Project description:Inhibition of the T-cell co-inhibitory checkpoint receptors or their ligands CTLA-4, PD-1 and PD-L1 using monoclonal antibodies has proven to be highly effective against many cancers. Yet many cancers remain resistant to checkpoint blockade, and durable remissions occur in only a minority of patients. Novel approaches to enhancing antitumor responses are thus necessary in order to expand the reach of these treatments. The inhibitor of apoptosis (IAP) protein family comprises a diverse group of proteins, many of which have immunoregulatory roles. Small molecule IAP antagonists have been developed and are undergoing early phase clinical testing. These drugs were initially developed to promote tumor cell apoptosis; however, a considerable body of work now indicates that IAP antagonists induce antitumor activity through modulation of innate and adaptive immunity. Primarily through inhibition of cellular (c)-IAP1 and c-IAP2, IAP antagonists can activate alternative NF-κB signaling, promoting B-cell survival, activation of dendritic cells and delivering a broad co-stimulatory signal to T cells. At the same time, IAP antagonists can promote tumor cell intrinsic sensitization to innate immune signals, and enhance tumor cell killing by inflammatory cytokines and phagocytic macrophages. These drugs thus represent an attractive investigational approach to immunotherapy, providing a positive signaling counterpart to the relief of signal inhibition conferred by checkpoint blockade.
Project description:Endothelial phospholipase Cγ (PLCγ) is essential for vascular development; however, its role in healthy, mature, or pathological vessels is unexplored. Here, we show that PLCγ was prominently expressed in vessels of several human cancer forms, notably in renal cell carcinoma (RCC). High PLCγ expression in clear cell RCC correlated with angiogenic activity and poor prognosis, while low expression correlated with immune cell activation. PLCγ was induced downstream of vascular endothelial growth factor receptor 2 (VEGFR2) phosphosite Y1173 (pY1173). Heterozygous Vegfr2Y1173F/+ mice or mice lacking endothelial PLCγ (Plcg1iECKO) exhibited a stabilized endothelial barrier and diminished vascular leakage. Barrier stabilization was accompanied by decreased expression of immunosuppressive cytokines, reduced infiltration of B cells, helper T cells and regulatory T cells, and improved response to chemo- and immunotherapy. Mechanistically, pY1173/PLCγ signaling induced Ca2+/protein kinase C-dependent activation of endothelial nitric oxide synthase (eNOS), required for tyrosine nitration and activation of Src. Src-induced phosphorylation of VE-cadherin at Y685 was accompanied by disintegration of endothelial junctions. This pY1173/PLCγ/eNOS/Src pathway was detected in both healthy and tumor vessels in Vegfr2Y1173F/+ mice, which displayed decreased activation of PLCγ and eNOS and suppressed vascular leakage. Thus, we believe that we have identified a clinically relevant endothelial PLCγ pathway downstream of VEGFR2 pY1173, which destabilizes the endothelial barrier and results in loss of antitumor immunity.
Project description:Ovarian cancer remains a challenging disease with limited treatment options and poor prognosis. The tumor microenvironment (TME) plays a crucial role in tumor growth, progression, and therapy response. One characteristic feature of the TME is the abnormal tumor vasculature, which is associated with inadequate blood perfusion, hypoxia, and immune evasion. Vascular normalization, a therapeutic strategy aiming to rectify the abnormal tumor vasculature, has emerged as a promising approach to reshape the TME, enhance antitumor immunity, and synergize with immunotherapy in ovarian cancer. This review paper provides a comprehensive overview of vascular normalization and its potential implications in ovarian cancer. In this review, we summarize the intricate interplay between anti-angiogenesis and immune modulation, as well as ICI combined with anti-angiogenesis therapy in ovarian cancer. The compelling evidence discussed in this review contributes to the growing body of knowledge supporting the utilization of combination therapy as a promising treatment paradigm for ovarian cancer, paving the way for further clinical development and optimization of this therapeutic approach.
Project description:The tumor microenvironment (TME), including infiltrated immune cells, is known to play an important role in tumor growth; however, the mechanisms underlying tumor immunogenicity have not been fully elucidated. Here, we discovered an unexpected role for the transcription factor SIX1 in regulating the tumor immune microenvironment. Based on analyses of patient datasets, we found that SIX1 was upregulated in human tumor tissues and that its expression levels were negatively correlated with immune cell infiltration in the TME and the overall survival rates of cancer patients. Deletion of Six1 in cancer cells significantly reduced tumor growth in an immune-dependent manner with enhanced antitumor immunity in the TME. Mechanistically, SIX1 was required for the expression of multiple collagen genes via the TGFBR2-dependent Smad2/3 activation pathway, and collagen deposition in the TME hampered immune cell infiltration and activation. Thus, our study uncovers a crucial role for SIX1 in modulating tumor immunogenicity and provides proof-of-concept evidence for targeting SIX1 in cancer immunotherapy.
Project description:Isocitrate dehydrogenase (IDH) mutations, a hallmark of gliomagenesis, result in the production of the oncometabolite R-2-hydroxyglutarate (R-2-HG) which is thought to promote tumorigenesis via DNA methylation. Here we identify an additional immunosuppressive activity of R-2-HG: Tumor cell-derived R-2-HG is taken up by T-cells where it induces a strong and immediate perturbation of calcium- and ATP-dependent signaling events, and polyamine biosynthesis. This results in a profound suppression of antigen-specific T-cell activation and effector cytokine production in experimental mouse and human systems. In a large cohort of WHO grade II and III gliomas, IDH1 mutant tumors display reduced infiltration by T-cells compared to IDH1 wildtype tumors. Spontaneous and induced mutation-specific antitumor immunity to syngeneic IDH1-mutant tumors in MHC-humanized mice is improved by isolated genetic ablation of the neomorphic enzymatic function of mutant IDH1. Taken together, these data attribute a novel, fundamentally non-tumor-cell-autonomous role of an oncometabolite in shaping the tumor immune microenvironment. We investigated the effects of exogenous R-2-HG on primary human T cells.
Project description:In cancer, activation of the IRE1/XBP1s axis of the unfolded protein response (UPR) promotes immunosuppression and tumor growth, by acting in cancer cells and tumor infiltrating immune cells. However, the role of IRE1/XBP1s in dendritic cells (DCs) in tumors, particularly in conventional type 1 DCs (cDC1s) which are cellular targets in immunotherapy, has not been fully elucidated. Here, we studied the role of IRE1/XBP1s in subcutaneous B16/B78 melanoma and MC38 tumors by generating loss-of-function models of IRE1 and/or XBP1s in DCs or in cDC1s. Data show that concomitant deletion of the RNase domain of IRE1 and XBP1s in DCs and cDC1s does not influence the kinetics of B16/B78 and MC38 tumor growth or the effector profile of tumor infiltrating T cells. A modest effect is observed in mice bearing single deletion of XBP1s in DCs, which showed slight acceleration of melanoma tumor growth and dysfunctional T cell responses, however, this effect was not recapitulated in animals lacking XBP1 only in cDC1s. Thus, evidence presented here argues against a general pro-tumorigenic role of the IRE1/XBP1s pathway in tumor associated DC subsets.
Project description:Sustained intratumoral delivery of interleukin-12 (IL-12) and granulocyte macrophage colony-stimulating factor induces tumor regression via restoration of tumor-resident CD8+ T-effector/memory cell cytotoxicity and subsequent repriming of a secondary CD8+ T-effector cell response in tumor-draining lymph nodes (TDLN). However, treatment-induced T-effector activity is transient and is accompanied with a CD4+ CD25+ Foxp3+ T-suppressor cell rebound. Molecular and cellular changes in posttherapy tumor microenvironment and TDLN were monitored to elucidate the mechanism of counterregulation. Real-time PCR analysis revealed a 5-fold enhancement of indoleamine 2,3-dioxygenase (IDO) expression in the tumor and the TDLN after treatment. IDO induction required IFNgamma and persisted for up to 7 days. Administration of the IDO inhibitor D-1-methyl tryptophan concurrent with treatment resulted in a dramatic enhancement of tumor regression. Enhanced efficacy was associated with a diminished T-suppressor cell rebound, revealing a link between IDO activity and posttherapy regulation. Further analysis established that abrogation of the regulatory counterresponse resulted in a 10-fold increase in the intratumoral CD8+ T-cell to CD4+ Foxp3+ T-cell ratio. The ratio of proliferating CD8+ T-effector to CD4+ Foxp3+ T-suppressor cells was prognostic for efficacy of tumor suppression in individual mice. IFNgamma-dependent IDO induction and T-suppressor cell expansion were primarily driven by IL-12. These findings show a critical role for IDO in the regulation of IL-12-mediated antitumor immune responses.
Project description:Melanoma is the most malignant skin cancer, which originates from epidermal melanocytes, with increasing worldwide incidence. The escape of immune surveillance is a hallmark of the tumor, which is manifested by the imbalance between the enhanced immune evasion of tumor cells and the impaired antitumor capacity of infiltrating immune cells. According to this notion, the invigoration of the exhausted immune cells by immune checkpoint blockades has gained encouraging outcomes in eliminating tumor cells and significantly prolonged the survival of patients, particularly in melanoma. Epigenetics is a pivotal non-genomic modulatory paradigm referring to heritable changes in gene expression without altering genome sequence, including DNA methylation, histone modification, non-coding RNAs, and m6A RNA methylation. Accumulating evidence has demonstrated how the dysregulation of epigenetics regulates multiple biological behaviors of tumor cells and contributes to carcinogenesis and tumor progression in melanoma. Nevertheless, the linkage between epigenetics and antitumor immunity, as well as its implication in melanoma immunotherapy, remains elusive. In this review, we first introduce the epidemiology, clinical characteristics, and therapeutic innovations of melanoma. Then, the tumor microenvironment and the functions of different types of infiltrating immune cells are discussed, with an emphasis on their involvement in antitumor immunity in melanoma. Subsequently, we systemically summarize the linkage between epigenetics and antitumor immunity in melanoma, from the perspective of distinct paradigms of epigenetics. Ultimately, the progression of the clinical trials regarding epigenetics-based melanoma immunotherapy is introduced.
Project description:The immune system plays a critical role in cancer, including lung cancer, which is the leading cause of cancer-related deaths worldwide. Immunotherapy, particularly immune checkpoint blockade, has revolutionized the treatment of lung cancer, but a large subset of patients either do not respond or develop resistance. Exosomes, essential mediators of cell-to-cell communication, exert a profound influence on the tumor microenvironment and the interplay between cancer and the immune system. This review focuses on the role of tumor-derived exosomes and immune cells-derived exosomes in the crosstalk between these cell types, influencing the initiation and progression of lung cancer. Depending on their cell of origin and microenvironment, exosomes can contain immunosuppressive or immunostimulatory molecules that can either promote or inhibit tumor growth, thus playing a dual role in the disease. Furthermore, the use of exosomes in lung cancer immunotherapy is discussed. Their potential applications as cell-free vaccines and drug delivery systems make them an attractive option for lung cancer treatment. Additionally, exosomal proteins and RNAs emerge as promising biomarkers that could be employed for the prediction, diagnosis, prognosis and monitoring of the disease. In summary, this review assesses the relationship between exosomes, lung cancer, and the immune system, shedding light on their potential clinical applications and future perspectives.
Project description:Given the effective immunotherapy of DC-based vaccine in other cancers, we hypothesized DC-based vaccines would induce effective immune responses against Ewing's sarcoma. To verify this hypothesis and develop the most effective dendritic cell vaccine against Ewing's sarcoma, we evaluated the antitumor efficacy of dendritic cell-Ewing's sarcoma hybrids and dendritic cells pulsed with other antigen-loading methods, including cell lysates and the characteristic EWS-FLI1 gene of Ewing's sarcoma, using an A673 cell line as a model. The hybrids were generated by electrofusion with fusion efficiency and viability determined by flow cytometry and fluorescent microscopy analyses. By interferon-gamma secretion assay, the capacity of hybrids to stimulate cytotoxic T-lymphocytes (CTLs) is higher than that of other antigen-loading methods showing stronger tumor antigen-specific CTL cytotoxicity to A673. By in vivo experiment in SCID mice, all dendritic cell-based strategies induced specific immune responses to Ewing's sarcoma after mice-human immune system reconstitution by inoculating human peripheral blood mononuclear cells into the peritoneal cavity of SCID mice. However, the hybrids most inhibited the subcutaneous tumor growth in SCID mice compared with dendritic cells pulsed with other loading methods. The data suggest A673 cells respond to dendritic cell-based immunotherapy.