bims-flamet 2023-08-13 papers

bims-flamet

Biomed News

on Cytokines and immunometabolism in metastasis

Issue of 2023‒08‒13
twenty papers selected by
Peio Azcoaga, Biodonostia HRI

Target delivery of a PD-1-TREM2 scFv by CAR-T cells enhances anti-tumor efficacy in colorectal cancer.
Unveiling the veil of lactate in tumor-associated macrophages: a successful strategy for immunometabolic therapy.
Tumor-associated macrophages: Potential therapeutic targets and diagnostic markers in cancer.
The Bladder Tumor Microenvironment Components That Modulate the Tumor and Impact Therapy.
C-Reactive Protein Signaling Pathways in Tumor Progression.
Targeting reactive oxygen species and fat acid oxidation for the modulation of tumor-associated macrophages: a narrative review.
Unveiling tumor immune evasion mechanisms: abnormal expression of transporters on immune cells in the tumor microenvironment.
Insights into the Tumor-Stromal-Immune Cell Metabolism Crosstalk in Ovarian Cancer.
Blocked Autophagy is Involved in Layered Double Hydroxide-Induced Repolarization and Immune Activation in Tumor-Associated Macrophages.
The Role of Cytokines in Neutrophil Development, Tissue Homing, Function and Plasticity in Health and Disease.
The recent progress of myeloid-derived suppressor cell and its targeted therapies in cancers.
Exosomes as a modulator of immune resistance in human cancers.
From Reductionistic Approach to Systems Immunology Approach for the Understanding of Tumor Microenvironment.
Tumor-resident memory T cells as a biomarker of the response to cancer immunotherapy.
Ginsenoside Rg1 improves anti-tumor efficacy of adoptive cell therapy by enhancing T cell effector functions.
Regulating tumor glycometabolism and the immune microenvironment by inhibiting lactate dehydrogenase with platinum(iv) complexes.
HIF-1α regulates the expression of the non-conventional isoform of the cd5 gene in T cells under the hypoxic condition: A potential mechanism for CD5neg/low phenotype of infiltrating cells in solid tumors.
Coengineering specificity, safety, and function into T cells for cancer immunotherapy.
Liposomal co-delivery of toll-like receptors 3 and 7 agonists induce a hot triple-negative breast cancer immune environment.
Regulation of post-translational modification of PD-L1 and advances in tumor immunotherapy.

Mol Cancer. 2023 Aug 10. 22(1): 131

Target delivery of a PD-1-TREM2 scFv by CAR-T cells enhances anti-tumor efficacy in colorectal cancer.

Jian Chen, Tianchuan Zhu, Guanmin Jiang, Qi Zeng, Zhijian Li, Xi Huang.

  BACKGROUND: Chimeric antigen receptor (CAR) -T cell therapy is an efficient therapeutic strategy for specific hematologic malignancies. However, positive outcomes of this novel therapy in treating solid tumors are curtailed by the immunosuppressive tumor microenvironment (TME), wherein signaling of the checkpoint programmed death-1 (PD-1)/PD-L1 directly inhibits T-cell responses. Although checkpoint-targeted immunotherapy succeeds in increasing the number of T cells produced to control tumor growth, the desired effect is mitigated by the action of myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) in the TME. Previous studies have confirmed that targeting triggering-receptor-expressed on myeloid cells 2 (TREM2) on TAMs and MDSCs enhances the outcomes of anti-PD-1 immunotherapy.METHODS: We constructed carcinoembryonic antigen (CEA)-specific CAR-T cells for colorectal cancer (CRC)-specific antigens with an autocrine PD-1-TREM2 single-chain variable fragment (scFv) to target the PD-1/PD-L1 pathway, MDSCs and TAMs.
RESULTS: We found that the PD-1-TREM2-targeting scFv inhibited the activation of the PD-1/PD-L1 pathway. In addition, these secreted scFvs blocked the binding of ligands to TREM2 receptors present on MDSCs and TAMs, reduced the proportion of MDSCs and TAMs, and enhanced T-cell effector function, thereby mitigating immune resistance in the TME. PD-1-TREM2 scFv-secreting CAR-T cells resulted in highly effective elimination of tumors compared to that achieved with PD-1 scFv-secreting CAR-T therapy in a subcutaneous CRC mouse model. Moreover, the PD-1-TREM2 scFv secreted by CAR-T cells remained localized within tumors and exhibited an extended half-life.
CONCLUSIONS: Together, these results indicate that PD-1-TREM2 scFv-secreting CAR-T cells have strong potential as an effective therapy for CRC.

Keywords:  CAR-T; Colorectal cancer; PD-1; Single-chain variable fragment (scFv); TREM2; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12943-023-01830-x
Front Immunol. 2023 ;14 1208870

Unveiling the veil of lactate in tumor-associated macrophages: a successful strategy for immunometabolic therapy.

Hongxia Tao, Xuansheng Zhong, Anqi Zeng, Linjiang Song.

  Lactate, traditionally regarded as a metabolic waste product at the terminal of the glycolysis process, has recently been found to have multifaceted functional roles in metabolism and beyond. A metabolic reprogramming phenomenon commonly seen in tumor cells, known as the "Warburg effect," sees high levels of aerobic glycolysis result in an excessive production of lactate. This lactate serves as a substrate that sustains not only the survival of cancer cells but also immune cells. However, it also inhibits the function of tumor-associated macrophages (TAMs), a group of innate immune cells ubiquitously present in solid tumors, thereby facilitating the immune evasion of malignant tumor cells. Characterized by their high plasticity, TAMs are generally divided into the pro-inflammatory M1 phenotype and the pro-tumour M2 phenotype. Through a process of 'education' by lactate, TAMs tend to adopt an immunosuppressive phenotype and collaborate with tumor cells to promote angiogenesis. Additionally, there is growing evidence linking metabolic reprogramming with epigenetic modifications, suggesting the participation of histone modification in diverse cellular events within the tumor microenvironment (TME). In this review, we delve into recent discoveries concerning lactate metabolism in tumors, with a particular focus on the impact of lactate on the function of TAMs. We aim to consolidate the molecular mechanisms underlying lactate-induced TAM polarization and angiogenesis and explore the lactate-mediated crosstalk between TAMs and tumor cells. Finally, we also touch upon the latest progress in immunometabolic therapies and drug delivery strategies targeting glycolysis and lactate production, offering new perspectives for future therapeutic approaches.

Keywords:  TAMs; immune escape; immunometabolism; lactate; targeted drug delivery

DOI:  https://doi.org/10.3389/fimmu.2023.1208870
Pathol Res Pract. 2023 Aug 04. pii: S0344-0338(23)00439-9. [Epub ahead of print]249 154739

Tumor-associated macrophages: Potential therapeutic targets and diagnostic markers in cancer.

Junyang Song, Tian Xiao, Mingyang Li, Qingge Jia.

  Macrophages are plastic and functionally diverse, present in all tissues, and play a key role in organisms from development, homeostasis and repair, to immune responses to pathogens. They are central to many disease states and have emerged as important therapeutic targets for many diseases. Tumor-associated macrophages (TAMs) are the most abundant immune cells in the tumor microenvironment (TME) and are key factors influencing cancer progression, metastasis and tumor recurrence. TAMs can be derived from different sources and exert different pro- or anti-tumor effects based on the type, stage and immune composition of the tumor. TAMs are highly heterogeneous and diverse, and have multiple functional phenotypes. There is still a great deal of controversy regarding the relationship between TAMs and prognosis of cancer patients. In this review, we summarize the characteristics of common markers of TAMs as well as explore the prognostic role of TAMs in different cancers including lung, breast, gastric, colorectal, esophageal and ovarian cancers.

Keywords:  Cancer; Maker; Prognosis; Tumor-associated macrophages

DOI:  https://doi.org/10.1016/j.prp.2023.154739
Int J Mol Sci. 2023 Aug 01. pii: 12311. [Epub ahead of print]24(15):

The Bladder Tumor Microenvironment Components That Modulate the Tumor and Impact Therapy.

Mugdha Vijay Patwardhan, Ratha Mahendran.

  The tumor microenvironment (TME) is complex and involves many different cell types that seemingly work together in helping cancer cells evade immune monitoring and survive therapy. The advent of single-cell sequencing has greatly increased our knowledge of the cell types present in the tumor microenvironment and their role in the developing cancer. This, coupled with clinical data showing that cancer development and the response to therapy may be influenced by drugs that indirectly influence the tumor environment, highlights the need to better understand how the cells present in the TME work together. This review looks at the different cell types (cancer cells, cancer stem cells, endothelial cells, pericytes, adipose cells, cancer-associated fibroblasts, and neuronal cells) in the bladder tumor microenvironment. Their impact on immune activation and on shaping the microenvironment are discussed as well as the effects of hypertensive drugs and anesthetics on bladder cancer.

Keywords:  bladder cancer; single cells; tumor microenvironment

DOI:  https://doi.org/10.3390/ijms241512311
Biomol Ther (Seoul). 2023 Aug 11.

C-Reactive Protein Signaling Pathways in Tumor Progression.

Eun-Sook Kim, Sun Young Kim, Aree Moon.

  Many cancers arise from sites of chronic inflammation, which creates an inflammatory microenvironment surrounding the tumor. Inflammatory substances secreted by cells in the inflammatory environment can induce the proliferation and survival of cancer cells, thereby promoting cancer metastasis and angiogenesis. Therefore, it is important to identify the role of inflammatory factors in cancer progression. This review summarizes the signaling pathways and roles of C-reactive protein (CRP) in various cancer types, including breast, liver, renal, and pancreatic cancer, and the tumor microenvironment. Mounting evidence suggests the role of CRP in breast cancer, especially in the triple-negative breast cancer (TNBC) which generally displays worse prognosis. Increased CRP in the inflammatory environment contributes to enhanced invasiveness and tumor formation in TNBC cells. CRP promotes endothelial cell formation and angiogenesis and contributes to the initiation and progression of atherosclerosis. In pancreatic and kidney cancers, CRP contributes to tumor progression. In liver cancer, CRP regulates inflammatory responses and lipid metabolism. CRP modulates the activity of various signaling molecules in macrophages and monocytes present in the tumor microenvironment, contributing to tumor development, the immune response, and inflammation. In the present review, we overviewed the role of CRP signaling pathways and the association between inflammation and cancer in various types of cancer. Identifying the interactions between CRP signaling pathways and other inflammatory mediators in cancer progression is crucial for understanding the complex relationship between inflammation and cancer.

Keywords:  C-reactive protein; Inflammation; Tumor progression

DOI:  https://doi.org/10.4062/biomolther.2023.132
Front Immunol. 2023 ;14 1224443

Targeting reactive oxygen species and fat acid oxidation for the modulation of tumor-associated macrophages: a narrative review.

Yujian Teng, Licheng Xu, Wenjing Li, Pengyan Liu, Linli Tian, Ming Liu.

  Tumor-associated macrophages (TAMs) are significant immunocytes infiltrating the tumor microenvironment(TME). Recent research has shown that TAMs exhibit diversity in terms of their phenotype, function, time, and spatial distribution, which allows for further classification of TAM subtypes. The metabolic efficiency of fatty acid oxidation (FAO) varies among TAM subtypes. FAO is closely linked to the production of reactive oxygen species (ROS), which play a role in processes such as oxidative stress. Current evidence demonstrates that FAO and ROS can influence TAMs' recruitment, polarization, and phagocytosis ability either individually or in combination, thereby impacting tumor progression. But the specific mechanisms associated with these relationships still require further investigation. We will review the current status of research on the relationship between TAMs and tumor development from three aspects: ROS and TAMs, FAO and TAMs, and the interconnectedness of FAO, ROS, and TAMs.

Keywords:  antioxidant systems; fatty acid oxidation; metabolism; polarization; reactive oxygen species; recruitment; tumor microenvironment; tumor-associated macrophages

DOI:  https://doi.org/10.3389/fimmu.2023.1224443
Front Immunol. 2023 ;14 1225948

Unveiling tumor immune evasion mechanisms: abnormal expression of transporters on immune cells in the tumor microenvironment.

Lu Chen, Yuchen Wang, Qingqing Hu, Yuxi Liu, Xuchen Qi, Zhihua Tang, Haihong Hu, Nengming Lin, Su Zeng, Lushan Yu.

  The tumor microenvironment (TME) is a crucial driving factor for tumor progression and it can hinder the body's immune response by altering the metabolic activity of immune cells. Both tumor and immune cells maintain their proliferative characteristics and physiological functions through transporter-mediated regulation of nutrient acquisition and metabolite efflux. Transporters also play an important role in modulating immune responses in the TME. In this review, we outline the metabolic characteristics of the TME and systematically elaborate on the effects of abundant metabolites on immune cell function and transporter expression. We also discuss the mechanism of tumor immune escape due to transporter dysfunction. Finally, we introduce some transporter-targeted antitumor therapeutic strategies, with the aim of providing new insights into the development of antitumor drugs and rational drug usage for clinical cancer therapy.

Keywords:  cancer therapy; metabolites; the tumor microenvironment; transporters; tumor immune evasion

DOI:  https://doi.org/10.3389/fimmu.2023.1225948
Am J Physiol Cell Physiol. 2023 Aug 07.

Insights into the Tumor-Stromal-Immune Cell Metabolism Crosstalk in Ovarian Cancer.

Priscilla W Tang, Leonard G Frisbie, Nadine Hempel, Lan G Coffman.

  The ovarian cancer tumor microenvironment (TME) consists of a constellation of abundant cellular components, extracellular matrix, and soluble factors. Soluble factors such as cytokines, chemokines, structural proteins, extracellular vesicles, and metabolites are critical means of non-contact cellular communication acting as messengers to convey pro- or anti-tumorigenic signals. Vast advancements have been made in our understanding of how cancer cells adapt their metabolism to meet environmental demands and utilize these adaptations to promote survival, metastasis, and therapeutic resistance. The stromal TME contribution to this metabolic rewiring has been relatively underexplored, particularly in ovarian cancer. Thus, metabolic activity alterations in the TME hold promise for further study and potential therapeutic exploitation. In this review, we focus on the cellular components of the TME with emphasis on: 1) metabolic signatures of ovarian cancer; 2) understanding the stromal cell network and their metabolic crosstalk with tumor cells; and 3) how stromal and tumor cell metabolites alter intratumoral immune cell metabolism and function. Together, these elements provide insight into the metabolic influence of the TME and emphasize the importance of understanding how metabolic performance drives cancer progression.

Keywords:  Ovarian cancer; metabolomics; stroma; tumor microenvironment

DOI:  https://doi.org/10.1152/ajpcell.00588.2022
Adv Healthc Mater. 2023 Aug 07. e2301471

Blocked Autophagy is Involved in Layered Double Hydroxide-Induced Repolarization and Immune Activation in Tumor-Associated Macrophages.

Guoxin Jing, Linnan Yang, Hong Wang, Jintong Niu, Huichao Wang, Yi Gao, Youyuan Li, Bangguo Wei, Yechang Qian, Shilong Wang.

  Tumor-associated macrophages (TAMs) are important immune cells in the tumor microenvironment (TME). The polar plasticity of TAMs makes them important targets for improving the immunosuppressive microenvironment of tumors. Our previous study revealed that layered double hydroxides (LDHs) can effectively promote the polarization of TAMs from the anti-inflammatory M2 type to the pro-inflammatory M1 type. However, their mechanisms of action remain unexplored. This study revealed that LDHs composed of different cations exhibit distinct abilities to regulate the polarity of TAMs. Compared to Mg-Fe LDH, Mg-Al LDH has a stronger ability to promote the repolarization of TAMs from M2 to M1 and inhibit the formation of myeloid-derived suppressor cells (MDSCs). In addition, Mg-Al LDH restrains the growth of tumors in vivo and promotes the infiltration of activated immune cells into the TME more effectively. Interestingly, Mg-Al LDH influenced the autophagy of TAMs; this negatively correlated with the pro-inflammatory ability of TAMs. Therefore, LDHs exert their polarization ability by inhibiting the autophagy of TAMs, and this mechanism might be related to the ionic composition of LDHs. This study lays the foundation for optimizing the performance of LDH-based immune adjuvants, which display excellent application prospects for tumor immunotherapy. This article is protected by copyright. All rights reserved.

Keywords:  Tumor-associated macrophages; autophagy; layered double hydroxide; repolarization; tumor immunotherapy

DOI:  https://doi.org/10.1002/adhm.202301471
Cells. 2023 Jul 31. pii: 1981. [Epub ahead of print]12(15):

The Role of Cytokines in Neutrophil Development, Tissue Homing, Function and Plasticity in Health and Disease.

Maria Tsioumpekou, Daniëlle Krijgsman, Jeanette H W Leusen, Patricia A Olofsen.

  Neutrophils are crucial innate immune cells and comprise 50-70% of the white blood cell population under homeostatic conditions. Upon infection and in cancer, blood neutrophil numbers significantly increase because of the secretion of various chemo- and cytokines by, e.g., leukocytes, pericytes, fibroblasts and endothelial cells present in the inflamed tissue or in the tumor microenvironment (TME). The function of neutrophils in cancer has recently gained considerable attention, as they can exert both pro- and anti-tumorigenic functions, dependent on the cytokine milieu present in the TME. Here, we review the effect of cytokines on neutrophil development, tissue homing, function and plasticity in cancer and autoimmune diseases as well as under physiological conditions in the bone marrow, bloodstream and various organs like the spleen, kidney, liver, lung and lymph nodes. In addition, we address several promising therapeutic options, such as cytokine therapy, immunocytokines and immunotherapy, which aim to exploit the anti-tumorigenic potential of neutrophils in cancer treatment or block excessive neutrophil-mediated inflammation in autoimmune diseases.

Keywords:  NETs; TME; autoimmune diseases; cancer; cytokine therapeutics; cytokines; immunocytokines; immunotherapy; neutrophils; tissue-resident neutrophils; tumor microenvironment

DOI:  https://doi.org/10.3390/cells12151981
MedComm (2020). 2023 Aug;4(4): e323

The recent progress of myeloid-derived suppressor cell and its targeted therapies in cancers.

Ruiyang Ren, Chenyi Xiong, Runyu Ma, Yixuan Wang, Tianyang Yue, Jiayun Yu, Bin Shao.

  Myeloid-derived suppressor cells (MDSCs) are an immature group of myeloid-derived cells generated from myeloid cell precursors in the bone marrow. MDSCs appear almost exclusively in pathological conditions, such as tumor progression and various inflammatory diseases. The leading function of MDSCs is their immunosuppressive ability, which plays a crucial role in tumor progression and metastasis through their immunosuppressive effects. Since MDSCs have specific molecular features, and only a tiny amount exists in physiological conditions, MDSC-targeted therapy has become a promising research direction for tumor treatment with minimal side effects. In this review, we briefly introduce the classification, generation and maturation process, and features of MDSCs, and detail their functions under various circumstances. The present review specifically demonstrates the environmental specificity of MDSCs, highlighting the differences between MDSCs from cancer and healthy individuals, as well as tumor-infiltrating MDSCs and circulating MDSCs. Then, we further describe recent advances in MDSC-targeted therapies. The existing and potential targeted drugs are divided into three categories, monoclonal antibodies, small-molecular inhibitors, and peptides. Their targeting mechanisms and characteristics have been summarized respectively. We believe that a comprehensive in-depth understanding of MDSC-targeted therapy could provide more possibilities for the treatment of cancer.

Keywords:  MDSC‐targeted drugs; inflammation; myeloid‐derived suppressor cells; targeted therapy; tumor microenvironment

DOI:  https://doi.org/10.1002/mco2.323
Cytokine Growth Factor Rev. 2023 Aug 02. pii: S1359-6101(23)00038-2. [Epub ahead of print]

Exosomes as a modulator of immune resistance in human cancers.

Lanzhou Li, Chunyue Wang, Qiucheng Li, Yue Guan, Xin Zhang, Fange Kong, Zixin Feng, Yuanjun Lu, Di Wang, Ning Wang.

  In the tumor microenvironment (TME), exosomes secreted by cells form interactive networks between the tumor cells and immune cells, thereby regulating immune signaling cascades in the TME. As key messengers of cell-to-cell communication in the TME, exosomes not only take charge of tumor cell antigen presentation to the immune cells, but also regulate the activities of immune cells, inhibit immune function, and, especially, promote immune resistance, all of which affects the therapeutic outcomes of tumors. Exosomes, which are small-sized vesicles, possess some remarkable advantages, including strong biological activity, a lack of immunogenicity and toxicity, and a strong targeting ability. Based on these characteristics, research on exosomes as biomarkers or carriers of tumor therapeutic drugs has become a research hotspot in related fields. This review describes the role of exosomes in cell communications in the TME, summarizes the effectiveness of exosome-based immunotherapy in overcoming immune resistance in cancer treatment, and systematically summarizes and discusses the characteristics of exosomes from different cell sources. Furthermore, the prospects and challenges of exosome-related therapies are discussed.

Keywords:  Cancer immunotherapy; Exosomes; Immune cells; Immune resistance; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.cytogfr.2023.07.007
Int J Mol Sci. 2023 Jul 28. pii: 12086. [Epub ahead of print]24(15):

From Reductionistic Approach to Systems Immunology Approach for the Understanding of Tumor Microenvironment.

Nicholas Koelsch, Masoud H Manjili.

  The tumor microenvironment (TME) is a complex and dynamic ecosystem that includes a variety of immune cells mutually interacting with tumor cells, structural/stromal cells, and each other. The immune cells in the TME can have dual functions as pro-tumorigenic and anti-tumorigenic. To understand such paradoxical functions, the reductionistic approach classifies the immune cells into pro- and anti-tumor cells and suggests the therapeutic blockade of the pro-tumor and induction of the anti-tumor immune cells. This strategy has proven to be partially effective in prolonging patients' survival only in a fraction of patients without offering a cancer cure. Recent advances in multi-omics allow taking systems immunology approach. This essay discusses how a systems immunology approach could revolutionize our understanding of the TME by suggesting that internetwork interactions of the immune cell types create distinct collective functions independent of the function of each cellular constituent. Such collective function can be understood by the discovery of the immunological patterns in the TME and may be modulated as a therapeutic means for immunotherapy of cancer.

Keywords:  hepatocellular carcinoma; immunological pattern; inflammation; systems immunology

DOI:  https://doi.org/10.3390/ijms241512086
Front Immunol. 2023 ;14 1205984

Tumor-resident memory T cells as a biomarker of the response to cancer immunotherapy.

Isabelle Damei, Tatiana Trickovic, Fathia Mami-Chouaib, Stéphanie Corgnac.

  Tumor-infiltrating lymphocytes (TIL) often include a substantial subset of CD8+ tissue-resident memory T (TRM) cells enriched in tumor-specific T cells. These TRM cells play a major role in antitumor immune response. They are identified on the basis of their expression of the CD103 (αE(CD103)β7) and/or CD49a (α1(CD49a)β1) integrins, and the C-type lectin CD69, which are involved in tissue residency. TRM cells express several T-cell inhibitory receptors on their surface but they nevertheless react strongly to malignant cells, exerting a strong cytotoxic function, particularly in the context of blocking interactions of PD-1 with PD-L1 on target cells. These TRM cells form stable conjugates with autologous tumor cells and interact with dendritic cells and other T cells within the tumor microenvironment to orchestrate an optimal in situ T-cell response. There is growing evidence to indicate that TGF-β is essential for the formation and maintenance of TRM cells in the tumor, through the induction of CD103 expression on activated CD8+ T cells, and for the regulation of TRM effector functions through bidirectional integrin signaling. CD8+ TRM cells were initially described as a prognostic marker for survival in patients with various types of cancer, including ovarian, lung and breast cancers and melanoma. More recently, these tumor-resident CD8+ T cells have been shown to be a potent predictive biomarker of the response of cancer patients to immunotherapies, including therapeutic cancer vaccines and immune checkpoint blockade. In this review, we will highlight the major characteristics of tumor TRM cell populations and the possibilities for their exploitation in the design of more effective immunotherapy strategies for cancer.

Keywords:  CD103 integrin; biomarker; cancer immunotherapy; tumor microenvironment; tumor-resident memory T (TRM) cells

DOI:  https://doi.org/10.3389/fimmu.2023.1205984
Blood Sci. 2023 Jul;5(3): 170-179

Ginsenoside Rg1 improves anti-tumor efficacy of adoptive cell therapy by enhancing T cell effector functions.

Yue Liu, Lingna An, Chengfei Yang, Xiaoqi Wang, Ruihao Huang, Xi Zhang.

  Adoptive cell therapy (ACT) has emerged with remarkable efficacies for tumor immunotherapy. Chimeric antigen receptor (CAR) T cell therapy, as one of most promising ACTs, has achieved prominent effects in treating malignant hematological tumors. However, the insufficient killing activity and limited persistence of T cells in the immunosuppressive tumor microenvironment limit the further application of ACTs for cancer patients. Many studies have focused on improving cytotoxicity and persistence of T cells to achieve improved therapeutic effects. In this study, we explored the potential function in ACT of ginsenoside Rg1, the main pharmacologically active component of ginseng. We introduced Rg1 during the in vitro activation and expansion phase of T cells, and found that Rg1 treatment upregulated two T cell activation markers, CD69 and CD25, while promoting T cell differentiation towards a mature state. Transcriptome sequencing revealed that Rg1 influenced T cell metabolic reprogramming by strengthening mitochondrial biosynthesis. When co-cultured with tumor cells, Rg1-treated T cells showed stronger cytotoxicity than untreated cells. Moreover, adding Rg1 to the culture endowed CAR-T cells with enhanced anti-tumor efficacy. This study suggests that ginsenoside Rg1 provides a potential approach for improving the anti-tumor efficacy of ACT by enhancing T cell effector functions.

Keywords:  Adoptive cell therapy; Anti-tumor efficacy; CAR-T; Ginsenoside Rg1; Metabolic regulation

DOI:  https://doi.org/10.1097/BS9.0000000000000165
Chem Sci. 2023 Aug 09. 14(31): 8327-8337

Regulating tumor glycometabolism and the immune microenvironment by inhibiting lactate dehydrogenase with platinum(iv) complexes.

Suxing Jin, Enmao Yin, Chenyao Feng, Yuewen Sun, Tao Yang, Hao Yuan, Zijian Guo, Xiaoyong Wang.

Lactate dehydrogenase (LDH) is a key enzyme involved in the process of glycolysis, assisting cancer cells to take in glucose and generate lactate, as well as to suppress and evade the immune system by altering the tumor microenvironment (TME). Platinum(iv) complexes MDP and DDP were prepared by modifying cisplatin with diclofenac at the axial position(s). These complexes exhibited potent antiproliferative activity against a panel of human cancer cell lines. In particular, DDP downregulated the expression of LDHA, LDHB, and MCTs to inhibit the production and influx/efflux of lactate in cancer cells, impeding both glycolysis and glucose oxidation. MDP and DDP also reduced the expression of HIF-1α, ARG1 and VEGF, thereby disrupting the formation of tumor vasculature. Furthermore, they promoted the repolarization of macrophages from the tumor-supportive M2 phenotype to the tumor-suppressive M1 phenotype in the TME, thus enhancing the antitumor immune response. The antitumor mechanism involves reprogramming the energy metabolism of tumor cells and relieving the immunosuppressive TME.

DOI: https://doi.org/10.1039/d3sc01874a
Cell Immunol. 2023 Aug 01. pii: S0008-8749(23)00094-1. [Epub ahead of print]391-392 104755

HIF-1α regulates the expression of the non-conventional isoform of the cd5 gene in T cells under the hypoxic condition: A potential mechanism for CD5neg/low phenotype of infiltrating cells in solid tumors.

Smita Kumari, Srishti Sahu, Bharat Singh, Swarnima Gupta, Amit Kumar Kureel, Ankit Srivastava, Deeksha Rikhari, Sameer Srivastava, Ambak Kumar Rai.

  CD5, a T-cell receptor (TCR) negative regulator, is reduced on the surface of CD8+ lymphocytes in the tumor microenvironment (TME). Reduced surface CD5 expression (sCD5) occurs due to the preferential transcription of HERV-E derived exon E1B, i.e., anon-conventional formofthe cd5gene instead of its conventional exon E1A. A tumor employs several mechanisms to evade anti-tumor response, and hypoxia is one such mechanism that prevails in the TME and modulates the infiltrated T lymphocytes. We identified hypoxia response elements (HREs) upstream of E1B. We showed binding of HIF-1α onto these HREs and increased E1B mRNA expression in hypoxic T cells. This results in decreased sCD5 expression and increased cytoplasmic accumulation in T cells. We also validated our study in a solid tumor, i.e., colorectal cancer (CRC) patient samples. This hypoxia-driven mechanism reduces the surface CD5 expression on infiltrated T-cells in solid tumors.

Keywords:  CD5; Human endogenous retrovirus; Hypoxia; T cells; Tumor

DOI:  https://doi.org/10.1016/j.cellimm.2023.104755
Immunol Rev. 2023 Aug 07.

Coengineering specificity, safety, and function into T cells for cancer immunotherapy.

Greta Maria Paola Giordano Attianese, Sarah Ash, Melita Irving.

  Adoptive T-cell transfer (ACT) therapies, including of tumor infiltrating lymphocytes (TILs) and T cells gene-modified to express either a T cell receptor (TCR) or a chimeric antigen receptor (CAR), have demonstrated clinical efficacy for a proportion of patients and cancer-types. The field of ACT has been driven forward by the clinical success of CD19-CAR therapy against various advanced B-cell malignancies, including curative responses for some leukemia patients. However, relapse remains problematic, in particular for lymphoma. Moreover, for a variety of reasons, relative limited efficacy has been demonstrated for ACT of non-hematological solid tumors. Indeed, in addition to pre-infusion challenges including lymphocyte collection and manufacturing, ACT failure can be attributed to several biological processes post-transfer including, (i) inefficient tumor trafficking, infiltration, expansion and retention, (ii) chronic antigen exposure coupled with insufficient costimulation resulting in T-cell exhaustion, (iii) a range of barriers in the tumor microenvironment (TME) mediated by both tumor cells and suppressive immune infiltrate, (iv) tumor antigen heterogeneity and loss, or down-regulation of antigen presentation machinery, (v) gain of tumor intrinsic mechanisms of resistance such as to apoptosis, and (vi) various forms of toxicity and other adverse events in patients. Affinity-optimized TCRs can improve T-cell function and innovative CAR designs as well as gene-modification strategies can be used to coengineer specificity, safety, and function into T cells. Coengineering strategies can be designed not only to directly support the transferred T cells, but also to block suppressive barriers in the TME and harness endogenous innate and adaptive immunity. Here, we review a selection of the remarkable T-cell coengineering strategies, including of tools, receptors, and gene-cargo, that have been developed in recent years to augment tumor control by ACT, more and more of which are advancing to the clinic.

Keywords:  T cell receptor (TCR); T cells; cancer; cell activation; chimeric antigen receptor (CAR); cytotoxic; gene-engineering; immunotherapies; tumor immunity

DOI:  https://doi.org/10.1111/imr.13252
J Control Release. 2023 Aug 07. pii: S0168-3659(23)00502-3. [Epub ahead of print]

Liposomal co-delivery of toll-like receptors 3 and 7 agonists induce a hot triple-negative breast cancer immune environment.

Bao Loc Nguyen, Cao Dai Phung, Duc-Vinh Pham, Ngoc Duy Le, Jee-Heon Jeong, Jeonghwan Kim, Ju-Hyun Kim, Jae-Hoon Chang, Sung Giu Jin, Han-Gon Choi, Sae Kwang Ku, Jong Oh Kim.

  Triple-negative breast cancer (TNBC) is highly aggressive and has no standard treatment. Although being considered as an alternative to conventional treatments for TNBC, immunotherapy has to deal with many challenges that hinder its efficacy, particularly the poor immunogenic condition of the tumor microenvironment (TME). Herein, we designed a liposomal nanoparticle (LN) platform that delivers simultaneously toll-like receptor 7 (imiquimod, IQ) and toll-like receptor 3 (poly(I:C), IC) agonists to take advantage of the different toll-like receptor (TLR) signaling pathways, which enhances the condition of TME from a "cold" to a "hot" immunogenic state. The optimized IQ/IC-loaded LN (IQ/IC-LN) was effectively internalized by cancer cells, macrophages, and dendritic cells, followed by the release of the delivered drugs and subsequent stimulation of the TLR3 and TLR7 signaling pathways. This stimulation encouraged the secretion of type I interferon (IFN-α, IFN-β) and CXCLl0, a T-cell and antigen-presenting cells (APCs) recruitment chemokine, from both cancer cells and macrophages and polarized macrophages to the M1 subtype in in vitro studies. Notably, systemic administration of IQ/IC-LN allowed for the high accumulation of drug content in the tumor, followed by the effective uptake by immune cells in the TME. IQ/IC-LN treatment comprehensively enhanced the immunogenic condition in the TME, which robustly inhibited tumor growth in tumor-bearing mice. Furthermore, synergistic antitumor efficacy was obtained when the IQ/IC-LN-induced immunogenic state in TME was combined with anti-PD1 antibody therapy. Thus, our results suggest the potential of combining 2 TLR agonists to reform the TME from a "cold" to a "hot" state, supporting the therapeutic efficacy of immune checkpoint inhibitors.

Keywords:  Immune checkpoint inhibitors; Immunotherapy; Liposomal formulation; Toll-like receptor agonist; Triple-negative breast cancer

DOI:  https://doi.org/10.1016/j.jconrel.2023.08.006
Front Immunol. 2023 ;14 1230135

Regulation of post-translational modification of PD-L1 and advances in tumor immunotherapy.

Chong Feng, Lening Zhang, Xin Chang, Dongliang Qin, Tao Zhang.

  The immune checkpoint molecules programmed cell death receptor 1 (PD-1) and programmed death ligand 1 (PD-L1) are one of the most promising targets for tumor immunotherapy. PD-L1 is overexpressed on the surface of tumor cells and inhibits T cell activation upon binding to PD⁃1 on the surface of T cells, resulting in tumor immune escape. The therapeutic strategy of targeting PD-1/PD-L1 involves blocking this binding and restoring the tumor-killing effect of immune cells. However, in clinical settings, a relatively low proportion of cancer patients have responded well to PD-1/PD-L1 blockade, and clinical outcomes have reached a bottleneck and no substantial progress has been made. In recent years, PD-L1 post-translation modifications (PTMs) have gradually become a hot topic in the field of PD-L1 research, which will provide new insights to improve the efficacy of current anti-PD-1/PD-L1 therapies. Here, we summarized and discussed multiple PTMs of PD-L1, including glycosylation, ubiquitination, phosphorylation, acetylation and palmitoylation, with a major emphasis on mechanism-based therapeutic strategies (including relevant enzymes and targets that are already in clinical use and that may become drugs in the future). We also summarized the latest research progress of PTMs of PD-L1/PD-1 in regulating immunotherapy. The review provided novel strategies and directions for tumor immunotherapy research based on the PTMs of PD-L1/PD-1.

Keywords:  S-palmitoylation; acetylation; glycosylation; phosphorylation; post-translational modification; programmed death ligand 1; tumor immunotherapy; ubiquitination

DOI:  https://doi.org/10.3389/fimmu.2023.1230135