bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2024–09–22
eightteen papers selected by
Peio Azcoaga, Biodonostia HRI
  1. Metabolic ripple effects - deciphering how lipid metabolism in cancer interfaces with the tumor microenvironment.
  2. Tumor-associated macrophages: orchestrators of cholangiocarcinoma progression.
  3. Rewiring the T cell-suppressive cytokine landscape of the tumor microenvironment: a new frontier for precision anti-cancer therapy.
  4. Innate immune cells in tumor microenvironment: A new frontier in cancer immunotherapy.
  5. Unveiling the contribution of tumor-associated macrophages in driving epithelial-mesenchymal transition: a review of mechanisms and therapeutic Strategies.
  6. Eliminating a barrier: Aiming at VISTA, reversing MDSC-mediated T cell suppression in the tumor microenvironment.
  7. Expression, regulation, and function of PD-L1 on non-tumor cells in the tumor microenvironment.
  8. Genomic map of the cellular composition of the tumor microenvironment.
  9. Tumor-associated macrophages within the immunological milieu: An emerging focal point for therapeutic intervention.
  10. Microenvironmental regulation of tumor-associated neutrophils in malignant glioma: from mechanism to therapy.
  11. Tumor-derived Exosomes and Antitumor Immunity.
  12. Inhibition of JNK Signaling Overcomes Cancer-Associated Fibroblast-Mediated Immunosuppression and Enhances the Efficacy of Immunotherapy in Bladder Cancer.
  13. Breast cancer cell derived exosomes reduces glycolysis of activated CD8 + T cells in a AKT-mTOR dependent manner.
  14. Unleashing nanotechnology to redefine tumor-associated macrophage dynamics and non-coding RNA crosstalk in breast cancer.
  15. Unconventional p65/p52 NF-κB module regulates key tumor microenvironment-related genes in breast tumor-associated macrophages (TAMs).
  16. Immunomodulation by endothelial cells: prospects for cancer therapy.
  17. Activation of T Lymphocytes with Anti-PDL1-BiTE in the Presence of Adipose-Derived Mesenchymal Stem Cells (ASCs).
  18. ReCARving the future: bridging CAR T-cell therapy gaps with synthetic biology, engineering, and economic insights.
  1. Dis Model Mech. 2024 Sep 01. pii: dmm050814. [Epub ahead of print]17(9):
    Metabolic ripple effects - deciphering how lipid metabolism in cancer interfaces with the tumor microenvironment.
    Patrick B Jonker, Alexander Muir.
      Cancer cells require a constant supply of lipids. Lipids are a diverse class of hydrophobic molecules that are essential for cellular homeostasis, growth and survival, and energy production. How tumors acquire lipids is under intensive investigation, as these mechanisms could provide attractive therapeutic targets for cancer. Cellular lipid metabolism is tightly regulated and responsive to environmental stimuli. Thus, lipid metabolism in cancer is heavily influenced by the tumor microenvironment. In this Review, we outline the mechanisms by which the tumor microenvironment determines the metabolic pathways used by tumors to acquire lipids. We also discuss emerging literature that reveals that lipid availability in the tumor microenvironment influences many metabolic pathways in cancers, including those not traditionally associated with lipid biology. Thus, metabolic changes instigated by the tumor microenvironment have 'ripple' effects throughout the densely interconnected metabolic network of cancer cells. Given the interconnectedness of tumor metabolism, we also discuss new tools and approaches to identify the lipid metabolic requirements of cancer cells in the tumor microenvironment and characterize how these requirements influence other aspects of tumor metabolism.
    Keywords:  Acidosis; Diet; Hypoxia; Lipid metabolism; Nutrient deprivation; Tumor microenvironment
    DOI:  https://doi.org/10.1242/dmm.050814
  2. Front Immunol. 2024 ;15 1451474
    Tumor-associated macrophages: orchestrators of cholangiocarcinoma progression.
    Fei Chen, Jian Sheng, Xiaoping Li, Zhaofeng Gao, Lingyu Hu, Minjie Chen, Jianguo Fei, Zhengwei Song.
      Cholangiocarcinoma (CCA) is a rare but highly invasive cancer, with its incidence rising in recent years. Currently, surgery remains the most definitive therapeutic option for CCA. However, similar to other malignancies, most CCA patients are not eligible for surgical intervention at the time of diagnosis. The chemotherapeutic regimen of gemcitabine combined with cisplatin is the standard treatment for advanced CCA, but its effectiveness is often hampered by therapeutic resistance. Recent research highlights the remarkable plasticity of tumor-associated macrophages (TAMs) within the tumor microenvironment (TME). TAMs play a crucial dual role in either promoting or suppressing tumor development, depending on the factors that polarize them toward pro-tumorigenic or anti-tumorigenic phenotypes, as well as their interactions with cancer cells and other stromal components. In this review, we critically examine recent studies on TAMs in CCA, detailing the expression patterns and prognostic significance of different TAM subtypes in CCA, the mechanisms by which TAMs influence CCA progression and immune evasion, and the potential for reprogramming TAMs to enhance anticancer therapies. This review aims to provide a framework for deeper future research.
    Keywords:  CCA; TAMs; immune evasion; macrophage reprogramming; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2024.1451474
  3. Front Immunol. 2024 ;15 1418527
    Rewiring the T cell-suppressive cytokine landscape of the tumor microenvironment: a new frontier for precision anti-cancer therapy.
    Ludovica Lopresti, Vanessa Tatangelo, Cosima T Baldari, Laura Patrussi.
      T lymphocytes that infiltrate the tumor microenvironment (TME) often fail to function as effective anti-cancer agents. Within the TME, cell-to-cell inhibitory interactions play significant roles in dampening their anti-tumor activities. Recent studies have revealed that soluble factors released in the TME by immune and non-immune cells, as well as by tumor cells themselves, contribute to the exacerbation of T cell exhaustion. Our understanding of the cytokine landscape of the TME, their interrelationships, and their impact on cancer development is still at its early stages. In this review, we aim to shed light on Interleukin (IL) -6, IL-9, and IL-10, a small group of JAK/STAT signaling-dependent cytokines harboring T cell-suppressive effects in the TME and summarize their mechanisms of action. Additionally, we will explore how advancements in scientific research can help us overcoming the obstacles posed by cytokines that suppress T cells in tumors, with the ultimate objective of stimulating further investigations for the development of novel therapeutic strategies to counteract their tumor-promoting activities.
    Keywords:  T cell suppression; TIL; cytokine; cytotoxic T lymphocyte; immune checkpoint; interleukin; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2024.1418527
  4. iScience. 2024 Sep 20. 27(9): 110750
    Innate immune cells in tumor microenvironment: A new frontier in cancer immunotherapy.
    Changhui Li, Xinyu Yu, Xinyan Han, Chen Lian, Zijin Wang, Shiqun Shao, Fangwei Shao, Hua Wang, Shenglin Ma, Jian Liu.
      Innate immune cells, crucial in resisting infections and initiating adaptive immunity, play diverse and significant roles in tumor development. These cells, including macrophages, granulocytes, dendritic cells (DCs), innate lymphoid cells, and innate-like T cells, are pivotal in the tumor microenvironment (TME). Innate immune cells are crucial components of the TME, based on which various immunotherapy strategies have been explored. Immunotherapy strategies, such as novel immune checkpoint inhibitors, STING/CD40 agonists, macrophage-based surface backpack anchoring, ex vivo polarization approaches, DC-based tumor vaccines, and CAR-engineered innate immune cells, aim to enhance their anti-tumor potential and counteract cancer-induced immunosuppression. The proximity of innate immune cells to tumor cells in the TME also makes them excellent drug carriers. In this review, we will first provide a systematic overview of innate immune cells within the TME and then discuss innate cell-based therapeutic strategies. Furthermore, the research obstacles and perspectives within the field will also be addressed.
    Keywords:  Cancer; Immune response; Microenvironment
    DOI:  https://doi.org/10.1016/j.isci.2024.110750
  5. Front Pharmacol. 2024 ;15 1404687
    Unveiling the contribution of tumor-associated macrophages in driving epithelial-mesenchymal transition: a review of mechanisms and therapeutic Strategies.
    Yijia Zhang, Xiaofei Ding, Xue Zhang, Ye Li, Rui Xu, Hai-Jun Li, Daiying Zuo, Guang Chen.
      Tumor-associated macrophages (TAMs), fundamental constituents of the tumor microenvironment (TME), significantly influence cancer development, primarily by promoting epithelial-mesenchymal transition (EMT). EMT endows cancer cells with increased motility, invasiveness, and resistance to therapies, marking a pivotal juncture in cancer progression. The review begins with a detailed exposition on the origins of TAMs and their functional heterogeneity, providing a foundational understanding of TAM characteristics. Next, it delves into the specific molecular mechanisms through which TAMs induce EMT, including cytokines, chemokines and stromal cross-talking. Following this, the review explores TAM-induced EMT features in select cancer types with notable EMT characteristics, highlighting recent insights and the impact of TAMs on cancer progression. Finally, the review concludes with a discussion of potential therapeutic targets and strategies aimed at mitigating TAM infiltration and disrupting the EMT signaling network, thereby underscoring the potential of emerging treatments to combat TAM-mediated EMT in cancer. This comprehensive analysis reaffirms the necessity for continued exploration into TAMs' regulatory roles within cancer biology to refine therapeutic approaches and improve patient outcomes.
    Keywords:  CSF1R, colony-stimulating factor 1 receptor; ECM, extracellular matrix; EMT, epithelialmesenchymal transition; TAM, tumor associated macrophage; TME, tumor microenvironment
    DOI:  https://doi.org/10.3389/fphar.2024.1404687
  6. Heliyon. 2024 Sep 15. 10(17): e37060
    Eliminating a barrier: Aiming at VISTA, reversing MDSC-mediated T cell suppression in the tumor microenvironment.
    Yayuan Deng, Mengjia Shi, Lin Yi, Muhammad Naveed Khan, Zhijia Xia, Xiaosong Li.
      Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment by producing remarkable clinical outcomes for patients with various cancer types. However, only a subset of patients benefits from immunotherapeutic interventions due to the primary and acquired resistance to ICIs. Myeloid-derived suppressor cells (MDSCs) play a crucial role in creating an immunosuppressive tumor microenvironment (TME) and contribute to resistance to immunotherapy. V-domain Ig suppressor of T cell activation (VISTA), a negative immune checkpoint protein highly expressed on MDSCs, presents a promising target for overcoming resistance to current ICIs. This article provides an overview of the evidence supporting VISTA's role in regulating MDSCs in shaping the TME, thus offering insights into how to overcome immunotherapy resistance.
    Keywords:  ICIs; Immunotherapy resistance; MDSC; Tumor microenvironment; VISTA
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e37060
  7. Drug Discov Today. 2024 Sep 13. pii: S1359-6446(24)00306-4. [Epub ahead of print] 104181
    Expression, regulation, and function of PD-L1 on non-tumor cells in the tumor microenvironment.
    Lingrong Hu, Chengliang Sun, Kai Yuan, Peng Yang.
      Antiprogrammed death ligand 1 (PD-L1) therapy is a leading immunotherapy, but only some patients with solid cancers benefit. Overwhelming evidence has revealed that PD-L1 is expressed on various immune cells in the tumor microenvironment (TME), including macrophages, dendritic cells, and regulatory T cells, modulating tumor immunity and influencing tumor progression. PD-L1 can also be located on tumor cell membranes as well as in exosomes and cytoplasm. Accordingly, the dynamic expression and various forms of PD-L1 might explain the therapy's limited efficacy and resistance. Herein a systematic summary of the expression of PD-L1 on different immune cells and their regulatory mechanisms is provided to offer a solid foundation for future studies.
    Keywords:  PD-L1; function; immunotherapy; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.drudis.2024.104181
  8. Nat Immunol. 2024 Sep 17.
    Genomic map of the cellular composition of the tumor microenvironment.
      
    DOI:  https://doi.org/10.1038/s41590-024-01964-0
  9. Heliyon. 2024 Sep 15. 10(17): e36839
    Tumor-associated macrophages within the immunological milieu: An emerging focal point for therapeutic intervention.
    Yanchi Shao, Song Han, Zhenxin Hou, Chen Yang, Yanbin Zhao.
      Tumor-associated macrophages play an important role in the tumor immune microenvironment, and regulating the function of tumor-associated macrophages has important therapeutic potential in tumor therapy. Mature macrophages could migrate to the tumor microenvironment, influencing multiple factors such as tumor cell proliferation, invasion, metastasis, extracellular matrix remodeling, immune suppression, and drug resistance. As a major component of the tumor microenvironment, tumor-associated macrophages crosstalk with other immune cells. Currently, tumor-associated macrophages have garnered considerable attention in tumor therapy, broadening the spectrum of drug selection to some extent, thereby aiding in mitigating the prevailing clinical drug resistance dilemma. This article summarizes the recent advances in tumor-associated macrophages concerning immunology, drug targeting mechanisms for tumor-associated macrophages treatment, new developments, and existing challenges, offering insights for future therapeutic approaches. In addition, this paper summarized the impact of tumor-associated macrophages on current clinical therapies, discussed the advantages and disadvantages of targeted tumor-associated macrophages therapy compared with existing tumor therapies, and predicted and discussed the future role of targeted tumor-associated macrophages therapy and the issues that need to be focused on.
    Keywords:  Immunity; TAMs; Targeted therapy; Tumor
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e36839
  10. J Neuroinflammation. 2024 Sep 16. 21(1): 226
    Microenvironmental regulation of tumor-associated neutrophils in malignant glioma: from mechanism to therapy.
    Jiayi Wen, Dan Liu, Hongtao Zhu, Kai Shu.
      Glioma is the most common primary intracranial tumor in adults, with high incidence, recurrence, and mortality rates. Tumor-associated neutrophils (TANs) are essential components of the tumor microenvironment (TME) in glioma and play a crucial role in glioma cell proliferation, invasion and proneural-mesenchymal transition. Besides the interactions between TANs and tumor cells, the multi-dimensional crosstalk between TANs and other components within TME have been reported to participate in glioma progression. More importantly, several therapies targeting TANs have been developed and relevant preclinical and clinical studies have been conducted in cancer therapy. In this review, we introduce the origin of TANs and the functions of TANs in malignant behaviors of glioma, highlighting the microenvironmental regulation of TANs. Moreover, we focus on summarizing the TANs-targeted methods in cancer therapy, aiming to provide insights into the mechanisms and therapeutic opportunities of TANs in the malignant glioma microenvironment.
    Keywords:  Immunotherapy; Malignant glioma; Targeted therapy; Tumor microenvironment; Tumor-associated neutrophils
    DOI:  https://doi.org/10.1186/s12974-024-03222-4
  11. J Immunol. 2024 Oct 01. 213(7): 923-931
    Tumor-derived Exosomes and Antitumor Immunity.
    Theresa L Whiteside.
      Cancer immunotherapy, including immune checkpoint blockade, has been approved for treatment of patients with many cancer types. However, some patients fail to respond to immunotherapy, and emerging evidence indicates that tumor-derived exosomes (TEX) play a major role in reprogramming the host immune cells by inducing their dysfunction. Focusing on effector T cells, this review illustrates mechanisms of suppression that TEX use, thus promoting tumor escape from the host immune system. TEX carry multiple suppressive signals that drive T cell dysfunction and convert the tumor microenvironment into "an immune desert" in which activated T cells either die or are reprogrammed to mediate protumor functions. The reprogrammed T cells produce a new crop of CD3+ immunoinhibitory exosomes that further amplify suppression mediated by TEX. The result is a profound depletion of antitumor immune effector cells that reflects the defective immune competence of the cancer patient and partly explains why TEX are a significant barrier for cancer immunotherapy.
    DOI:  https://doi.org/10.4049/jimmunol.2400335
  12. Cancer Res. 2024 Sep 18.
    Inhibition of JNK Signaling Overcomes Cancer-Associated Fibroblast-Mediated Immunosuppression and Enhances the Efficacy of Immunotherapy in Bladder Cancer.
    Chengying Cui, Haojie Zhang, Congcong Yang, Mingwei Yin, Xinkun Teng, Miaomiao Yang, Dejie Kong, Jinzhi Zhang, Weidong Peng, Zhimin Chu, Jingjing Wang, Yating Sun, Liping Kang, Bin Lyu, Qian Gao, Mingqing Wu, Yongqiang Wang, Yang Li.
      Currently, only 20-40% of cancer patients benefit from immune checkpoint inhibitors. Understanding the mechanisms underlying the immunosuppressive tumor microenvironment (TME) and characterizing dynamic changes in the immunological landscape during treatment are critical for improving responsiveness to immunotherapy. Here, we identified JNK signaling in cancer-associated fibroblasts (CAFs) as a regulator of the immunosuppressive tumor microenvironment. Single-cell RNA sequencing of bladder cancer treated with a JNK inhibitor revealed enhanced cytotoxicity and effector functions of CD8+ T cells. In untreated tumors, CAFs interacted frequently with CD8+ T cells and mediated their exhaustion. JNK inhibition abrogated the immunosuppression function of CAFs by downregulating the expression of TSLP, thereby restoring CD8+ T cell cytotoxicity. In addition, blockade of CAF-derived TSLP in combination with anti-PD1 treatment promoted tumor elimination by CD8+ T cells in vivo. Collectively, these results indicate that JNK signaling plays an important immunosuppressive role in the tumor microenvironment by promoting expression of TSLP in CAFs and suggest that inhibiting JNK signaling could be a promising immunotherapeutic strategy for cancer treatment.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-0940
  13. Cell Biol Int. 2024 Sep 16.
    Breast cancer cell derived exosomes reduces glycolysis of activated CD8 + T cells in a AKT-mTOR dependent manner.
    Abhishek Choudhury, Soumya Chatterjee, Shauryabrota Dalui, Pronabesh Ghosh, Altamas Hossain Daptary, Golam Kibria Mollah, Arindam Bhattacharyya.
      Cytotoxic CD8+ T cells plays a pivotal role in the adaptive immune system to protect the organism against infections and cancer. During activation and response, T cells undergo a metabolic reprogramming that involves various metabolic pathways, with a predominant reliance on glycolysis to meet their increased energy demands and enhanced effector response. Recently, extracellular vesicles (EVs) known as exosomes have been recognized as crucial signaling mediators in regulating the tumor microenvironment (TME). Recent reports indicates that exosomes may transfer biologically functional molecules to the recipient cells, thereby facilitate cancer progression, angiogenesis, metastasis, drug resistance, and immunosuppression by reprogramming the metabolism of cancer cells. This study sought to enlighten possible involvement of cancer-derived exosomes in CD8 + T cell glucose metabolism and discover a regulated signalome as a mechanism of action. We observed reduction in glucose metabolism due to downregulation of AKT/mTOR signalome in activated CD8 + T cells after cancer derived exosome exposure. In-vivo murine breast tumor studies showed better tumor control and antitumor CD8 + T cell glycolysis and effector response after abrogation of exosome release from breast cancer cells. Summarizing, the present study establishes an immune evasion mechanism of breast cancer cell secreted exosomes that will act as a foundation for future precision cancer therapeutics.
    Keywords:  CD8 + T cells; breast cancer; effector response; exhaustion; exosomes; glycolysis
    DOI:  https://doi.org/10.1002/cbin.12241
  14. Nanoscale. 2024 Sep 18.
    Unleashing nanotechnology to redefine tumor-associated macrophage dynamics and non-coding RNA crosstalk in breast cancer.
    Hardik Patni, Ramesh Chaudhary, Ashutosh Kumar.
      Breast cancer is a significant global health issue. Tumor-associated macrophages (TAMs) are crucial in influencing the tumor microenvironment and the progression of the disease. TAMs exhibit remarkable plasticity in adopting distinct phenotypes ranging from pro-inflammatory and anti-tumorigenic (M1-like) to immunosuppressive and tumor-promoting (M2-like). This review elucidates the multifaceted roles of TAMs in driving breast tumor growth, angiogenesis, invasion, and metastatic dissemination. Significantly, it highlights the intricate crosstalk between TAMs and non-coding RNAs (ncRNAs), including microRNAs, long noncoding RNAs, and circular RNAs, as a crucial regulatory mechanism modulating TAM polarization and functional dynamics that present potential therapeutic targets. Nanotechnology-based strategies are explored as a promising approach to reprogramming TAMs toward an anti-tumor phenotype. Various nanoparticle delivery systems have shown potential for modulating TAM polarization and inhibiting tumor-promoting effects. Notably, nanoparticles can deliver ncRNA therapeutics to TAMs, offering unique opportunities to modulate their polarization and activity.
    DOI:  https://doi.org/10.1039/d4nr02795g
  15. Life Sci. 2024 Sep 13. pii: S0024-3205(24)00649-0. [Epub ahead of print]357 123059
    Unconventional p65/p52 NF-κB module regulates key tumor microenvironment-related genes in breast tumor-associated macrophages (TAMs).
    Veronica De Paolis, Virginia Troisi, Antonella Bordin, Francesca Pagano, Viviana Caputo, Chiara Parisi.
      The complex heterogeneity of tumor microenvironment (TME) of triple-negative breast cancer (TNBC) presents a significant obstacle to cytotoxic immune response and successful treatment, building up one of the most hostile oncological phenotypes. Among the most abundant TME components, tumor-associated macrophages (TAMs) have pivotal pro-tumoral functions, involving discordant roles for the nuclear factor kappa-B (NF-κB) transcription factors and directing to higher levels of pathway complexity. In both resting macrophages and TAMs, we recently revealed the existence of the uncharacterized NF-κB p65/p52 dimer. In the present study, we demonstrated its enhanced active nuclear localization in TAMs and validated selected immune target genes as directly regulated by dimer binding on DNA sequences. We demonstrated by ChIP-qPCR that p65/p52 enrichment on HSPG2 and CSF-1 regulatory regions is strictly dependent on macrophage polarization and tumor environment. Our data provide novel mechanisms of transcriptional regulation in TAMs, orchestrated by the varied and dynamic nature of NF-κB combinations, which needs to be considered when targeting this pathway in cancer therapies. Our results offer p65/p52, together with identified regulatory regions on genes impacting macrophage behavior and tumor biology, as novel molecular targets for TNBC, aimed at modulating TAMs functions towards anti-tumoral phenotypes and thus improving cancer treatment outcomes.
    Keywords:  Nuclear factor kappa-B (NF-κB); Triple-negative breast cancer (TNBC); Tumor microenvironment (TME); Tumor-associated macrophages (TAMs)
    DOI:  https://doi.org/10.1016/j.lfs.2024.123059
  16. Trends Cancer. 2024 Sep 16. pii: S2405-8033(24)00169-9. [Epub ahead of print]
    Immunomodulation by endothelial cells: prospects for cancer therapy.
    Halima Alnaqbi, Lisa M Becker, Mira Mousa, Fatima Alshamsi, Sarah K Azzam, Besa Emini Veseli, Lauren A Hymel, Khalood Alhosani, Marwa Alhusain, Massimiliano Mazzone, Habiba Alsafar, Peter Carmeliet.
      Growing evidence highlights the importance of tumor endothelial cells (TECs) in the tumor microenvironment (TME) for promoting tumor growth and evading immune responses. Immunomodulatory endothelial cells (IMECs) represent a distinct plastic phenotype of ECs that exerts the ability to modulate immunity in health and disease. This review discusses our current understanding of IMECs in cancer biology, scrutinizing insights from single-cell reports to compare their characteristics and function dynamics across diverse tumor types, conditions, and species. We investigate possible implications of exploiting IMECs in the context of cancer treatment, particularly examining their influence on the efficacy of existing therapies and the potential to leverage them as targets in optimizing immunotherapeutic strategies.
    Keywords:  angiogenesis; cancer; endothelial cell; immunomodulation; immunotherapy; tumor
    DOI:  https://doi.org/10.1016/j.trecan.2024.08.002
  17. Biomed Res Int. 2023 ;2023 7692726
    Activation of T Lymphocytes with Anti-PDL1-BiTE in the Presence of Adipose-Derived Mesenchymal Stem Cells (ASCs).
    Leila Moeinzadeh, Amin Ramezani, Fereshteh Mehdipour, Mahsa Yazdanpanah-Samani, Mahboobeh Razmkhah.
       Background: Due to their ability to recruit immune cells to kill tumor cells directly, bispecific T cell engager antibodies (BiTE) hold great potential in T cell redirecting therapies. BiTE is able to activate T cells through CD3 and target them to tumor-expressed antigens. However, there are many components in the tumor microenvironment (TME) such as mesenchymal stem cells (MSCs) that may interfere with BiTE function. Herein, we designed an anti-PDL1-BiTE that targets programmed death ligand 1 (PDL1) and CD3 and investigated its effect on PDL1pos cancer cells in the presence or absence of adipose-derived MSCs (ASCs).
    Method: Our anti-PDL1-BiTE comprises of VL and VH chains of anti-CD3 monoclonal antibody (mAb) linked to the VL and VH chains of anti-PDL1 mAb, which simultaneously bind to the CD3ε subunit on T cells and PDL1 on tumor cells. Flow cytometry was employed to assess the strength of binding of anti-PDL1-BiTE to tumor cells and T cells. Cytotoxicity, proliferation, and activation of peripheral blood lymphocyte (PBLs) were evaluated by CFSE assay and flow cytometry after using anti-PDL1-BiTE in the presence or absence of ASCs and their conditioned media (C.M.).
    Results: Anti-PDL1-BiTE had the ability to induce selective lysis of PDL1pos U251-MG cancer cells while PDL1neg cells were not affected. Also, anti-PDL1-BiTE significantly stimulated peripheral blood lymphocyte (PBL) proliferation and CD69 expression. ASCs/C.M. did not show a significant effect on the biological activity of anti-PDL1-BiTE.
    Conclusion: Overall, anti-PDL1-BiTE selectively depletes PDL1pos cells and represents a new immunotherapeutic approach. It would increase the accumulation of T cells and can improve the prognosis of PDL1pos cancers in spite of the immunomodulatory effects of ASCs and C.M.
    DOI:  https://doi.org/10.1155/2023/7692726
  18. Front Immunol. 2024 ;15 1432799
    ReCARving the future: bridging CAR T-cell therapy gaps with synthetic biology, engineering, and economic insights.
    Alaa Ali, John F DiPersio.
      Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of hematologic malignancies, offering remarkable remission rates in otherwise refractory conditions. However, its expansion into broader oncological applications faces significant hurdles, including limited efficacy in solid tumors, safety concerns related to toxicity, and logistical challenges in manufacturing and scalability. This review critically examines the latest advancements aimed at overcoming these obstacles, highlighting innovations in CAR T-cell engineering, novel antigen targeting strategies, and improvements in delivery and persistence within the tumor microenvironment. We also discuss the development of allogeneic CAR T cells as off-the-shelf therapies, strategies to mitigate adverse effects, and the integration of CAR T cells with other therapeutic modalities. This comprehensive analysis underscores the synergistic potential of these strategies to enhance the safety, efficacy, and accessibility of CAR T-cell therapies, providing a forward-looking perspective on their evolutionary trajectory in cancer treatment.
    Keywords:  CAR T-cell therapy; allogeneic CAR T cells; gene editing; immunosuppressive microenvironment; immunotherapy; synthetic biology
    DOI:  https://doi.org/10.3389/fimmu.2024.1432799
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