Abstract 1803: ACOD1 is a key regulator of immunosuppressive MDSCs, prostate cancer progression, and resistance to immunotherapy
0
Citation
0
Reference
10
Related Paper
Abstract:
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.Keywords:
Tramp
Immune checkpoint
Cancer Immunotherapy
Immunotherapy has recently become a promising strategy for the treatment of a wide range of cancers. However, the broad implementation of cancer immunotherapy suffers from inadequate efficacy and toxic side effects. Integrating pH-responsive nanoparticles into immunotherapy is a powerful approach to tackle these challenges because they are able to target the tumor tissues and organelles of antigen-presenting cells (APCs) which have a characteristic acidic microenvironment. The spatiotemporal control of immunotherapeutic drugs using pH-responsive nanoparticles endows cancer immunotherapy with enhanced antitumor immunity and reduced off-tumor immunity. In this review, we first discuss the cancer-immunity circle and how nanoparticles can modulate the key steps in this circle. Then, we highlight the recent advances in cancer immunotherapy with pH-responsive nanoparticles and discuss the perspective for this emerging area.
Cancer Immunotherapy
Cancer Therapy
Cancer Treatment
Cite
Citations (69)
Immunotherapy aiming at suppressing tumor development by relying on modifying or strengthening the immune system prevails among cancer treatments and points out a new direction for cancer therapy. B7 homolog 3 protein (B7-H3, also known as CD276), a newly identified immunoregulatory protein member of the B7 family, is an attractive and promising target for cancer immunotherapy because it is overexpressed in tumor tissues while showing limited expression in normal tissues and participating in tumor microenvironment (TME) shaping and development. Thus far, numerous B7-H3-based immunotherapy strategies have demonstrated potent antitumor activity and acceptable safety profiles in preclinical models. Herein, we present the expression and biological function of B7-H3 in distinct cancer and normal cells, as well as B7-H3-mediated signal pathways in cancer cells and B7-H3-based tumor immunotherapy strategies. This review provides a comprehensive overview that encompasses B7-H3’s role in TME to its potential as a target in cancer immunotherapy.
Cancer Immunotherapy
Cite
Citations (188)
Abstract Cancer immunotherapy has rapidly transformed cancer treatment, yet resistance remains a significant hurdle, limiting its efficacy in many patients. Circular RNAs (circRNAs), a novel class of non-coding RNAs, have emerged as pivotal regulators of gene expression and cellular processes. Increasing evidence indicates their involvement in modulating resistance to cancer immunotherapy. Notably, certain circRNAs function as miRNA sponges or interact with proteins, influencing the expression of immune-related genes, including crucial immune checkpoint molecules. This, in turn, shapes the tumor microenvironment and significantly impacts the response to immunotherapy. In this comprehensive review, we explore the evolving role of circRNAs in orchestrating resistance to cancer immunotherapy, with a specific focus on their mechanisms in influencing immune checkpoint gene expression. Additionally, we underscore the potential of circRNAs as promising therapeutic targets to augment the effectiveness of cancer immunotherapy. Understanding the role of circRNAs in cancer immunotherapy resistance could contribute to the development of new therapeutic strategies to overcome resistance and improve patient outcomes.
Cancer Immunotherapy
Limiting
Immune checkpoint
Cite
Citations (11)
Abstract Background Recently, cancer immunotherapy has become standard for cancer treatment. Immunotherapy not only treats primary tumors, but also prevents metastasis and recurrence, representing a major advantage over conventional cancer treatments. However, existing cancer immunotherapies have limited clinical benefits because cancer antigens are often not effectively delivered to immune cells. Furthermore, unlike lymphoma, solid tumors evade anti-cancer immunity by forming an immune-suppressive tumor microenvironment (TME). One approach for overcoming these limitations of cancer immunotherapy involves nanoparticles based on biomaterials. Main body Here, we review in detail recent trends in the use of nanoparticles in cancer immunotherapy. First, to illustrate the unmet needs for nanoparticles in this field, we describe the mechanisms underlying cancer immunotherapy. We then explain the role of nanoparticles in the delivery of cancer antigens and adjuvants. Next, we discuss how nanoparticles can be helpful within the immune-suppressive TME. Finally, we summarize current and future uses of nanoparticles with image-guided interventional techniques in cancer immunotherapy. Conclusion Recently developed approaches for using nanoparticles in cancer immunotherapy have enormous potential for improving cancer treatment. Cancer immunotherapy based on nanoparticles is anticipated not only to overcome the limitations of existing immunotherapy, but also to generate synergistic effects via cooperation between nanoparticles and immune cells.
Cancer Immunotherapy
Cite
Citations (180)
Recently, the nanotechnology-based bacterial immunotherapy emerged as a new combinatory therapeutic approach for the effective treatment of cancer, which combines the bacterial immunotherapy with nanotechnology for treating cancer. Although both bacterial immunotherapy and nanotechnology are very effective and advantageous solely, single treatment system is insufficient for complete eradication of cancer. Combining nanotechnology with bacterial immunotherapy opens new avenues for treating various diseases, abates the complication of bacterial immunotherapy, and overcomes the deficiency of both systems. Nanotechnology is helpful in targeting deep into the cancer cell due to its small size, enhanced permeability and retention (EPR) effect, and immunomodulatory activity. It also plays an important role in thermal and radio immunotherapy and cancer diagnostic. In this chapter, we highlighted the role of immunity in cancer and the role of bacteria in cancerogenesis, how bacterial immunotherapy is used in combating cancer, and how nanotechnology-based bacterial immunotherapy works on cancer regression.
Cancer Immunotherapy
Cancer Therapy
Cancer Treatment
Cite
Citations (1)
In the last few decades, cancer immunotherapy becomes an important tactic for cancer treatment. However, some immunotherapy shows certain limitations including poor therapeutic targeting and unwanted side effects that hinder its use in clinics. Recently, several researchers are exploring an alternative methodology to overcome the above limitations. One of the emerging tracks in this field area is nano-immunotherapy which has gone through rapid progress and revealed considerable potentials to solve limitations related to immunotherapy. Targeted and stimuli-sensitive biocompatible nanoparticles (NPs) can be synthesized to deliver immunotherapeutic agents in their native conformations to the site of interest to enhance their antitumor activity and to enhance the survival rate of cancer patients. In this review, we have discussed cancer immunotherapy and the application of NPs in cancer immunotherapy, as a carrier of immunotherapeutic agents and as a direct immunomodulator.
Cancer Immunotherapy
Cite
Citations (55)
Cancer Immunotherapy
Cancer Treatment
Cancer Therapy
Cite
Citations (18)
Cancer is a major cause of incidence rate and mortality worldwide. In recent years, cancer immunotherapy has made great progress in the preclinical and clinical treatment of advanced malignant tumors. However, cancer patients will have transient cancer suppression reaction and serious immune related adverse reactions when receiving immunotherapy. In recent years, nanoparticle-based immunotherapy, which can accurately deliver immunogens, activate antigen presenting cells (APCs) and effector cells, provides a new insight to solve the above problems. In this review, we discuss the research progress of nanomaterials in immunotherapy including nanoparticle-based delivery systems, nanoparticle-based photothermal and photodynamic immunotherapy, nanovaccines, nanoparticle-based T cell cancer immunotherapy and nanoparticle-based bacteria cancer immunotherapy. We also put forward the current challenges and prospects of immunomodulatory therapy.
Cancer Immunotherapy
Cite
Citations (13)
Cancer is a serious hazard to human health all around the world; however, many current therapies remain toxic and poor. In view of the understanding of immunology and tumor biology, cancer immunotherapy with minimal toxicity has been regarded as a promising strategy for cancer treatment because of immune surveillance. Unfortunately, the efficacy of immunotherapy was impeded and resisted due to the tumor immune evasion mechanism. Hence, targeted cancer immunotherapy has been proposed to tackle the tumor immune suppression and complexity of malignant tumor cells. Nanotechnology-based immunotherapy has improved the limitations and enhanced the therapeutic efficiency of traditional immunotherapy. This review illustrates the recent progresses in immunotherapy based on nanotechnology, and reveals that nanodevices could be utilized for active and passive cancer immunotherapy. Keywords: Cancer, immunotherapy, tumor immune surveillance, escape mechanism, nanotechnology, drug delivery.
Cancer Immunotherapy
Cancer Treatment
Cite
Citations (4)
Cancer Immunotherapy
Cancer Treatment
Cancer Therapy
Cite
Citations (38)