bims-flamet 2024-12-08 papers

bims-flamet

Biomed News

on Cytokines and immunometabolism in metastasis

Issue of 2024–12–08
twenty-one papers selected by
Peio Azcoaga, Biodonostia HRI

Nanomaterial-enabled metabolic reprogramming strategies for boosting antitumor immunity.
Adenosine signaling in tumor-associated macrophages and targeting adenosine signaling for cancer therapy.
Multifaceted roles of neutrophils in tumor microenvironment.
Co-evolution of glioma and immune microenvironment.
Assessing CD36 and CD47 expression levels in solid tumor indications to stratify patients for VT1021 treatment.
Current advances on the role of ferroptosis in tumor immune evasion.
Advances in tumor immunotherapy targeting macrophages.
Genetic immune escape in cancer: timing and implications for treatment.
Sex-dimorphic tumor growth is regulated by tumor microenvironmental and systemic signals.
Reprogrammed lipid metabolism in advanced resistant cancers: an upcoming therapeutic opportunity.
Impact of gut microbiota and its metabolites on immunometabolism in colorectal cancer.
Therapeutic potential of trained immunity for malignant disease.
Decoding T cell senescence in cancer: is revisiting required?
Inhibition of furin in CAR macrophages directs them toward a proinflammatory phenotype and enhances their antitumor activities.
Role of vascular endothelium and exosomes in cancer progression and therapy (Review).
Function and Spatial Organization of Tumor-Invasive Human γδ T Cells-What Do We Know?
Glutamine is critical for the maintenance of type 1 conventional dendritic cells in normal tissue and the tumor microenvironment.
The role of ceRNAs in breast cancer microenvironmental regulation and therapeutic implications.
Immunological facets of prostate cancer and the potential of immune checkpoint inhibition in disease management.
Decoding tumor microenvironment: EMT modulation in breast cancer metastasis and therapeutic resistance, and implications of novel immune checkpoint blockers.
Single-cell RNA sequencing analysis reveals the dynamic changes in the tumor microenvironment during NMIBC recurrence.

Chem Soc Rev. 2024 Dec 02.

Nanomaterial-enabled metabolic reprogramming strategies for boosting antitumor immunity.

Muye Ma, Yongliang Zhang, Kanyi Pu, Wei Tang.

Immunotherapy has become a crucial strategy in cancer treatment, but its effectiveness is often constrained. Most cancer immunotherapies focus on stimulating T-cell-mediated immunity by driving the cancer-immunity cycle, which includes tumor antigen release, antigen presentation, T cell activation, infiltration, and tumor cell killing. However, metabolism reprogramming in the tumor microenvironment (TME) supports the viability of cancer cells and inhibits the function of immune cells within this cycle, presenting clinical challenges. The distinct metabolic needs of tumor cells and immune cells require precise and selective metabolic interventions to maximize therapeutic outcomes while minimizing adverse effects. Recent advances in nanotherapeutics offer a promising approach to target tumor metabolism reprogramming and enhance the cancer-immunity cycle through tailored metabolic modulation. In this review, we explore cutting-edge nanomaterial strategies for modulating tumor metabolism to improve therapeutic outcomes. We review the design principles of nanoplatforms for immunometabolic modulation, key metabolic pathways and their regulation, recent advances in targeting these pathways for the cancer-immunity cycle enhancement, and future prospects for next-generation metabolic nanomodulators in cancer immunotherapy. We expect that emerging immunometabolic modulatory nanotechnology will establish a new frontier in cancer immunotherapy in the near future.

DOI: https://doi.org/10.1039/d4cs00679h
Cancer Biol Med. 2024 Dec 03. pii: j.issn.2095-3941.2024.0228. [Epub ahead of print]

Adenosine signaling in tumor-associated macrophages and targeting adenosine signaling for cancer therapy.

Lei Yang, Yi Zhang, Li Yang.

  This review examined the critical role of adenosine signaling in modulating the behavior of tumor-associated macrophages (TAMs), a key determinant of the tumor microenvironment (TME). Adenosine is an immunosuppressive metabolite that is highly enriched in the TME due to elevated expression of adenosine triphosphatase (ATPase). Adenosine influences polarization of TAMs through A2A and A2B receptors, which drives a phenotype that supports tumor progression and immune evasion. The adenosine-mediated regulation of TAMs significantly suppresses the TME, dampening the efficacy of current immunotherapies. Targeting the adenosine pathway has shown potential in preclinical studies through reversal of the immunosuppressive microenvironment and antitumor immune response enhancement. Clinical trials are currently underway to determine the impact of A2A receptor antagonists, and CD39 and CD73 inhibition, enzymes that are pivotal in adenosine production, in various cancers. The current understanding of the CD39-CD73-adenosine axis in TAM regulation and the emerging strategies targeting adenosine signaling pathway for therapeutic intervention are the subjects of this review. The current clinical trials focusing on adenosine pathway inhibitors in combination with existing therapies to improve clinical outcomes are summarized and the need for continued research to refine these approaches for cancer treatment is emphasized.

Keywords:  Adenosine signaling; CD39; CD73; cancer therapy; tumor associated macrophages

DOI:  https://doi.org/10.20892/j.issn.2095-3941.2024.0228
Biochim Biophys Acta Rev Cancer. 2024 Nov 28. pii: S0304-419X(24)00162-8. [Epub ahead of print]1879(6): 189231

Multifaceted roles of neutrophils in tumor microenvironment.

Xueyin Pan, Qiang Wang, Beicheng Sun.

  Neutrophils, the most abundant leukocyte population in circulation, play a crucial role in detecting and responding to foreign cells, such as pathogens and tumor cells. However, the impact of neutrophils on cancer pathogenesis has been overlooked because of their short lifespan, terminal differentiation, and limited transcriptional activity. Within the tumor microenvironment (TME), neutrophils can be influenced by tumor cells or other stromal cells to acquire either protumor or antitumor properties via the cytokine environment. Despite progress in neutrophil-related research, a comprehensive understanding of tissue-specific neutrophil diversity and adaptability in the TME is still lacking, which poses a significant obstacle to the development of neutrophil-based cancer therapies. This review evaluated the current studies on the dual roles of neutrophils in cancer progression, emphasizing their importance in predicting clinical outcomes, and explored various approaches for targeting neutrophils in cancer treatment, including their potential synergy with cancer immunotherapy.

Keywords:  Immune suppression; Metastasis; Neutrophil; Tumor-associated neutrophil

DOI:  https://doi.org/10.1016/j.bbcan.2024.189231
J Immunother Cancer. 2024 Dec 03. pii: e009175. [Epub ahead of print]12(12):

Co-evolution of glioma and immune microenvironment.

Mahmoud M Elguindy, Jacob S Young, Winson S Ho, Rongze O Lu.

  Glioma evolution is governed by a multitude of dynamic interactions between tumor cells and heterogenous neighboring, non-cancerous cells. This complex ecosystem, termed the tumor microenvironment (TME), includes diverse immune cell types that have gained increasing attention for their critical and paradoxical roles in tumor control and tumorigenesis. Recent work has revealed that the cellular composition and functional state of immune cells in the TME can evolve extensively depending on the tumor stage and intrinsic features of surrounding glioma cells. Concurrently, adaptations to the glioma cellular phenotype, including activation of various cellular states, occur in the context of these immune cell alterations. In this review, we summarize important features of the immune TME that play key roles during each stage of glioma progression, from initiation to immune escape, invasion and recurrence. Understanding the complex interplay between tumor and immune cells is critical for the development of effective immunotherapies for glioma treatment.

Keywords:  Immune modulatory; Immunosuppression; Immunotherapy; Tumor microenvironment - TME

DOI:  https://doi.org/10.1136/jitc-2024-009175
NPJ Precis Oncol. 2024 Dec 03. 8(1): 278

Assessing CD36 and CD47 expression levels in solid tumor indications to stratify patients for VT1021 treatment.

Suming Wang, Victor Zota, Melanie Y Vincent, Donna Clossey, Jian Jenny Chen, Michael Cieslewicz, Randolph S Watnick, James Mahoney, Jing Watnick.

Despite the development of cancer biomarkers and targeted therapies, most cancer patients do not have a specific biomarker directly associated with effective treatment options. We have developed VT1021 that induces the expression of thrombospondin-1 (TSP-1) in myeloid-derived suppressor cells (MDSCs) recruited to the tumor microenvironment (TME). Our studies identified CD36 and CD47 as dual biomarkers that can be used as patient stratifying tools and prognostic biomarkers for VT1021 treatment.

DOI: https://doi.org/10.1038/s41698-024-00774-9
Discov Oncol. 2024 Dec 02. 15(1): 736

Current advances on the role of ferroptosis in tumor immune evasion.

Changlin Gao, Haoran Zhang, Xianwei Wang.

  Ferroptosis is a non-apoptotic form of regulated cell death characterized by iron accumulation and uncontrolled lipid peroxidation, leading to plasma membrane rupture and intracellular content release. Cancer immunotherapy, especially immune checkpoint inhibitors (ICIs) targeting PD-1 and PD-L1, has been considered a breakthrough in cancer treatment, achieving encouraging clinical anti-tumor effects in a variety of cancers. However, tumor immune evasion is indispensable to immunotherapy failure. The mechanisms of tumor immune evasion are quite complex, and its occurrence is inseparable from the ferroptosis in tumor microenvironment (TME). Thus, a comprehensive understanding of the role of ferroptosis in tumor immune evasion is crucial to enhance the efficacy of immunotherapy. In this review, we provide an overview of the recent advancements in understanding ferroptosis in cancer, covering molecular mechanisms and interactions with the TME. We also summarize the potential applications of ferroptosis induction in immunotherapy, as well as ferroptosis inhibition for cancer treatment in various conditions. We finally discuss ferroptosis as a double-edged sword, including the current challenges and future directions regarding its potential for cancer treatment.

Keywords:  Cancer immunotherapy; Ferroptosis; Tumor immune evasion; Tumor microenvironment

DOI:  https://doi.org/10.1007/s12672-024-01573-1
Expert Rev Clin Immunol. 2024 Dec 05.

Advances in tumor immunotherapy targeting macrophages.

Binrui Shi, Meng Du, Zhiyi Chen.

   INTRODUCTION: In recent years, immunotherapy has shown significant therapeutic potential in patients with advanced tumors. However, only a small number of individuals benefit, mainly due to the tumor microenvironment (TME), which provides conditions for the development of tumors. Macrophages in TME, known as tumor-associated macrophages (TAM), are mainly divided into M1 anti-tumor and M2 pro-tumor phenotypes, which play a regulatory role in various stages of tumorigenesis, promote tumorigenesis and metastasis, and cause immunotherapy resistance.
AREAS COVERED: This review focuses on research strategies and preclinical/clinical research progress in translating TAM into antitumor phenotype by referring to the pubmed database for five years. These include small molecule chemotherapy drug development, metabolic regulation, gene editing, physical stimulation, nanotechnology-mediated combination therapy strategies, and chimeric antigen receptor-based immunotherapy.
EXPERT OPINION: It is necessary to explore the surface-specific receptors and cell signaling pathways of TAM further to improve the specificity and targeting of drugs and to strengthen research in the field of probes that can monitor changes in TAM in real time. In addition, the physical stimulation polarization strategy has the advantages of being noninvasive, economical, and stable and will have excellent clinical transformation value in the future.

Keywords:  Immunotherapy; Tumor-associated macrophage; macrophage polarization; tumor microenvironment; tumor therapy

DOI:  https://doi.org/10.1080/1744666X.2024.2438721
Trends Cancer. 2024 Dec 03. pii: S2405-8033(24)00254-1. [Epub ahead of print]

Genetic immune escape in cancer: timing and implications for treatment.

Francisco Martínez-Jiménez, Diego Chowell.

  Genetic immune escape (GIE) alterations pose a significant challenge in cancer by enabling tumors to evade immune detection. These alterations, which can vary significantly across cancer types, may often arise early in clonal evolution and contribute to malignant transformation. As tumors evolve, GIE alterations are positively selected, allowing immune-resistant clones to proliferate. In addition to genetic changes, the tumor microenvironment (TME) and non-genetic factors such as inflammation, smoking, and environmental exposures play crucial roles in promoting immune evasion. Understanding the timing and mechanisms of GIE, alongside microenvironmental influences, is crucial for improving early detection and developing more effective therapeutic interventions. This review highlights the implications of GIE in cancer development and immunotherapy resistance, and emphasizes the need for integrative approaches.

Keywords:  HLA; immune escape; immunotherapy resistance; precancer; tumor evolution; tumor microenvironment

DOI:  https://doi.org/10.1016/j.trecan.2024.11.002
Sci Adv. 2024 Dec 06. 10(49): eads4229

Sex-dimorphic tumor growth is regulated by tumor microenvironmental and systemic signals.

Xianfeng Wang, Hongcun Bao, Yi-Chun Huang, Anindita Barua, Chun-Ming Lai, Jie Sun, Youfang Zhou, Fei Cong, Shangyu Gong, Chih-Hsuan Chang, Wu-Min Deng.

Tumor growth and progression involve coordinated regulation by internal, microenvironmental, and systemic signals and often display conspicuous sexual dimorphism. The mechanisms governing the integration and coordination of these signals, along with their sex-based differences, remain largely unknown. Using a Drosophila tumor model originating from nonreproductive tissue, we show that female-biased tumor growth involves multifaceted communications among tumor cells, hemocytes, and neuroendocrine insulin-producing cells (IPCs). Notch-active tumor cells recruit hemocytes carrying the tumor necrosis factor-α (TNF-α) homolog Eiger to the tumor microenvironment (TME), activating the c-Jun N-terminal kinase (JNK) pathway in tumor cells, instigating the sexually dimorphic up-regulation of cytokine Unpaired 2 (Upd2). Upd2, in turn, exerts a distal influence by modulating the release of a Drosophila insulin-like peptide (Dilp2) from IPCs. Dilp2 then activates the insulin signaling in the tumor, thereby fostering sexual-dimorphic tumor growth. Together, these findings reveal a relay mechanism involving the TME and systemic signals that collectively control the sexual dimorphism of tumor growth.

DOI: https://doi.org/10.1126/sciadv.ads4229
Cancer Drug Resist. 2024 ;7 45

Reprogrammed lipid metabolism in advanced resistant cancers: an upcoming therapeutic opportunity.

Mario Cioce, Mariamena Arbitrio, Nicoletta Polerà, Emanuela Altomare, Antonia Rizzuto, Carmela De Marco, Vito Michele Fazio, Giuseppe Viglietto, Maria Lucibello.

  Resistance of cancer to therapy is the main challenge to its therapeutic management and is still an unsolved problem. Rearranged lipid metabolism is a strategy adopted by cancer cells to counteract adversity during their evolution toward aggressiveness and immune evasion. This relies on several mechanisms, ranging from altered metabolic pathways within cancer cells to evolved dynamic crosstalk between cancer cells and the tumor microenvironment (TME), with some cell populations at the forefront of metabolic reprogramming, thereby contributing to the resistance of the whole ecosystem during therapy. Unraveling these mechanisms may contribute to the development of more effective combinatorial therapy in resistant patients. This review highlights the alterations in lipid metabolism that contribute to cancer progression, with a focus on the potential clinical relevance of such findings for the management of therapy resistance.

Keywords:  Metabolic signaling; immune evasion; metastasis; therapy resistance; tumor microenvironment

DOI:  https://doi.org/10.20517/cdr.2024.131
Immunometabolism (Cobham). 2024 Oct;6(4): e00050

Impact of gut microbiota and its metabolites on immunometabolism in colorectal cancer.

Madison Flory, Paloma Bravo, Ashfaqul Alam.

  Colorectal cancer (CRC) is highly prevalent, accounting for approximately one-tenth of cancer cases and deaths globally. It stands as the second most deadly and third most common cancer type. Although the gut microbiota has been implicated in CRC carcinogenesis for the last several decades, it remains one of the least understood risk factors for CRC development, as the gut microbiota is highly diverse and variable. Many studies have uncovered unique microbial signatures in CRC patients compared with healthy matched controls, with variations dependent on patient age, disease stage, and location. In addition, mechanistic studies revealed that tumor-associated bacteria produce diverse metabolites, proteins, and macromolecules during tumor development and progression in the colon, which impact both cancer cells and immune cells. Here, we summarize microbiota's role in tumor development and progression, then we discuss how the metabolic alterations in CRC tumor cells, immune cells, and the tumor microenvironment result in the reprogramming of activation, differentiation, functions, and phenotypes of immune cells within the tumor. Tumor-associated microbiota also undergoes metabolic adaptation to survive within the tumor environment, leading to immune evasion, accumulation of mutations, and impairment of immune cells. Finally, we conclude with a discussion on the interplay between gut microbiota, immunometabolism, and CRC, highlighting a complex interaction that influences cancer development, progression, and cancer therapy efficacy.

Keywords:  colorectal cancer; gut microbiota; immunometabolism; metabolites; microbiome

DOI:  https://doi.org/10.1097/IN9.0000000000000050
Immunol Med. 2024 Dec 05. 1-12

Therapeutic potential of trained immunity for malignant disease.

Hiroyuki Takahashi, Daibo Kojima, Masato Watanabe.

  Trained immunity (TI) is functional memory displayed by innate immune cells (IICs). TI facilitates rapid, non-specific responses to pathogens upon secondary challenge. It is driven by immunological signaling and metabolic rewriting via epigenetic alteration, triggered by recognition of certain stimuli. Recently, immune checkpoint inhibitors have come into common use in clinical oncology settings, and genetically engineered cytotoxic T cells comprise a potent cancer treatment strategy. However, the contributions of TI in the tumor microenvironment (TME) are only beginning to be uncovered. Accumulating evidence that various microorganisms and vaccines convey tumoricidal ability suggest that TI may become a useful anti-cancer tool. The expected roles of TI in tumor therapy are the 1) promotion of proinflammatory cytokine section, 2) enhancement of phagocytosis, 3) quick expansion and recruitment of cancer-specific cytotoxic T cells to the TME through neoantigen presentation, 4) reversal of immunosuppression in the TME, and 5) removal of pathogens associated with carcinogenesis or tumor development. Medium- to long-term TI durability may reduce the risk of tumor development. Recent findings on TI usher in new aspirations for cancer treatment.

Keywords:  Bacillus calmette–guérin; Trained immunity; immune checkpoint inhibitor; tumor microenvironment

DOI:  https://doi.org/10.1080/25785826.2024.2438426
Semin Cancer Biol. 2024 Nov 28. pii: S1044-579X(24)00087-7. [Epub ahead of print]

Decoding T cell senescence in cancer: is revisiting required?

Sophia Magkouta, Efrosyni Markaki, Konstantinos Evangelou, Russell Petty, Panayotis Verginis, Vassilis Gorgoulis.

  Senescence is an inherent cellular mechanism triggered as a response to stressful insults. It associates with several aspects of cancer progression and therapy. Senescent cells constitute a highly heterogeneous cellular population and their identification can be very challenging. In fact, the term "senescence" has been often misused. This is also true in the case of immune cells. While several studies indicate the presence of senescent-like features (mainly in T cells), senescent immune cells are poorly described. Under this prism, we herein review the current literature on what has been characterized as T cell senescence and provide insights on how to accurately discriminate senescent cells against exhausted or anergic ones. We also summarize the major metabolic and epigenetic modifications associated with T cell senescence and underline the role of senescent T cells in the tumor microenvironment (TME). Moreover, we discuss how these cells associate with standard clinical therapeutic interventions and how they impact their efficacy. Finally, we underline the importance of precise identification and thorough characterization of "truly" senescent T cells in order to design successful therapeutic manipulations that would delay cancer incidence and maximize efficacy of immunotherapy.

Keywords:  T- cell; cancer; cellular senescence; immunosenescence; therapy

DOI:  https://doi.org/10.1016/j.semcancer.2024.11.003
Cell Death Dis. 2024 Dec 04. 15(12): 879

Inhibition of furin in CAR macrophages directs them toward a proinflammatory phenotype and enhances their antitumor activities.

Lydia Ziane-Chaouche, Antonella Raffo-Romero, Nawale Hajjaji, Firas Kobeissy, Donna Pinheiro, Soulaimane Aboulouard, Adeline Cozzani, Suman Mitra, Isabelle Fournier, Dasa Cizkova, Michel Salzet, Marie Duhamel.

Chimeric antigen receptor (CAR)-T-cell therapy has revolutionized cellular immunotherapy, demonstrating remarkable efficacy in hematological cancers. However, its application in solid tumors faces significant challenges, including limited T-cell infiltration and tumor-induced immunosuppression. Given the prominent role of macrophages in the tumor microenvironment, their phenotypic plasticity and inherent antitumor properties, such as phagocytosis, offer a promising avenue for therapeutic intervention. This study focuses on the development of a second generation of CAR macrophages (CAR-Ms). We elucidated the role of the proprotein convertase furin in macrophages, demonstrating its overexpression in the presence of tumor cells. Importantly, furin inhibition maintains a proinflammatory macrophage phenotype, potentially redirecting them towards an antitumor state. Compared to furin-expressing counterparts, furin-inhibited CAR-Ms exhibited heightened antitumor phagocytic activity against breast cancer cells and ex vivo patient-derived tumoroids. Notably, they sustained a persistent proinflammatory profile, indicative of enhanced tumoricidal potential. Additionally, furin-inhibited CAR-Ms secreted factors that promote T-cell activation, offering a means to modulate the tumor microenvironment. In summary, our work highlights the translational potential of furin-inhibited CAR-Ms as a potent cellular therapy to mitigate macrophage exhaustion within the tumor environment. By capitalizing on macrophage-mediated antitumor responses, these findings pave the way for the development of second-generation CAR-M therapeutic strategies tailored for solid tumors.

DOI: https://doi.org/10.1038/s41419-024-07267-4
Int J Oncol. 2025 Jan;pii: 6. [Epub ahead of print]66(1):

Role of vascular endothelium and exosomes in cancer progression and therapy (Review).

Yonghao Dai, Yutong Yao, Yuquan He, Xin Hu.

  Cancer poses a significant global health challenge and its progression is intricately connected to the interplay among various cell types and molecular pathways. In recent years, research has focused on the roles of vascular endothelial cells (VECs) and exosomes within the tumor microenvironment. Anomalies in tumor vascular integrity and function create a conducive milieu for cancer cell proliferation. Despite efforts in clinical anti‑angiogenic interventions, the anticipated outcomes remain elusive. VECs have the capability to transition into mesenchymal cells through endothelial‑to‑mesenchymal transition, thereby affecting cancer advancement. Exosomes are minute membrane‑bound vesicles generated by cells, serving as vital extracellular elements that facilitate cell‑to‑cell communication. They participate in modulating the tumor microenvironment, thereby influencing tumor progression, metastasis, drug resistance and angiogenesis. Additionally, exosomes serve as efficient carriers for drug delivery, as well as targeting and suppressing tumor cells. In summary, understanding the intricate and interconnected mechanisms of VECs and exosomes in cancer, encompassing tumor angiogenesis, microenvironment modulation and immune regulation, is crucial. A comprehensive exploration of these mechanisms may provide insight into cancer treatment and prevention and yield novel therapeutic targets.

Keywords:  angiogenesis; cancer therapy; endothelial‑to‑mesenchymal transition; exosomes; vascular endothelium

DOI:  https://doi.org/10.3892/ijo.2024.5712
Eur J Immunol. 2024 Dec 02. e202451075

Function and Spatial Organization of Tumor-Invasive Human γδ T Cells-What Do We Know?

Kilian Wistuba-Hamprecht, Hans-Heinrich Oberg, Daniela Wesch.

  Human gammadelta (γδ) T cells not only infiltrate or reside in healthy tissues but also enter solid cancers. A large body of evidence suggests that γδ T cells can exert potent anti-tumor effects, although conflicting or unfavorable effects have been reported in some cancer entities. Infiltration patterns are key to understanding the complexity of the tumor microenvironment (TME) and its interplay with γδ T cells. The limited data available describe different γδ T cell subsets that are located in different areas around and within tumors. Tumor-infiltrating γδ lymphocytes (γδ TIL) exert cytotoxicity, for example, via the CD95- or TRAIL-axis, produce high amounts of granzymes, and after their activation, tumor necrosis factor (TNF)-α or IFN-γ and express immune checkpoint receptors. Under certain conditions, γδ T cell subsets can express low amounts of IL-17 and seem to contribute to immune regulation/suppression. A polarization of γδ T cells can be influenced by the TME. Inflammatory cytokines, growth factors, or tumor promoters can suppress γδ T cell functionality or even push them toward tumor promotion. To avoid this and to exploit the unique features of γδ T cell-mediated anti-cancer and immune-orchestrating capabilities in future immune therapy approaches, a growing body of preclinical but also clinical studies can be observed.

Keywords:  cancer immunotherapy; checkpoint inhibitors; tumor; tumor microenvironment; tumor‐infiltrating gammadelta T cells

DOI:  https://doi.org/10.1002/eji.202451075
Proc Natl Acad Sci U S A. 2024 Dec 10. 121(50): e2412157121

Glutamine is critical for the maintenance of type 1 conventional dendritic cells in normal tissue and the tumor microenvironment.

Graham P Lobel, Nanumi Han, William A Molina Arocho, Michal Silber, Jason Shoush, Michael C Noji, Tsun Ki Jerrick To, Li Zhai, Nicholas P Lesner, M Celeste Simon, Malay Haldar.

  Proliferating tumor cells take up glutamine for anabolic processes, engendering glutamine deficiency in the tumor microenvironment. How this might impact immune cells is not well understood. Using multiple mouse models of soft tissue sarcomas, glutamine antagonists, as well as genetic and pharmacological inhibition of glutamine utilization, we found that the number and frequency of conventional dendritic cells (cDCs) is dependent on microenvironmental glutamine levels. cDCs comprise two distinct subsets-cDC1s and cDC2s, with the former subset playing a critical role in antigen cross-presentation and tumor immunity. While both subsets show dependence on glutamine, cDC1s are particularly sensitive. Notably, glutamine antagonism did not reduce the frequency of DC precursors but decreased the proliferation and survival of cDC1s. Further studies suggest a role of the nutrient sensing mechanistic target of rapamycin (mTOR) signaling pathway in this process. Taken together, these findings uncover glutamine dependence of cDC1s that is coopted by tumors to escape immune responses.

Keywords:  dendritic cells; glutamine; tumor microenvironment

DOI:  https://doi.org/10.1073/pnas.2412157121
J Mol Med (Berl). 2024 Dec 06.

The role of ceRNAs in breast cancer microenvironmental regulation and therapeutic implications.

Alper Yilmaz, Selcen Ari Yuka.

  The tumor microenvironment, which is the tailored physiological milieu of heterogeneous cancer cell populations surrounded by stromal and immune cells as well as extracellular matrix components, is a leading modulator of critical cancer hallmarks and one of the most significant prognostic indicators in breast cancer. In the last few decades, with the discovery of the interactions of ncRNAs with diverse cellular molecules, considerable emphasis has been devoted to understanding their direct and indirect roles in specific functions in breast cancer. Collectively, all of these have revealed that the competitive action of protein-coding RNAs and ncRNAs such as circRNAs and lncRNAs, which have a shared affinity for miRNAs, play a vital role in the molecular regulation of breast cancer. This phenomenon, termed as competing endogenous RNAs (ceRNAs), facilitates modeling the microenvironment through intercellular shuttles. Microenvironment ceRNA interactions have emerged as a frontier in the deep understanding of the complex mechanisms of breast cancer. In this review, we first discuss cellular ceRNAs in four key biological processes critical for microenvironmental regulation in breast cancer tissues: hypoxia, angiogenesis, immune regulations, and ECM remodeling. Further, we draw a complete portrait of microenvironment regulation by cell-to-cell cross-talk of shuttled ceRNAs and offer a framework of potential applications and challenges in overcoming the aggressive phenotype of the breast cancer microenvironment.

Keywords:  Breast cancer microenvironment; Competing endogenous RNA; circRNA; lncRNA; miRNA

DOI:  https://doi.org/10.1007/s00109-024-02503-y
Theranostics. 2024 ;14(18): 6913-6934

Immunological facets of prostate cancer and the potential of immune checkpoint inhibition in disease management.

Stian Bakke Hansen, Bilal Unal, Omer Faruk Kuzu, Fahri Saatcioglu.

  Prostate cancer (PCa) is the most common non-cutaneous cancer in men and a major cause of cancer-related deaths. Whereas localized PCa can be cured by surgery and radiotherapy, metastatic disease can be treated, but is not curable. Inhibition of androgen signaling remains the main therapeutic intervention for treatment of metastatic PCa, in addition to chemotherapy, radionuclide therapy and emerging targeted therapies. Although initial responses are favorable, resistance to these therapies invariably arise with development of castration resistant PCa (CRPC) and lethal phenotypes. Recent findings have implicated the crosstalk between PCa cells and the tumor microenvironment (TME) as a key factor for disease progression and metastasis, and the immune system is becoming an increasingly attractive target for therapy. Given the striking success of immune checkpoint inhibitors (ICIs) in various cancer types, preclinical and clinical studies have begun to explore their potential in PCa. It has become clear that the PCa TME is largely immunosuppressive, and ICI therapy does not have efficacy for PCa. Intense effort is therefore being made in the field to understand the mechanisms of suppression and to turn the immunosuppressive TME into an immune active one that would enable ICI efficacy. Herein we examine this recent body of knowledge and how the mutational landscape of PCa integrates with an immunosuppressive TME to circumvent ICI-mediated T-cell activity and tumor killing. We then review the emerging potential success of combinatorial ICI approaches, utility of careful patient selection, and potential novel strategies to improve the efficacy of ICI for PCa therapy.

Keywords:  Cold tumor; Combination therapy; Immune checkpoint inhibitor; Immunotherapy; Prostate cancer; Tumor microenvironment.

DOI:  https://doi.org/10.7150/thno.100555
Biomed Pharmacother. 2024 Nov 29. pii: S0753-3322(24)01600-7. [Epub ahead of print]181 117714

Decoding tumor microenvironment: EMT modulation in breast cancer metastasis and therapeutic resistance, and implications of novel immune checkpoint blockers.

Jie Yuan, Li Yang, Hua Zhang, Narasimha M Beeraka, Danfeng Zhang, Qun Wang, Minghua Wang, Hemanth Vikram Pr, Gautam Sethi, Geng Wang.

  Tumor microenvironment (TME) and epithelial-mesenchymal transition (EMT) play crucial roles in the initiation and progression of tumors. TME is composed of various cell types, such as immune cells, fibroblasts, and endothelial cells, as well as non-cellular components like extracellular matrix (ECM) proteins and soluble factors. These elements interact with tumor cells through a complex network of signaling pathways involving cytokines, growth factors, metabolites, and non-coding RNA-carrying exosomes. Hypoxic conditions within the TME further modulate these interactions, collectively influencing tumor growth, metastatic potential, and response to therapy. EMT represents a dynamic and reversible process where epithelial cells undergo phenotypic changes to adopt mesenchymal characteristics in several cancers, including breast cancers. This transformation enhances cell motility and imparts stem cell-like properties, which are closely associated with increased metastatic capability and resistance to conventional cancer treatments. Thus, understanding the crosstalk between the TME and EMT is essential for unraveling the underlying mechanisms of breast cancer metastasis and therapeutic resistance. This review uniquely examines the intricate interplay between the tumor TME and epithelial-mesenchymal transition EMT in driving breast cancer metastasis and treatment resistance. It explores the therapeutic potential of targeting the TME-EMT axis, specifically through CD73-TGF-β dual-blockade, to improve outcomes in triple-negative breast cancer. Additionally, it underscores new strategies to enhance immune checkpoint blockade (ICB) responses by modulating EMT, thereby offering innovative insights for more effective cancer treatment.

Keywords:  Breast cancer; Drug resistance; Epithelial-mesenchymal transition; Metastasis; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.biopha.2024.117714
Apoptosis. 2024 Dec 04.

Single-cell RNA sequencing analysis reveals the dynamic changes in the tumor microenvironment during NMIBC recurrence.

Ziang Chen, Tianxiang Zhang, Weijian Li, Jia Hu, Yuxi Ou, Fangdie Ye, Jinhao Zhang, Haowen Jiang, Shenghua Liu.

   BACKGROUND: Due to the clinical characteristic of frequent recurrence in urothelial bladder cancer (UBC), patients face significant health impacts and economic burdens. Therefore, understanding the molecular mechanisms involved in UBC recurrence is crucial for reducing its recurrence rate. The aim of our study is to help urologists and clinical researchers gain a deeper understanding of the changes in the tumor microenvironment (TME) during UBC recurrence.
METHODS: We collected 10 samples from primary and recurrent non-muscle-invasive bladder cancer (NMIBC) and performed single-cell RNA sequencing. By distinguishing and annotating cell subpopulations, we identified tissue preferences of some novel cell subgroups. Next, pseudotime trajectory analysis, cell-cell communication analysis, and function enrichment analysis were applied to evaluate the dynamic changes in the TME and biological functions. Finally, we validated the distribution of some of these cell subgroups using multiplex immunofluorescence experiments.
RESULTS: We identified a tumor-associated fibroblast (CAF) subtype with high COL18A1 expression that is highly expressed in recurrent NMIBC, suggesting that the stromal component of the tumor may play a crucial role in the recurrence process. Additionally, pseudotime trajectory analysis revealed a macrophage subtype with high IL-6 expression at the terminal stage of macrophage differentiation, exhibiting significant immunosuppressive features. This indicated the presence of immune exhaustion during NMIBC recurrence. Lastly, we found an upregulation of estrogen in recurrent urothelial cancer cells, which may partially explain the gender disparity observed in UBC.
CONCLUSION: This study identified several cell subpopulations influencing NMIBC recurrence, which were heavily infiltrated in the TME of recurrent NMIBC. Additionally, the enrichment of estrogen in urothelial cancer cells from various sources suggested a role of sex hormones in NMIBC recurrence.

Keywords:  Non-muscle-invasive bladder cancer; Recurrence; Sex differences; Single-cell; Tumor-associated fibroblast; Tumor-associated macrophages

DOI:  https://doi.org/10.1007/s10495-024-02044-2