Project description:Metabolic programming is a central regulator of T cell activation, differentiation and effector function. These metabolic processes are intricately linked to the anti-tumor properties of T cells and manipulation of T cell metabolism has shown promise in enhancing immunotherapy. To gain further insight into the metabolic pathways associated with increased anti-tumor T cell function, we utilized a metabolomics approach to interrogate the metabolic profile of three different CD8+ T cell subsets each with varying degrees of anti-tumor activity in murine models. These subsets include IFN-γ+ Tc1, IL-17+ Tc17 and IL-22+ Tc22 CD8+ effector subsets, of which Tc22 cells display the most robust anti-tumor activity. Here, we show that Tc22s were distinct in their up-regulation of the pantothenate/coenzyme A (CoA) pathway and requirement for oxidative phosphorylation (OXPHOS) for differentiation. Further investigation revealed that the exogenous administration of CoA metabolically reprogrammed T cells to increase OXPHOS and adopt the CD8+ Tc22 phenotype independent of polarizing conditions via the transcription factors HIF-1α and the aryl hydrocarbon receptor (AhR). CoA-treated CD8+ T cells demonstrated enhanced anti-tumor function and persistence following adoptive transfer in murine tumor models. Treatment of mice with the CoA precursor pantothenate also enhanced the efficacy of anti-PD-L1 antibody therapy in preclinical models. These findings were extended to human melanoma patients, as we correlated increased pre-treatment plasma pantothenate levels with response to anti-PD1 antibody therapy. Collectively, our data demonstrate that pantothenate and its metabolite CoA drive T cell polarization, bioenergetics and anti-tumor immunity.
Project description:scRNAseq-based unsupervised clustering and clonotyping revealed that Th1/17 and CCR6 SP clusters formed metacluster Th7R, which was distinct from Th1 or Th17, characterized by high expression of the IL-7 receptor. Use of this cluster to assess antitumor CD4+ T cell immunity from the peripheral blood and to predict the efficacy of immune checkpoint inhibitors will pave the way for novel antitumor immunotherapy strategies for patients.
Project description:The anatomic location and immunologic characteristics of brain tumors result in strong lymphocyte suppression. Consequently, conventional immunotherapies targeting CD8 T-cells are ineffective against brain tumors. Tumor cells escape immunosurveillance by various mechanisms, and tumor cell metabolism can affect the metabolic states and functions of tumor-infiltrating lymphocytes. Oxygen tension is one important factor influencing immune responses. Here, we discovered that brain tumor cells had a particularly high demand for oxygen, which affected γδ T-cell-mediated antitumor immune responses but not those of conventional T-cells. Specifically, tumor hypoxia activated the γδ T-cell protein kinase A (PKA) pathway at a transcriptional level, resulting in repression of NKG2D expression. Alleviating tumor hypoxia reinvigorated NKG2D expression and the antitumor function of γδ T-cells. These results reveal a hypoxia-mediated mechanism by which brain tumors and γδ T-cells interact and emphasize the importance of γδ T-cells for antitumor immunity against brain tumors.
Project description:Abstract: Radiation therapy is a key component of the standard of care for glioblastoma (GBM). Although this treatment is known to trigger pro-inflammatory immune responses, it also results in several immune resistance mechanisms such as the upregulation of CD47 by tumors leading to avoidance of phagocytosis and the overexpression of PD-L1 in tumor-associated myeloid cells (TAMCs). Leveraging these RT-elicited processes, we generated a bispecific-lipid nanoparticle (B-LNP) that engaged TAMCs to glioma cells via anti-CD47/PD-L1 dual-ligation. We show that B-LNP blocked these two vital immune checkpoint molecules and promoted the phagocytic activity of TAMCs. In order to boost subsequent T cell recruitment and antitumor activity after tumor engulfment, the B-LNP was encapsulated with diABZI, a non-nucleotidyl agonist for stimulator of interferon genes (STING). In vivo treatment with the diABZI-loaded B-LNP induced a transcriptomic and metabolic switch in TAMCs, transforming them into potent antitumor effector cells, which induced T cell infiltration and activation of in the brain tumors. In preclinical murine glioma models, B-LNP therapy significantly potentiated the antitumor effects of radiotherapy, promoted brain tumor regression, and induced immunological memory against gliomas. The nano37 therapy was efficacious through both intra-tumoral and systemic delivery routes. In summary, our study shows a unique nanotechnology-based approach that hijacks multiple immune checkpoints to boost potent and long-lasting antitumor immunity against GBM.
Project description:MAVS-mediated cytosolic RNA sensing plays a central role in tumor immunogenicity. However, the effects of host MAVS signaling on antitumor immunity remains uncertain. Here, we demonstrate that host MAVS pathway drives accelerated tumor growth and impairs antitumor immunity, while MAVS knockout in dendritic cells (DCs) promotes tumor-reactive CD8+ T cell responses. Specifically, the CD8+ T cell priming capacity is enhanced by lack of functional MAVS in a type I interferon-independent, but IL-12-dependent, manner. Mechanistically, loss of RIG-I/MAVS cascade activates non-canonical NF-κB pathway and in turn induces IL-12 production by DCs, resulting in CD8+ T cell: DC crosstalk licensed by IFN-γ and IL-12. Moreover, ablation of host MAVS sensitizes tumors to immunotherapy and attenuates radiation resistance, thereby facilitating the maintenance of effector CD8+ T cells. These findings identify that host MAVS pathway acts as an immune checkpoint of DC-driven antitumor immunity, indicating the development of DC-based immunotherapies through MAVS signaling antagonism.
Project description:Epigenetic mechanism contributes to immune landscapes in cancer. Here we identify the SETDB1-TRIM28 complex as a critical suppressor of antitumor immunity. An epigenetic CRISPR-Cas9 screen of 1,218 chromatin regulators identified TRIM28 as a novel suppressor of PD-L1 expression. We revealed that expression of the SETDB1-TRIM28 complex negatively correlates with infiltration of effector CD8+ T cells. Inhibition of SETDB1-TRIM28 simultaneously upregulates PD-L1 and activates the cGAS-STING innate immune response to increase infiltration of CD8+ T cells. Mechanistically, SETDB1-TRIM28 inhibition leads to micronuclei formation in cytoplasm, a known activator of the cGAS-STING pathway. Thus, SETDB1-TRIM28 inhibition bridges the innate and adaptive immunity. Indeed, SETDB1 knockout enhances the antitumor effects of immune checkpoint blockade anti-PD-L1 in an ovarian cancer mouse model in a cGAS dependent manner. Our findings establish SETDB1-TRIM28 complex as a regulator of antitumor immunity and its loss activates cGAS-STING innate immunity to boost antitumor effects of immune checkpoint blockades.
Project description:RNA N1-methyladenosine methylation (m1A) modification is critical in regulating mRNA translation and thus protein synthesis, but the role of m1A modification in the occurrence, progression, and immunotherapy of head and neck squamous cell cancer (HNSCC) remains largely unknown. In Tgfbr1/Pten 2cKO mice, we found that the spontaneous neoplastic transformation of oral mucosa is accompanied by elevated levels of m1A modification. Analysis of m1A-associated genes identified TRMT61A as the key m1A writer associated with cancer progression, and poor prognosis. Mechanically, TRMT61A-induced tRNA-m1A modification promotes MYC protein synthesis and subsequent programmed death-ligand 1 (PD-L1) expression. In Tgfbr1/Pten 2cKO mice, RNA-m1A modification levels are also elevated in tumors that developed resistance to oncolytic herpes simplex virus (oHSV) treatment. Therapeutic inhibition of m1A modification sustains oncolytic virus-induced antitumor immunity and reduces tumor growth, providing a promising strategy for alleviating resistance to oHSV therapy. These findings indicate that m1A inhibition can prevent immune escape after oHSV therapy by reducing the expression of PD-L1. Our results provide a mutually reinforcing strategy for clinical combination immunotherapy.
Project description:Depleting the NURF chromatin remodeling complex results in enhanced antitumor immunity using mouse tumor models syngenic to two strain backgrounds. Selective depletion of immune cells from tumor-bearing mice discovers that both CD8+ and CD4+ cells are necessary for enhanced antitumor immunity to NURF-depleted cells. Our results suggest that NURF-depleted cells have significant differences in antigenicity compared to control cells.