Abstract Immune checkpoint blockade is effective in “hot” tumors like melanoma with pre-existing immune infiltrates; however, “cold” tumors like prostate cancer fail to respond. We found that prostate cancers harbor regions of hypoxia that resist T cell infiltration even in the context of anti-CTLA-4 (cytotoxic T lymphocyte associated protein-4) and anti-PD-1 (programmed cell death protein 1) blockade. These hypoxic zones serve as islands of immune privilege through the recruitment and suppressive polarization of immature myeloid cells into myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM). We found that targeted hypoxia ablation using TH-302, a hypoxia-activated prodrug, sensitized both transplantable and spontaneous models of prostate cancer to checkpoint blockade, coincident with enhanced T cell infiltration and effector function and loss of MDSC recruitment and suppressive function. Tumors treated with the combination of TH-302 and checkpoint blockade showed a reduced capacity to suppressively polarize new myeloid immigrants, implying a durable reconditioning of the tumor microenvironment (TME) into an immune-infiltrated, pro-inflammatory milieu. T cells infiltrating combination-treated tumors exhibited increased mitochondrial respiration, consistent with creation of a metabolically favorable milieu for T cell function. Based on these findings, we hypothesized that other approaches capable of metabolically rewiring the TME should promote anti-tumor immunity and sensitize checkpoint blockade-resistant tumors to immunotherapy. With this in mind, we performed a longitudinal study comparing a panel of different mitochondrial respiration inhibitors and a glutaminase inhibitor for their efficacy in reducing hypoxia, improving T cell infiltration and decreasing myeloid cell recruitment and suppressive polarization using immunofluorescence staining and confocal microscopy. Our preliminary data suggests that inhibitors targeting mitochondrial respiration, rather than those targeting glutamine metabolism synergize with checkpoint blockade and exhibit the highest efficacy in increasing T cell recruitment. We continue to characterize the dynamics of hypoxia reduction, duration of normalization following drug withdrawal, and impact on the immune microenvironment of these diverse approaches to metabolic reconditioning. Citation Format: Priyamvada Jayaprakash, Midan Ai, Arthur Liu, Pratha Budhani, Todd Bartkowiak, Jie Sheng, Casey Ager, Courtney Nicholas, Ashvin Jaiswal, Yanqiu Sun, Krishna Shah, Sadhana Balasubramanyam, Nan Li, Guocan Wang, Jing Ning, Anna Zal, Tomasz Zal, Michael Curran. Targeting hypoxia-induced immune suppression to overcome immunotherapy resistance in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5011.
The regulatory factors governing adult mesenchymal stem cell (MSC) physiology and their tumorigenic potential are still largely unknown, which substantially delays the identification of effective therapeutic approaches for the treatment of aggressive and lethal forms of MSC-derived mesenchymal tumors, such as undifferentiated sarcomas. Here, we have developed a novel platform to screen and quickly identify genes and pathways responsible for adult MSC transformation, modeled undifferentiated sarcoma in vivo, and, ultimately, tested the efficacy of targeting the identified oncopathways. Importantly, by taking advantage of this new platform, we demonstrate the key role of an aberrant LRF-DLK1-SOX9 pathway in the pathogenesis of undifferentiated sarcoma, with important therapeutic implications.The paucity of therapeutic options for the treatment of sarcoma calls for a rapid and effective preclinical assessment of new therapeutic modalities. We have here developed a new platform to deconstruct the molecular genetics underlying the pathogenesis of sarcoma and to evaluate in vivo the efficacy of novel targeted therapies.
<p>Overlapped genes between Genes upregulated in Ptenpc-/-Smad4pc-/- tumors as compared to Ptenpc-/- tumors ({greater than or equal to}2 fold) and genes upregulated in GFP+ tumors cells from Ptenpc-/-Smad4pc-/- mice as compared to Tomato+ cells ({greater than or equal to}4 fold).</p>
Abstract Although Immune checkpoint therapy (ICT) is highly effective in a wide range of malignancies, patients with metastatic castration-resistant prostate cancer (mCRPC) are largely resistant to ICT. Yet, the cellular and molecular basis of the poor response to ICT in lethal prostate cancer remain poorly defined. Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) have emerged as a key driver of prostate cancer progression and resistance to immunotherapy. Yet the molecular mechanisms underlying the immunosuppressive activities of PMN-MDSCs remains poorly defined. By performing single-cell RNA-sequencing (scRNA-seq) of prostate tumors, we identified Acod1, a gene that encodes cis-aconitate decarboxylase (ACOD1) and catalyzes the synthesis of itaconate from cis-aconitate in the tricarboxylic acid (TCA) cycle, is among the top 5 metabolic-related genes that are overexpressed in PMN-MDSCs. Moreover, bulk RNA-seq and microarray datasets revealed that intratumoral and splenic PMN-MDSCs express a significantly higher level of Acod1 compared to less immunosuppressive bone marrow PMN-MDSCs. Importantly, high ACOD1 expression is strongly associated with significantly shorter overall survival and higher Gleason scores in human mCRPC. Using an autochthonous whole-body Acod1-KO mouse model, we showed that Acod1 KO in TRAMP mice led to a reduction in tumor burden and an increase in overall survival. Furthermore, using syngeneic prostate cancer models, we showed that whole-body or PMN-specific Acod1-KO delayed tumor progression. As expected, Acod1 KO dramatically reduced the production of itaconate in bone marrow-derived MDSCs (BM-MDSC) as shown by targeted metabolic profiling. Importantly, we found that Acod1 KO impaired immunosuppressive activities of BM-MDSC and an increase in CD3+ and CD8+ T cell infiltration in the tumors. Also, Acod1-KO in BM-MDSC led to a reduction of H2DCFDA staining intensity suggesting a reduction in the production of reactive oxygen species (ROS). Gene set enrichment analysis (GSEA) revealed that Acod1-KO MDSCs have hyperactive oxidative phosphorylation (OXPHOS) compared to Acod1-WT BM-MDSCs. KO of Acod1 also leads to suppression of key MDSC functions signaling such as TNFα/NFκB, IL6/JAK/STAT3, and C/EBPβ pathways. In summary, our data suggests that the upregulation of ACOD1 in PMN-MDSCs has a vital role in prostate cancer progression and resistance to ICT by regulating their immunosuppressive activities through metabolic reprogramming. Also, our data suggest that targeting ACOD1 could be an effective therapeutic strategy for lethal prostate cancer as a monotherapy and in combination with immunotherapy. Citation Format: Celia Sze Ling Mak, Xin Liang, Jessica Suh, Derek Liang, Ming Zhu, Guocan Wang. ACOD1 is a key regulator of immunosuppressive MDSCs, prostate cancer progression, and resistance to immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1803.
Cell type transition occurs during normal development and under pathological conditions. In prostate cancer bone metastasis, prostate cancer-secreted BMP4 induces endothelial-to-osteoblast (EC-to-OSB) transition, leading to aberrant bone formation. Such tumor-induced stromal reprogramming supports prostate cancer progression. Here, we delineate signaling pathways mediating EC-to-OSB transition using endothelial cell lines 2H11 and SVR. We found that for EC-to-OSB transition to occur, inhibition of angiogenesis, through the Smad1-Notch-Hey1 pathway that inhibits EC migration and tube formation, together with activation of osteogenesis, through the p38MAPK(p44/42ERK,AKT)-GSK3β-βcatenin-Slug pathway that stimulates osterix and osteocalcin expression, are required. In addition, Smad1-regulated Dlx2 plays a role in converging the Smad1 and β-catenin pathways during EC-to-OSB transition. Importantly, by just co-expressing the four transcription factors, osterix, Dlx2, Slug and Hey1, we were able to achieve EC-to-OSB transition, leading to bone matrix mineralization even in the absence of BMP4. Thus, the interplay of cell fate determinants and transcription factors mediates BMP4-induced EC-to-OSB transition during stromal reprogramming. In human prostate cancer bone metastasis specimens, immunohistochemical analysis showed that β-catenin and pSmad1 are detected in activated osteoblasts rimming the tumor-induced bone. Similarly, in MDA-PCa-118b and C4-2b-BMP4 osteogenic xenografts, β-catenin and pSmad1 are expressed in EC-OSB hybrid cells that rim the tumor-induced bone. Our results elucidated the pathways and key molecules coordinating prostate cancer-induced stromal programming and provide potential targets for therapeutic intervention.
Chimeric antigen receptor (CAR) therapy has been proved effective in a stream of clinical trials, especially in hematologic malignancies. However, current CAR therapy is highly personalized as cells used are derived from patients themselves, which can be costly, time-consuming, and sometimes fails to achieve optimal therapeutic results due to poor quality/quantity of patient-derived cells. On the contrary, universal CAR therapy, which is based on healthy individuals’ cells, circumvents several limitations of current autologous CAR therapy. To achieve the universality of CAR therapy, the allogeneic cell transplantation related issues, such as graft- versus -host disease (GVHD) and host- versus -graft activities (HVGA), must be addressed. In this review, we focus on current progress regarding GVHD and HVGA in the universal CAR therapy, followed by a universal CAR design that may be applied to allogeneic cells and a summary of key clinical trials in this field. This review may provide valuable insights into the future design of universal CAR products.
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