function of cDC1. TIM-3 is a receptor that is highly expressed by cDC1 in murine and human mammary tumors, and TIM-3 blocking antibodies are currently being evaluated in clinical trials for a number of solid and hematological malignancies. In order to best design combinatorial therapeutic approaches, it is important to understand the mechanism by which therapies act. This project aims to understand the mechanism by which combination therapy with paclitaxel (PTX) and TIM-3 blockade reduces the rate of mammary tumor growth.In order to do so, we identify Cxcl9, Cxcl10, Cxcl11, and Il12b as being upregulated by cDC1 following PTX/TIM-3 blockade. By blocking signaling through CXCR3 (the receptor for CXCL9, CXCL10, and CXCL11) we determine that signaling through the CXCR3 axis was responsible for the observed reduction in the rate of tumor growth. We next evaluate whether the chemokines themselves are necessary for therapeutic response, using mixed bone marrow chimeras and diphtheria toxin depletion. In doing so, we identify CXCL9 production by cDC1 as a requirement for the observed reduction in tumor growth. As one role for CXCL9 has been shown to be mediating lymph node migration by CD8+ T cells, we then inhibit lymph node egress and use a fluorescently labelled tumor model to assess involvement of the lymph node following initiation of anti-tumor immunity. We did not observe changes in antigen presentation by cDC1 in the lymph node, or alterations in responsiveness to PTX/TIM-3 blockade when lymph node egress was inhibited. Together, these data point suggest that cDC1 may be interacting with CD8+ T cells within the tumor, and that these interactions may be supporting CD8+ T cell functionality.To evaluate this, we first use flow cytometry to assess T cell production of IFNγ, as a measure of the effector function. We find that treatment with PTX/TIM-3 blockade increases IFNγ production by CD8+ T cells, and that this is increase is prevented when signaling through CXCR3 is blocked. We next assess the distance between CD8+ T cells and their nearest cDC1 in tumors treated with PTX/TIM-3 blockade as compared to a PTX/IgG2a control. We find that CD8+ T cells are located closer to cDC1 in tumors treated with PTX/TIM-3 blockade, without increases in either CD8+ T cell or cDC1 infiltration. We then use mixed bone marrow chimeras and diphtheria toxin depletion to evaluate the role of two main functions of cDC1 within tumors: antigen cross-presentation on MHCI and production of IL-12. We find that IL-12 production by cDC1 is required for response to PTX/TIM-3 blockade, while antigen presentation by MHCI is dispensable. Taken together, the data described herein suggests that treatment with TIM-3 blockade drives increased CXCL9 production by cDC1, bringing CD8+ T cells into closer proximity and increasing their exposure to IL-12, thereby supporting CD8+ T cell functionality.Overall, these studies propose a mechanism by which TIM-3 blockade functions in mammary tumors and provide direct evidence for the ability of cDC1 to support CD8+ T cells within the tumor. Understanding these aspects has implications for the design of therapeutic strategies using antibodies against TIM-3.

Men with advanced prostate cancer are typically treated with androgen deprivation therapy, but most ultimately develop resistance and incurable disease (e.g. castration-resistant prostate cancer (CRPC)). The majority of CRPCs overexpress the epigenetic enzyme EZH2 and harbor alterations in the PI3K pathway, providing two targetable pathways outside of AR. Here we show that EZH2 inhibitors synergize with PI3K, AKT, or mTORC1 inhibitors to kill CRPC in vitro and promote tumor regression in vivo. Strikingly, these agents trigger a catastrophic energy crisis by cooperatively suppressing glycolysis, the TCA cycle, and oxidative phosphorylation prior to cell death. EZH2 and PI3K pathway inhibitors achieve this by respectively inhibiting two key regulators of metabolism, MYC and HIF-1A, while concomitantly derepressing a pro-apoptotic stress sensor. Together, these studies reveal a promising therapeutic strategy for CRPC and demonstrate how metabolic plasticity can be fatally impaired by co-targeting upstream oncogenic nodes that converge on this important process.

BackgroundT cell immunoglobulin and mucin domain containing−3 (TIM-3) blocking antibodies are currently being evaluated in clinical trials for solid and hematological malignancies. Despite its identification on T cells, TIM-3 is predominantly expressed by myeloid cells, including XCR1+ type I conventional dendritic cells (cDC1s). We have recently shown that TIM-3 blockade promotes expression of CXCR3 chemokine ligands by tumor cDCs, but how this drives a CD8+ T cell-dependent response to therapy is unclear.MethodsT cell infiltration, effector function, and spatial localization in relation to XCR1+ cDC1s were evaluated in a murine orthotopic mammary carcinoma model during response to TIM-3 blockade and paclitaxel chemotherapy. Mixed bone marrow chimeras and diphtheria toxin depletion were used to determine the role of specific genes in cDC1s during therapeutic responses.ResultsTIM-3 blockade increased interferon-γ expression by CD8+ T cells without altering immune infiltration. cDC1 expression of CXCL9, but not CXCL10, was required for response to TIM-3 blockade. CXCL9 was also necessary for the increased proximity observed between CD8+ T cells and XCR1+ cDC1s during therapy. Tumor responses were dependent on cDC1 expression of interleukin-12, but not MHCI.ConclusionsTIM-3 blockade increases exposure of intratumoral CD8+ T cells to cDC1-derived cytokines, with implications for the design of therapeutic strategies using antibodies against TIM-3.

Immunotherapy efficacy is limited in melanoma, and combinations of immunotherapies with other modalities have yielded limited improvements but also adverse events requiring cessation of treatment. In addition to ineffective patient stratification, efficacy is impaired by paucity of intratumoral immune cells (itICs); thus, effective strategies to safely increase itICs are needed. We report that dietary administration of l -fucose induces fucosylation and cell surface enrichment of the major histocompatibility complex (MHC)-II protein HLA-DRB1 in melanoma cells, triggering CD4 + T cell-mediated increases in itICs and anti-tumor immunity, enhancing immune checkpoint blockade responses. Melanoma fucosylation and fucosylated HLA-DRB1 associate with intratumoral T cell abundance and anti-programmed cell death protein 1 (PD1) responder status in patient melanoma specimens, suggesting the potential use of melanoma fucosylation as a strategy for stratifying patients for immunotherapies. Our findings demonstrate that fucosylation is a key mediator of anti-tumor immunity and, importantly, suggest that l -fucose is a powerful agent for safely increasing itICs and immunotherapy efficacy in melanoma.

Introduction: People who inject drugs (PWIDs) often experience a range of health, socioeconomic, and legal challenges. Supervised injection facilities (SIFs) are controlled health care settings where people can safely inject pre-obtained drugs under clinical supervision, with access to sterile equipment and resources such as; counseling, referrals to health and social services, and drug treatment. Objective: A growing body of evidence suggests that drug treatment services that attend to social needs can contribute to engagement and retention in treatment, and improved outcomes. This thesis examines the relationship between the provision of social services and treatment uptake in SIFs through managerial perspectives, which were obtained through key informant surveys. Methods: An assessment of three SIF’s priorities and provision of services was conducted through key informant survey interviews with SIF managers, as well as a literature review. Results: After assessing survey responses, we found that all SIFs in the study held provision of social services at the highest priority, with varying levels of priority for social reintegration interventions. Most of the SIFs had treatment as an objective, with varying attitudes towards treatment facilitation. The lack of space was a barrier and/or limitation for all facilities, and all desired to expand specific services or resources. Conclusion: Clients utilize the injection room at all SIFs, with higher daily utilization at the SIFs with more services on site. Regularly engaging the hard to reach population of PWID, with reinforcement of harm reduction practices, increases safety and connects clients to social/health services and treatment they may otherwise never seek or obtain. Further study inclusive of a majority of SIFs will yield generalizable evidence in reference to associations between social service provision and treatment uptake and/or maintenance. Subsequently, more detailed client tracking of the utilization of social services at all facilities should be employed.