bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2023–07–23
24 papers selected by
Peio Azcoaga, Biodonostia HRI
  1. Do macrophages follow the beat of circadian rhythm in TIME (Tumor Immune Microenvironment)?
  2. The protective and pathogenic role of Th17 cell plasticity and function in the tumor microenvironment.
  3. MDSCs in breast cancer: an important enabler of tumor progression and an emerging therapeutic target.
  4. Macrophage fusion event as one prerequisite for inorganic nanoparticle-induced antitumor response.
  5. Remodeling the tumor microenvironment to overcome treatment resistance in HPV-negative head and neck cancer.
  6. Relevance of tumor microbiome in cancer incidence, prognosis, and its clinical implications in therapeutics.
  7. Intrinsic and extrinsic factors determining natural killer cell fate: Phenotype and function.
  8. Three-dimensional heterotypic colorectal cancer spheroid models for evaluation of drug response.
  9. Exosomal miRNAs assist in the crosstalk between tumor cells and immune cells and its potential therapeutics.
  10. Cancer Stem Cells and the Tumor Microenvironment in Tumor Drug Resistance.
  11. Immunotherapy: an emerging modality to checkmate brain metastasis.
  12. Anti-tumor effect of Crocus sativus petals polysaccharides by reconstructing tumor microenvironment.
  13. A feed-forward loop based on aerobic glycolysis and TGF-β between tumor-associated macrophages and bladder cancer cells promoted malignant progression and immune escape.
  14. T cells, NK cells, and tumor-associated macrophages in cancer immunotherapy and the current state of the art of drug delivery systems.
  15. How nearby nutrients shape tumor growth.
  16. Fungal mycobiome-mediated immune response: a non-negligible promoter in pancreatic oncogenesis and chemoresistance.
  17. Neutrophil-sourced TNF in cancer: deciphering an intricate orchestrator of immunosuppressive communication in the tumor microenvironment.
  18. Targeted co-delivery of resiquimod and a SIRPα variant by liposomes to activate macrophage immune responses for tumor immunotherapy.
  19. Dual anti-PD-(L)1/TGF-β inhibitors in cancer immunotherapy - Updated.
  20. PGE2-EP2/EP4 signaling elicits mesoCAR T cell immunosuppression in pancreatic cancer.
  21. Targeting YTHDF2/MDSCs to improve radiotherapy.
  22. d-lactate modulates M2 tumor-associated macrophages and remodels immunosuppressive tumor microenvironment for hepatocellular carcinoma.
  23. Tumor-Associated Macrophages Regulating a Polymer Nanoplatform for Synergistic Treatment of Breast Tumors.
  24. Role of IL8 in myeloid malignancies.
  1. F1000Res. 2023 ;12 101
    Do macrophages follow the beat of circadian rhythm in TIME (Tumor Immune Microenvironment)?
    Amelia M Knudsen-Clark, Juliana Cazarin, Brian J Altman.
      Advances in cancer research have made clear the critical role of the immune response in clearing tumors. This breakthrough in scientific understanding was heralded by the success of immune checkpoint blockade (ICB) therapies such as anti-programmed cell death protein 1 (PD-1)/ programmed death-ligand 1 (PD-L1) and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), as well as the success of chimeric antigen receptor (CAR) T cells in treating liquid tumors. Thus, much effort has been made to further understand the role of the immune response in tumor progression, and how we may target it to treat cancer. Macrophages are a component of the tumor immune microenvironment (TIME) that can promote tumor growth both indirectly, by suppressing T cell responses necessary for tumor killing, as well as directly, through deposition of extracellular matrix and promotion of angiogenesis. Thus, understanding regulation of macrophages within the tumor microenvironment (TME) is key to targeting them for immunotherapy. However, circadian rhythms (24-hour cycles) are a fundamental aspect of macrophage biology that have yet to be investigated for their role in macrophage-mediated suppression of the anti-tumor immune response Circadian rhythms regulate macrophage-mediated immune responses through time-of-day-dependent regulation of macrophage function. A better understanding of the circadian biology of macrophages in the context of the TME may allow us to exploit synergy between existing and upcoming treatments and circadian regulation of immunity.
    Keywords:  Circadian; cancer; immunity; tumor immunology
    DOI:  https://doi.org/10.12688/f1000research.129863.1
  2. Front Immunol. 2023 ;14 1192303
    The protective and pathogenic role of Th17 cell plasticity and function in the tumor microenvironment.
    Yuanyuan Pan, Wenjing Yang, Bo Tang, Xiaobo Wang, Qi Zhang, Weiping Li, Li Li.
      At the turn of the century, researchers discovered a unique subtype of T helper cells that secretes IL-17 and defined it as Th17. The latest study found that Th17 cells play both positive and negative definitive roles in the regulation of antitumor immune responses. Although the function of Th17 in the tumor microenvironment remains poorly understood, more and more studies have shown that this paradoxical dual role is closely related to the plasticity of Th17 cells in recent decades. Further understanding of the characteristics of Th17 cells in the tumor microenvironment could yield novel and useful therapeutic approaches to treat cancer. In this review, we further present the high plasticity of Th17 cells and the function of Th17-producing IL-17 in tumor immunity.
    Keywords:  IL-17; Th1; Th17; Treg; cancer; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2023.1192303
  3. Front Immunol. 2023 ;14 1199273
    MDSCs in breast cancer: an important enabler of tumor progression and an emerging therapeutic target.
    Haoyu Liu, Zhicheng Wang, Yuntao Zhou, Yanming Yang.
      Women worldwide are more likely to develop breast cancer (BC) than any other type of cancer. The treatment of BC depends on the subtype and stage of the cancer, such as surgery, radiotherapy, chemotherapy, and immunotherapy. Although significant progress has been made in recent years, advanced or metastatic BC presents a poor prognosis, due to drug resistance and recurrences. During embryonic development, myeloid-derived suppressor cells (MDSCs) develop that suppress the immune system. By inhibiting anti-immune effects and promoting non-immune mechanisms such as tumor cell stemness, epithelial-mesenchymal transformation (EMT) and angiogenesis, MDSCs effectively promote tumor growth and metastasis. In various BC models, peripheral tissues, and tumor microenvironments (TME), MDSCs have been found to amplification. Clinical progression or poor prognosis are strongly associated with increased MDSCs. In this review, we describe the activation, recruitment, and differentiation of MDSCs production in BC, the involvement of MDSCs in BC progression, and the clinical characteristics of MDSCs as a potential BC therapy target.
    Keywords:  breast cancer; immunosuppression; immunotherapy; myeloid-derived suppressor cells; tumor microenvironments
    DOI:  https://doi.org/10.3389/fimmu.2023.1199273
  4. Sci Adv. 2023 Jul 21. 9(29): eadd9871
    Macrophage fusion event as one prerequisite for inorganic nanoparticle-induced antitumor response.
    Siyu Chen, Zhengyi Xing, Mengyu Geng, Rui Zhao, Xiao Yang, Xiangdong Zhu, James M Anderson, Xingdong Zhang.
      While most nanomaterials are designed to assist tumor therapy, some inorganic nanoparticles have been reported to impede cancer development. We assume that the immune response elicited by these foreign nanoparticles might be associated with the remodeling of immune landscape in the tumor microenvironment (TME). We studied representative inorganic nanoparticles widely used in the biomedical field and first demonstrated that needle-shaped hydroxyapatite (n-nHA), granule-shaped hydroxyapatite, and silicon dioxide can effectively impair tumor progression in vivo. Substantial multinucleated giant cells (MNGCs) were formed around these antitumor nanoparticles, while the ratio of monocytes and macrophages was decreased in the TME. We found that high expression of the STXBP6 protein induced by n-nHA-treated macrophages triggers autophagy, which markedly promotes macrophage fusion into MNGCs. In this way, extensive depletion of tumor-associated macrophages in the TME was achieved, which suppressed tumor growth and metastasis. This intrinsic antitumor immunity of inorganic nanoparticles should not be neglected when designing future nanomedicines to treat cancer.
    DOI:  https://doi.org/10.1126/sciadv.add9871
  5. Cancer Drug Resist. 2023 ;6(2): 291-313
    Remodeling the tumor microenvironment to overcome treatment resistance in HPV-negative head and neck cancer.
    Sergi Benavente.
      Despite intensive efforts and refined techniques, overall survival in HPV-negative head and neck cancer remains poor. Robust immune priming is required to elicit a strong and durable antitumor immune response in immunologically cold and excluded tumors like HPV-negative head and neck cancer. This review highlights how the tumor microenvironment could be affected by different immune and stromal cell types, weighs the need to integrate metabolic regulation of the tumor microenvironment into cancer treatment strategies and summarizes the emerging clinical applicability of personalized immunotherapeutic strategies in HPV-negative head and neck cancer.
    Keywords:  HPV-negative; SBRT; Tumor microenvironments; head and neck cancer; immunotherapy; metabolic reprogramming; radiotherapy
    DOI:  https://doi.org/10.20517/cdr.2022.141
  6. Biochim Biophys Acta Rev Cancer. 2023 Jul 18. pii: S0304-419X(23)00105-1. [Epub ahead of print] 188956
    Relevance of tumor microbiome in cancer incidence, prognosis, and its clinical implications in therapeutics.
    Ananya Bahuguna, Shiv Kumar Dubey.
      The microbiota is garnering progressively greater consideration as an essential facet of the tumor microenvironment that regulates tumor proliferation and affects cancer prognosis. Microbial populations that inhabit different body locations are involved in the carcinogenesis and tumor progression of their corresponding malignancies. It has been learned that the microbial populations primarily thriving within tumors are tumor-type specific. Mechanistic studies have revealed that the tumor-associated microbiota contributes to playing a pivotal role in the establishment of the tumor microenvironment, regulation of local immunity, modulation of tumor cell biology, and directly influences the therapeutic efficacy of drug treatment for tumors. This review article incorporates the pertinent studies on recent advancements in tumor microbiome studies, the interplay between the intratumor microbiota and cancer, and, discusses their role and mechanism of action in the emergence and treatment of cancer, and their relationship to clinical characteristics.
    Keywords:  Anti-cancer; Biomarker; Engineered bacteria; Intratumor microbiota; Tumor microbiome
    DOI:  https://doi.org/10.1016/j.bbcan.2023.188956
  7. Biomed Pharmacother. 2023 Jul 13. pii: S0753-3322(23)00927-7. [Epub ahead of print]165 115136
    Intrinsic and extrinsic factors determining natural killer cell fate: Phenotype and function.
    Lingtong Zhi, Xing Wang, Qing Gao, Wenhui He, Chongye Shang, Changjiang Guo, Zhiyuan Niu, Wuling Zhu, Xuan Zhang.
      Natural killer (NK) cells are derived from hematopoietic stem cells. They belong to the innate lymphoid cell family, which is an important part of innate immunity. This family plays a role in the body mainly through the release of perforin, granzyme, and various cytokines and is involved in cytotoxicity and cytokine-mediated immune regulation. NK cells involved in normal immune regulation and the tumor microenvironment (TME) can exhibit completely different states. Here, we discuss the growth, development, and function of NK cells in regard to intrinsic and extrinsic factors. Intrinsic factors are those that influence NK cells to promote cell maturation and exert their effector functions under the control of internal metabolism and self-related genes. Extrinsic factors include the metabolism of the TME and the influence of related proteins on the "fate" of NK cells. This review targets the potential of NK cell metabolism, cellular molecules, regulatory genes, and other mechanisms involved in immune regulation. We further discuss immune-mediated tumor therapy, which is the trend of current research.
    Keywords:  Cell fate; Cell metabolism; Intrinsic and extrinsic factors; NK cells; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.biopha.2023.115136
  8. Front Oncol. 2023 ;13 1148930
    Three-dimensional heterotypic colorectal cancer spheroid models for evaluation of drug response.
    Jia Ning Nicolette Yau, Giulia Adriani.
      Colorectal cancer (CRC) is a leading cause of death worldwide. Improved preclinical tumor models are needed to make treatment screening clinically relevant and address disease mortality. Advancements in 3D cell culture have enabled a greater recapitulation of the architecture and heterogeneity of the tumor microenvironment (TME). This has enhanced their pathophysiological relevance and enabled more accurate predictions of tumor progression and drug response in patients. An increasing number of 3D CRC spheroid models include cell populations such as cancer-associated fibroblasts (CAFs), endothelial cells (ECs), immune cells, and gut bacteria to better mimic the in vivo regulation of signaling pathways. Furthermore, cell heterogeneity within the 3D spheroid models enables the identification of new therapeutic targets to develop alternative treatments and test TME-target therapies. In this mini review, we present the advances in mimicking tumor heterogeneity in 3D CRC spheroid models by incorporating CAFs, ECs, immune cells, and gut bacteria. We introduce how, in these models, the diverse cells influence chemoresistance and tumor progression of the CRC spheroids. We also highlight important parameters evaluated during drug screening in the CRC heterocellular spheroids.
    Keywords:  cancer associated fibroblast (CAF); colorectal cancer; drug screening; endothelial cell; gut microbiota; heterotypic 3D model; spheroid; tumor associated macrophages (TAMs)
    DOI:  https://doi.org/10.3389/fonc.2023.1148930
  9. Life Sci. 2023 Jul 15. pii: S0024-3205(23)00569-6. [Epub ahead of print] 121934
    Exosomal miRNAs assist in the crosstalk between tumor cells and immune cells and its potential therapeutics.
    Xinyue Chen, Yuqiu Li, Miao Li, Yujie Xie, Keqin Wang, Lifang Zhang, Zhuoling Zou, Lixia Xiong.
      Exosomes are small extracellular vesicles that carry active substances (including proteins, lipids, and nucleic acids) and are essential for homeostasis and signal transmission. Recent studies have focused on the function of exosomal miRNAs in tumor progression. Researchers have expanded the use of exosomes and miRNAs as potential therapeutic tools and biomarkers to detect tumor progression. Immune cells, as an important part of the tumor microenvironment (TME), secrete a majority of exosome-derived miRNAs involved in the biological processes of malignancies. However, the underlying mechanisms remain unclear. Currently, there is no literature that systematically summarizes the communication of exosome-derived miRNAs between tumor cells and immune cells. Based on the cell specificity of exosome-derived miRNAs, this review provides the first comprehensive summary of the significant miRNAs from the standpoint of exosome sources, which are tumor cells and immune cells. Furthermore, we elaborated on the potential clinical applications of these miRNAs, attempting to propose existing difficulties and future possibilities in tumor diagnostics and therapy.
    Keywords:  Exosomal miRNAs; Immune cells; Potential therapy; Tumor microenvironment; Tumors
    DOI:  https://doi.org/10.1016/j.lfs.2023.121934
  10. Stem Cell Rev Rep. 2023 Jul 21.
    Cancer Stem Cells and the Tumor Microenvironment in Tumor Drug Resistance.
    Qiuzhi Gao, Yixiang Zhan, Li Sun, Wei Zhu.
      Although there has been some progress in the efficacy of anti-cancer drugs, drug resistance remains challenging. Cancer stem cells (CSCs) are self-renewing and differentiate into cancer tissues with tumor heterogeneity. CSCs are associated with the progression of breast, colon, and lung cancers. Hence, recent studies have focused on the role of CSCs in resistance to anti-cancer drugs. Increasing evidence suggests that CSCs interact with components of the tumor microenvironment (TME), such as vascular and immune cells, as well as various cytokines, and are regulated by multiple signaling pathways, thereby promoting drug resistance in various cancers. Therefore, it is important to clarify the mechanisms underlying the crosstalk between CSCs and the TME for the development of targeted anti-cancer therapies.
    Keywords:  Cancer stem cells; Drug resistance; Targeted therapy; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s12015-023-10593-3
  11. Mol Cancer. 2023 Jul 15. 22(1): 111
    Immunotherapy: an emerging modality to checkmate brain metastasis.
    Aatiya Ahmad, Parvez Khan, Asad Ur Rehman, Surinder Kumar Batra, Mohd Wasim Nasser.
      The diagnosis of brain metastasis (BrM) has historically been a dooming diagnosis that is nothing less than a death sentence, with few treatment options for palliation or prolonging life. Among the few treatment options available, brain radiotherapy (RT) and surgical resection have been the backbone of therapy. Within the past couple of years, immunotherapy (IT), alone and in combination with traditional treatments, has emerged as a reckoning force to combat the spread of BrM and shrink tumor burden. This review compiles recent reports describing the potential role of IT in the treatment of BrM in various cancers. It also examines the impact of the tumor microenvironment of BrM on regulating the spread of cancer and the role IT can play in mitigating that spread. Lastly, this review also focuses on the future of IT and new clinical trials pushing the boundaries of IT in BrM.
    Keywords:  Anticancer immunity; Brain metastases; Immune checkpoint inhibitors; Immunotherapy; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s12943-023-01818-7
  12. Int J Biol Macromol. 2023 Jul 17. pii: S0141-8130(23)02773-3. [Epub ahead of print] 125878
    Anti-tumor effect of Crocus sativus petals polysaccharides by reconstructing tumor microenvironment.
    Jue Tu, Yanfei He, Huifang Zhang, Juanjuan Wang, Zhenhao Li, Hongxiang Sun.
      Two polysaccharides from Crocus sativus petals (PCSPs), PCSPA and PCSPB have been previously reported to possess the immunopotentiation activity and improve innate immunity in mice. In this study, PCSPB was evaluated for the anti-tumor activity and explored its immunological mechanisms based on tumor microenvironment (TME) using S180 sarcoma-bearing mice. Although PCSPB showed the lower toxicity to a series of tumor cells, it significantly and dose-dependently suppressed the growth of S180 sarcomas transplanted in mice. HE staining, immunohistochemical analysis, and TUNEL assay revealed that PCSPB significantly induced tumor cell necrosis, apoptosis, and vessel disruption in sarcoma tissues. Meanwhile, PCSPB markedly decreased the levels of inflammatory factors TGF-β, IFN-γ, IL-10 and TNF-α and down-regulated the mRNA expression levels of TGF-β and TNF-α in tumor tissues. Flow cytometric analysis showed that PCSPB significantly increased the proportion of CD8+ T cells and NK cells, but decreased that of regulatory T cells (Tregs), total myeloid-derived suppressor cells (total MDSCs), and tumor-associated macrophages (TAMs) in sarcoma tissues. Furthermore, immunofluorescence assay demonstrated that PCSPB noteworthily reprogrammed TAMs from a tumorigenic M2 towards an antitumorigenic M1 phenotype in S180 tissues. These findings demonstrated that PCSPB might exert the anti-tumor activity by reconstructing TME and could act as an anti-tumor candidate with low toxicity.
    Keywords:  Anti-tumor; Crocus sativus petal polysaccharides; Tumor microenvironment (TME)
    DOI:  https://doi.org/10.1016/j.ijbiomac.2023.125878
  13. J Cancer Res Clin Oncol. 2023 Jul 18.
    A feed-forward loop based on aerobic glycolysis and TGF-β between tumor-associated macrophages and bladder cancer cells promoted malignant progression and immune escape.
    Chengquan Shen, Jing Liu, Wei Jiao, Xuezhou Zhang, Xinzhao Zhao, Xuecheng Yang, Yonghua Wang.
       PURPOSE: Immunotherapy with programmed cell death 1/ligand 1 (PD-1/PD-L1) checkpoint inhibitors has revolutionized the systemic treatment of solid tumors, including bladder cancer. Previous studies have shown that enhanced glycolysis, tumor-associated macrophage (TAM) infiltration, and TGF-β secretion in the tumor microenvironment (TME) are closely related to PD-1/PD-L1 inhibitor immunotherapy resistance. However, the potential mechanism of their interaction in bladder cancer has not been fully uncovered.
    METHODS: By coculturing bladder cancer cells and TAMs, we studied the relationship and interaction mechanism between tumor cell glycolysis, TAM functional remodeling, TGF-β positive feedback secretion, and PD-L1 mRNA m6A methylation in the bladder cancer microenvironment.
    RESULTS: Bioinformatics analysis and IHC staining found a close correlation between tumor glycolysis, M2 TAM infiltration, and the prognosis of bladder cancer patients. In Vitro experiments demonstrated that bladder cancer cells could re-educate M2 TAMs through lactate and promote TGF-β secretion via the HIF-1α signaling pathway. Reciprocally, in vitro, and in vivo experiments validated that M2 TAMs could promote glycolysis in bladder cancer cells by TGF-β via the Smad2/3 signaling pathways. Furthermore, M2 TAMs could also promote CSCs and EMT of bladder cancer cells. More importantly, we found M2 TAMs enhance PD-L1 mRNA m6A methylation by promoting METLL3 expression in bladder cancer via the TGF-β/Smad2/3 pathway in the TME.
    CONCLUSIONS: Our study highlights a feed-forward loop based on aerobic glycolysis and TGF-β between M2 TAMs and bladder cancer cells, which may be a potential mechanism of malignant progression and immunotherapy resistance in bladder cancer.
    Keywords:  Bladder cancer; Glycolysis; PD-1/PD-L1 inhibitor; TGF-β; Tumor-associated macrophage
    DOI:  https://doi.org/10.1007/s00432-023-05164-5
  14. Front Immunol. 2023 ;14 1199173
    T cells, NK cells, and tumor-associated macrophages in cancer immunotherapy and the current state of the art of drug delivery systems.
    Ya-Long Yang, Fei Yang, Zhuan-Qing Huang, Yuan-Yuan Li, Hao-Yuan Shi, Qi Sun, Yue Ma, Yao Wang, Ying Zhang, Sen Yang, Guan-Ren Zhao, Feng-Hua Xu.
      The immune system provides full protection for the body by specifically identifying 'self' and removing 'others'; thus protecting the body from diseases. The immune system includes innate immunity and adaptive immunity, which jointly coordinate the antitumor immune response. T cells, natural killer (NK) cells and tumor-associated macrophages (TAMs) are the main tumor-killing immune cells active in three antitumor immune cycle. Cancer immunotherapy focusses on activating and strengthening immune response or eliminating suppression from tumor cells in each step of the cancer-immunity cycle; thus, it strengthens the body's immunity against tumors. In this review, the antitumor immune cycles of T cells, natural killer (NK) cells and tumor-associated macrophages (TAMs) are discussed. Co-stimulatory and co-inhibitory molecules in the three activity cycles and the development of drugs and delivery systems targeting these molecules are emphasized, and the current state of the art of drug delivery systems for cancer immunotherapy are summarized.
    Keywords:  NK cells; T cells; TAM; cancer immunotherapy; cancer-immunotherapy cycle; drug delivery systems
    DOI:  https://doi.org/10.3389/fimmu.2023.1199173
  15. Elife. 2023 07 17. pii: e89825. [Epub ahead of print]12
    How nearby nutrients shape tumor growth.
    Nada Kalaany.
      Studying the nutrient composition immediately surrounding pancreatic cancer cells provides new insights into their metabolic properties and how they can evade the immune system to promote disease progression.
    Keywords:  amino acid homeostasis; biochemistry; cancer; cancer biology; chemical biology; human; immunotherapy; metabolism; mouse; nutrient stress; tumor microenvironment
    DOI:  https://doi.org/10.7554/eLife.89825
  16. Cancer Drug Resist. 2023 ;6(2): 284-290
    Fungal mycobiome-mediated immune response: a non-negligible promoter in pancreatic oncogenesis and chemoresistance.
    Yaling Jiang, Valentina Donati, Godefridus J Peters, Elisa Giovannetti, Dong Mei Deng.
      Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers in humans due to late diagnosis and poor response to treatments. The tumor microenvironment (TME) of PDAC is characterized by a distinctive, suppressive immune profile, which inhibits the protective functions of anti-tumor immunity and thereby contributes to PDAC progression. Recently, the study of Alam et al. discovered for the first time that the intratumoral fungal mycobiome could contribute to the recruitment and activation of type 2 immune cells in the TME of PDAC via enhancing the secretion of a chemoattractant, interleukin (IL-) 33. In this article, we reviewed the important findings of this study. Together with our findings, we synthetically discussed the role of the fungal mycobiome in orchestrating the immune response and thereby modulating tumor progression.
    Keywords:  Mycobiome; chemoresistance; interleukin 33; pancreatic cancer; type 2 immune cells
    DOI:  https://doi.org/10.20517/cdr.2023.06
  17. Signal Transduct Target Ther. 2023 07 17. 8(1): 272
    Neutrophil-sourced TNF in cancer: deciphering an intricate orchestrator of immunosuppressive communication in the tumor microenvironment.
    Xinyuan Zhao, Ye Lu, Li Cui.
      
    DOI:  https://doi.org/10.1038/s41392-023-01530-4
  18. J Control Release. 2023 Jul 18. pii: S0168-3659(23)00454-6. [Epub ahead of print]
    Targeted co-delivery of resiquimod and a SIRPα variant by liposomes to activate macrophage immune responses for tumor immunotherapy.
    Dianlong Jia, Yue Lu, Mingjia Lv, Feifei Wang, Xiaomeng Lu, Weifan Zhu, Jianmei Wei, Wen Guo, Renmin Liu, Guangrong Li, Rui Wang, Jun Li, Fengjiao Yuan.
      Tumor-associated macrophages (TAMs) are the major immune cells infiltrating the tumor microenvironment (TME) and typically exhibit an immunosuppressive M2-like phenotype, which facilitates tumor growth and promotes resistance to immunotherapy. Additionally, tumor cells tend to express high levels of CD47, a "don't eat me" signal, that obstructs macrophage phagocytosis. Consequently, re-educating TAMs in combination with CD47 blockage is promising to trigger intense macrophage immune responses against tumors. As a toll-like receptor 7/8 agonist, resiquimod (R848) possesses the capacity to re-educate TAMs from M2 type to M1 type. We found that intratumoral administration of R848 synergistically improved the antitumor immunotherapeutic effect of CV1 protein (a SIRPα variant with high antagonism to CD47). However, the poor bioavailability and potential toxicity of this combo strategy remain a challenge. Here, a TAMs-targeted liposome (named: R-LS/M/CV1) co-delivering R848 and CV1 protein was constructed via decorating mannose on the liposomal surface. R-LS/M/CV1 exhibited high abilities of targeting, re-education and pro-phagocytosis of tumor cells to M2 macrophages in vitro. Intratumoral administration of R-LS/M/CV1 remarkedly eliminated tumor burden in the MC38 tumor model via repolarization of TAMs to M1 type, pro-phagocytosis of TAMs against tumors, and recruitment of tumor-infiltrating T cells. More encouragingly, due to the double targeting to TAMs and tumor cells of mannose and CV1 protein, R-LS/M/CV1 effectively accumulated at the tumor site, thereby not only remarkedly inhibiting tumors, but also exerting no hematological and histopathological toxicity when administered systemically. Our integrated strategy based on re-educating TAMs and CD47 blockade provides a promising approach to trigger macrophage immune responses against tumors for immunotherapy.
    Keywords:  CD47; Liposome; Resiquimod; SIRPα; Tumor immunotherapy; Tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.jconrel.2023.07.030
  19. Int Immunopharmacol. 2023 Jul 15. pii: S1567-5769(23)00973-6. [Epub ahead of print]122 110648
    Dual anti-PD-(L)1/TGF-β inhibitors in cancer immunotherapy - Updated.
    Zana Karami, Keywan Mortezaee, Jamal Majidpoor.
      Immune checkpoint inhibitor (ICI) therapy suffers from tumor resistance and relapse in majority of patients due to the suppressive tumor immune microenvironment (TIME). Advances in the field have brought about development of fusion proteins able to target two signaling simultaneously and to exert maximal anti-cancer immunity. Bispecific inhibitors of transforming growth factor (TGF)-β signaling and programmed death-1 (PD-1) or programmed death-ligand 1 (PD-L1) are developed to reduce the rate of relapse and to achieve durable anti-cancer therapy. TGF-β is well-known for its immunosuppressive activity, and it takes critical roles in promotion of all tumor hallmarks. Bispecific anti-PD-(L)1/TGF-β inhibitors reinvigorate effector activity of CD8+ T and natural killer (NK) cells, hamper regulatory T cell (Treg) expansion, and increase the density of anti-tumor type 1 macrophages (M1). Responses to the bispecific approach are higher compared with solo anti-PD-(L)1 or TGF-β targeted therapy, and are seemingly more pronounced in human papillomavirus (HPV)+ patients. High expression of PD-L1 or immune-excluded phenotype in a tumor can also be markers of better response to the bispecific strategy. Besides, anti-PD-(L)1/TGF-β inhibitor therapy can be used safely with other therapeutic modalities including vaccination, radiation and chemotherapy.
    Keywords:  Immune checkpoint inhibitor (ICI); Programmed death-1 (PD-1); Programmed death-ligand 1 (PD-L1); Resistance; Transforming growth factor (TGF); Tumor immune microenvironment (TIME)
    DOI:  https://doi.org/10.1016/j.intimp.2023.110648
  20. Front Immunol. 2023 ;14 1209572
    PGE2-EP2/EP4 signaling elicits mesoCAR T cell immunosuppression in pancreatic cancer.
    Behnia Akbari, Tahereh Soltantoyeh, Zahra Shahosseini, Farhad Jadidi-Niaragh, Jamshid Hadjati, Christine E Brown, Hamid Reza Mirzaei.
       Introduction: For many years, surgery, adjuvant and combination chemotherapy have been the cornerstone of pancreatic cancer treatment. Although these approaches have improved patient survival, relapse remains a common occurrence, necessitating the exploration of novel therapeutic strategies. CAR T cell therapies are now showing tremendous success in hematological cancers. However, the clinical efficacy of CAR T cells in solid tumors remained low, notably due to presence of an immunosuppressive tumor microenvironment (TME). Prostaglandin E2, a bioactive lipid metabolite found within the TME, plays a significant role in promoting cancer progression by increasing tumor proliferation, improving angiogenesis, and impairing immune cell's function. Despite the well-established impact of PGE2 signaling on cancer, its specific effects on CAR T cell therapy remain under investigation.
    Methods: To address this gap in knowledge the role of PGE2-related genes in cancer tissue and T cells of pancreatic cancer patients were evaluated in-silico. Through our in vitro study, we manufactured fully human functional mesoCAR T cells specific for pancreatic cancer and investigated the influence of PGE2-EP2/EP4 signaling on proliferation, cytotoxicity, and cytokine production of mesoCAR T cells against pancreatic cancer cells.
    Results: In-silico investigations uncovered a significant negative correlation between PGE2 expression and gene signature of memory T cells. Furthermore, in vitro experiments demonstrated that the activation of PGE2 signaling through EP2 and EP4 receptors suppressed the proliferation and major antitumor functions of mesoCAR T cells. Interestingly, the dual blockade of EP2 and EP4 receptors effectively reversed PGE2-mediated suppression of mesoCAR T cells, while individual receptor antagonists failed to mitigate the PGE2-induced suppression.
    Discussion: In summary, our findings suggest that mitigating PGE2-EP2/EP4 signaling may be a viable strategy for enhancing CAR T cell activity within the challenging TME, thereby improving the efficacy of CAR T cell therapy in clinical settings.
    Keywords:  EP2; EP4; mesoCAR T cell; pancreatic cancer; pharmacological targeting; prostaglandin E2
    DOI:  https://doi.org/10.3389/fimmu.2023.1209572
  21. Cell Chem Biol. 2023 Jul 20. pii: S2451-9456(23)00202-7. [Epub ahead of print]30(7): 703-705
    Targeting YTHDF2/MDSCs to improve radiotherapy.
    Xiaolan Deng, Ying Qing, Jianjun Chen.
      Immunosuppression contributes to tumor-radiotherapy failure, but the mechanism remains elusive. Wang et al.1 reported that ionizing radiation (IR) induces YTHDF2 expression in myeloid-derived suppressor cells (MDSCs) via an IR-YTHDF2-NF-κB circuit, which contributes to MDSC expansion/migration and treatment failure. Genetic depletion or pharmacological inhibition of YTHDF2 overcomes immunosuppression and improves radiotherapy.
    DOI:  https://doi.org/10.1016/j.chembiol.2023.06.024
  22. Sci Adv. 2023 Jul 21. 9(29): eadg2697
    d-lactate modulates M2 tumor-associated macrophages and remodels immunosuppressive tumor microenvironment for hepatocellular carcinoma.
    Shulan Han, Xueying Bao, Yifang Zou, Lingzhi Wang, Yutong Li, Leilei Yang, Anqi Liao, Xuemei Zhang, Xin Jiang, Di Liang, Yun Dai, Qing-Chuan Zheng, Zhuo Yu, Jianfeng Guo.
      The polarization of tumor-associated macrophages (TAMs) from M2 to M1 phenotype demonstrates great potential for remodeling the immunosuppressive tumor microenvironment (TME) of hepatocellular carcinoma (HCC). d-lactate (DL; a gut microbiome metabolite) acts as an endogenous immunomodulatory agent that enhances Kupffer cells for clearance of pathogens. In this study, the potential of DL for transformation of M2 TAMs to M1 was confirmed, and the mechanisms underlying such polarization were mainly due to the modulation of phosphatidylinositol 3-kinase/protein kinase B pathway. A poly(lactide-co-glycolide) nanoparticle (NP) was used to load DL, and the DL-loaded NP was modified with HCC membrane and M2 macrophage-binding peptide (M2pep), forming a nanoformulation (DL@NP-M-M2pep). DL@NP-M-M2pep transformed M2 TAMs to M1 and remodeled the immunosuppressive TME in HCC mice, promoting the efficacy of anti-CD47 antibody for long-term animal survival. These findings reveal a potential TAM modulatory function of DL and provide a combinatorial strategy for HCC immunotherapy.
    DOI:  https://doi.org/10.1126/sciadv.adg2697
  23. ACS Appl Mater Interfaces. 2023 Jul 18.
    Tumor-Associated Macrophages Regulating a Polymer Nanoplatform for Synergistic Treatment of Breast Tumors.
    Li Zhang, Shuai Cui, Ning Ding, Jing Zhang, Enna Cui, Qian Xiang, Zhenghao Zhou, Bo Sun, Yinan Wang, Hao Hong, Yunsu Ma, Dongzhi Yang.
      Tumor-associated macrophages (TAMs) play a critical role in tumor progression and metastasis. Modulation of TAM polarization is one of the most effective strategies to change the immunosuppressive tumor microenvironment (TME). In this study, organic polymer nanoparticles (CPHT) were prepared using hyaluronic acid (HA)-conjugated disulfide-bonded polyethylene imide (PEIS) as a carrier through a self-assembly strategy. These nanoparticles were modified by transferrin (Tf) and loaded with chlorin e6 (Ce6). The results showed that CPHT had good dispersion with a particle size of about 30 nm. CPHT gradually disintegrated under the exposure with a high concentration of glutathione (GSH) in tumor cells, proving the possibility for the controlled release of Ce6 and photodynamic therapy. An in vitro test showed that the uptake of CPHT in tumor cells was mediated by both HA and Tf, indicating the active tumor-targeting capacity of CPHT. CPHT significantly downregulated the ratio of CD206/CD86 and triggered the upregulation of immune factors such as TNF-α and iNOS, suggesting the repolarization of TAMs. We also found that CPHT effectively induced ferroptosis in tumor cells through lipid peroxide accumulation, GSH depletion, and downregulation of lipid peroxidase (GPX4) expression. Animal experiments confirmed that CPHT not only effectively inhibited the growth of tumors in situ but also significantly decelerated the growth of the distal tumor. Elevated levels of CD86 and IFN-γ and decreased expression of CD206 were observed at the tumor sites post CPHT treatment. These results confirmed the value of CPHT as a multifunctional nanoplatform that can tune the TME and provide new hope for tumor treatment.
    Keywords:  ferroptosis; photodynamic therapy; polymer nanoplatform; synergistic treatment; tumor-associated macrophages
    DOI:  https://doi.org/10.1021/acsami.3c05497
  24. Leuk Lymphoma. 2023 Jul 19. 1-10
    Role of IL8 in myeloid malignancies.
    Nandini Ramachandra, Malini Gupta, Leya Schwartz, Tihomira Todorova, Aditi Shastri, Britta Will, Ulrich Steidl, Amit Verma.
      Aberrant overexpression of Interleukin-8 (IL8) has been reported in Myelodysplastic Syndromes (MDS), Acute Myeloid Leukemia (AML), Myeloproliferative Neoplasms (MPNs) and other myeloid malignancies. IL8 (CXCL8) is a CXC chemokine that is secreted by aberrant hematopoietic stem and progenitors as well as other cells in the tumor microenvironment. IL8 can bind to CXCR1/CXCR2 receptors and activate oncogenic signaling pathways, and also increase the recruitment of myeloid derived suppressor cells to the tumor microenvironment. IL8/CXCR1/2 overexpression has been associated with poorer prognosis in MDS and AML and increased bone marrow fibrosis in Myelofibrosis. Preclinical studies have demonstrated benefit of inhibiting the IL8/CXCR1/2 pathways via restricting the growth of leukemic stem cells as well as normalizing the immunosuppressive microenvironment in tumors. Targeting the IL8-CXCR1/2 pathway is a potential therapeutic strategy in myeloid neoplasms and is being evaluated with small molecule inhibitors as well as monoclonal antibodies in ongoing clinical trials. We review the role of IL8 signaling pathway in myeloid cancers and discuss future directions on therapeutic targeting of IL8 in these diseases.
    Keywords:  AML; IL8 inhibition; Leukemic stem cells; MDS; MPN
    DOI:  https://doi.org/10.1080/10428194.2023.2232492
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