bims-flamet 2025-01-26 papers

bims-flamet

Biomed News

on Cytokines and immunometabolism in metastasis

Issue of 2025–01–26
eight papers selected by
Peio Azcoaga, Biodonostia HRI

Interleukin-6 (IL-6)-associated tumor microenvironment remodelling and cancer immunotherapy.
Sympathetic nerve signaling rewires the tumor microenvironment: a shift in "microenvironmental-ity".
Targeting CD84 protein on myeloid-derived suppressor cells as a novel immunotherapy in solid tumors.
The accumulation of myeloid-derived suppressor cells participates in abdominal infection-induced tumor progression through the PD-L1/PD-1 axis.
Flow cytometry-based monitoring of myeloid-derived suppressor cells in the peripheral blood of patients with solid tumors.
Endocrine treatment mechanisms in triple-positive breast cancer: from targeted therapies to advances in precision medicine.
TGF-β signaling orchestrates cancer-associated fibroblasts in the tumor microenvironment of human hepatocellular carcinoma: unveiling insights and clinical significance.
Efficacy of Anti-Cancer Immune Responses Elicited Using Tumor-Targeted IL-2 Cytokine and Its Derivatives in Combined Preclinical Therapies.

Cytokine Growth Factor Rev. 2025 Jan 10. pii: S1359-6101(25)00001-2. [Epub ahead of print]

Interleukin-6 (IL-6)-associated tumor microenvironment remodelling and cancer immunotherapy.

Songsong Wu, Zhumin Cao, Rongying Lu, Zhenwang Zhang, Gautam Sethi, Yulai You.

  Interleukin-6 (IL-6) is a pro-inflammatory cytokine playing a pivotal role during inflammation and immune responses. In the recent years, the function of IL-6 in the tumor microenvironment (TME) for affecting tumorigenesis and immunotherapy response has been investigated. The genetic mutations are mainly responsible for the development of cancer, while interactions in TME are also important, involving both cancers and non-cancerous cells. IL-6 plays a significant role in these interactions, enhancing the proliferation, survival and metastasis of tumor cells through inflammatory pathways, highlighting its carcinogenic function. Multiple immune cells including macrophages, T cells, myeloid-derived suppressor cells, dendritic cells and natural killer cells can be affected by IL-6 to develop immunosuppressive TME. IL-6 can also participate in the immune evasion through increasing levels of PD-L1, compromising the efficacy of therapeutics. Notably, IL-6 exerts a double-edge sword function and it can dually increase or decrease cancer immunotherapy, providing a challenge for targeting this cytokine in cancer therapy. Highlighting the complicated function of IL-6 in TME can lead to the development of effective therapeutics for cancer immunity.

Keywords:  Cancer immunotherapy; Cytokine; Immune evasion; Interleukin-6; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.cytogfr.2025.01.001
Cancer Metastasis Rev. 2025 Jan 20. 44(1): 25

Sympathetic nerve signaling rewires the tumor microenvironment: a shift in "microenvironmental-ity".

Ariana Sattler, Tetiana Korzun, Kasmira Gupta, Parham Diba, Natasha Kyprianou, Sebnem Ece Eksi.

  Nerve signaling within the tumor microenvironment (TME) plays a critical role in the initiation, progression, and metastasis of solid tumors. Due to their highly responsive behavior and activation upon injury and cancer onset, this review specifically focuses on how sympathetic nerves rewire the TME. Within tumors, sympathetic nerves closely interact with various TME components, and their combined signaling often shifts tumor-intrinsic physiology toward tumor-supportive phenotypes. In turn, the TME components, such as myeloid cells, lymphoid cells, extracellular matrix (ECM), endothelial cells, cancer associated fibroblasts (CAFs), and Schwann cells, secrete neurotrophic and axon guidance factors that influence both sympathetic outgrowth and tumor cell behavior, further exacerbating tumor progression and metastasis. Here, we review the current evidence on the multidirectional impacts of sympathetic nerves and both immune and non-immune TME components, the nature of these communication processes, and how exploring these interactions may inform future therapeutics to impair cancer progression and metastasis.

Keywords:  Cancer neuroscience; Neuro-immune axis; Sympathetic signaling; Tumor microenvironment

DOI:  https://doi.org/10.1007/s10555-025-10241-x
Comput Methods Programs Biomed. 2025 Jan 14. pii: S0169-2607(25)00024-0. [Epub ahead of print]261 108607

Targeting CD84 protein on myeloid-derived suppressor cells as a novel immunotherapy in solid tumors.

Saeed Mobini, Milad Chizari, Elham Rismani, Ladan Mafakher, Mohammad Javad Sadrzadeh, Massoud Vosough.

   BACKGROUND AND OBJECTIVE: Myeloid-derived suppressor cells (MDSCs) are a crucial and diverse group of cells found in the tumor microenvironment (TME) that facilitate progression, invasion, and metastasis within solid tumors. CD84, a homophilic adhesion molecule expressed on MDSCs, plays a critical role in their accumulation and function within the TME. This study aims to investigate the protein-protein interactions of CD84 using molecular dynamics simulations and to explore potential therapeutic strategies targeting these interactions.
METHODS: Through computational techniques, we generated highly potent mutated CD84 mini-proteins and peptides as antagonists with significantly higher affinity for CD84 to mimic the key features of the IgV-like domain of the protein. Additionally, we engineered an antibody capable of blocking CD84. Binding affinities were assessed using dissociation constant (Kd) calculations.
RESULTS: Data analysis shows that the Kd values for the designed peptides ranged from 10 to 100 times stronger than those of the natural CD84 interactions, indicating efficient inhibition of CD84 interactions. Additionally, mutagenesis of the Ig-like V domain of CD84 resulted in variants with improved binding stability, with a Gibbs free energy change (ΔΔG) indicating enhanced interaction potential.
CONCLUSIONS: This study provides insights into CD84 interactions and their implications for immunotherapy targeting MDSCs in solid tumors. However, experimental validation is necessary to confirm the findings of this study and evaluate peptide selectivity as potential molecular therapeutics.

Keywords:  Cancer immunotherapy; Myeloid-derived suppressor cells; SLAMF5 glycoprotein

DOI:  https://doi.org/10.1016/j.cmpb.2025.108607
Mol Oncol. 2025 Jan 21.

The accumulation of myeloid-derived suppressor cells participates in abdominal infection-induced tumor progression through the PD-L1/PD-1 axis.

Yiding Wang, Ting Guo, Xiaofang Xing, Xijuan Liu, Xuejun Gan, Yingai Li, Yan Liu, Fei Shan, Zhouqiao Wu, Jiafu Ji, Ziyu Li.

  Gastric cancer (GC) is the third leading cause of cancer-related deaths worldwide, with gastrectomy being the primary treatment option. Sepsis, a systemic inflammatory response to infection, may influence tumor growth by creating an immunosuppressive environment conducive to cancer cell proliferation and metastasis. Here, the effect of abdominal infection on tumor growth and metastasis was investigated through the implementation of a peritoneal metastasis model and a subcutaneous tumor model. In a murine model induced by cecal ligation and puncture (CLP) to simulate the effects of sepsis, we observed significant immune dysregulation, including T-cell exhaustion and the release of myeloid-derived suppressor cells (MDSCs). This immune alteration was associated with increased programmed cell death protein 1 (PD-1) expression on T cells and programmed cell death 1 ligand 1 (PD-L1) expression on MDSCs within the tumor microenvironment, fostering an immune-suppressive environment. Polymorphonuclear MDSCs (PMN-MDSCs) expressing elevated PD-L1 after sepsis demonstrated more substantial suppressive effects on T-cell proliferation than controls. Treatment with anti-PD-1 monoclonal antibodies successfully restored T-cell function, reduced mortality, and decreased metastasis in CLP mice. These findings emphasize the impact of sepsis on tumor progression and suggest targeting the PD-1/PD-L1 axis as a potential therapeutic strategy for managing immune dysfunction in patients with cancer.

Keywords:  MDSC; PD‐1; gastric cancer; intra‐abdominal infectious complications; tumor microenvironment

DOI:  https://doi.org/10.1002/1878-0261.13767
Methods Cell Biol. 2025 ;pii: S0091-679X(24)00218-8. [Epub ahead of print]191 135-150

Flow cytometry-based monitoring of myeloid-derived suppressor cells in the peripheral blood of patients with solid tumors.

Anna-Jasmina Donaubauer, Ilka Scheer, Rainer Fietkau, Udo S Gaipl, Benjamin Frey.

  Myeloid-derived suppressor cells (MDSCs) ameliorate inflammation by inhibiting T cell responses. In pathological conditions, such as autoimmunity, chronic infections or cancer they accumulate in the periphery. In cancer, MDSCs can also be part of the tumor microenvironment and are associated with a worse prognosis and limited response to immunotherapy. Nowadays attempts are made to specifically target MDSCs in cancer therapy. Still, the role of MDSCs in standard cancer treatment modalities, such as radiotherapy remains mostly elusive. Here, we describe a flow cytometry-based method to determine and monitor monocytic and granulocytic-derived MDSCs directly from whole blood in an easy, fast and reliable assay. As specific surface markers for MDSCs are lacking, the assay follows a gating strategy that excludes successively the main immune cells types and analyzes the remaining events for a set of molecules that are expressed on MDSCs. This assay is especially appropriate for longitudinal analyses and clinical trials and is suitable for being integrated into more complex immunophenotyping panels to generate a comprehensive immune status.

Keywords:  Flow cytometry; Immune monitoring; Immune status; Immunophenotyping; Myeloid-derived suppressor cells

DOI:  https://doi.org/10.1016/bs.mcb.2024.10.009
Front Oncol. 2024 ;14 1467033

Endocrine treatment mechanisms in triple-positive breast cancer: from targeted therapies to advances in precision medicine.

Xiu Yang, Daxin Yang, Xue Qi, Xiujuan Luo, Guangmei Zhang.

  Triple-positive breast cancer (TPBC), defined by the co-expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), poses unique therapeutic challenges due to complex signaling interactions and resulting treatment resistance. This review summarizes key findings on the molecular mechanisms and cross-talk among ER, PR, and HER2 pathways, which drive tumor proliferation and resistance to conventional therapies. Current strategies in TPBC treatment, including endocrine and HER2-targeted therapies, are explored alongside emerging approaches such as immunotherapy and CRISPR/Cas9 gene editing. Additionally, we discuss the tumor microenvironment (TME) and its role in treatment resistance, highlighting promising avenues for intervention through combination therapies and predictive biomarkers. By addressing these interdependent pathways and optimizing therapeutic strategies, precision medicine holds significant potential for improving TPBC patient outcomes and advancing individualized cancer care.

Keywords:  endocrine therapy resistance; gene editing (CRISPR/Cas9); molecular mechanisms; precision medicine; triple-positive breast cancer

DOI:  https://doi.org/10.3389/fonc.2024.1467033
BMC Cancer. 2025 Jan 21. 25(1): 113

TGF-β signaling orchestrates cancer-associated fibroblasts in the tumor microenvironment of human hepatocellular carcinoma: unveiling insights and clinical significance.

Junwei Ge, Hongwei Jiang, Junjun Chen, Xuemin Chen, Yue Zhang, Liangrong Shi, Xiao Zheng, Jingting Jiang, Lujun Chen.

  Liver cancer, specifically hepatocellular carcinoma (HCC), stands out as one of the most formidable solid tumors, characterized by a dauntingly low survival rate. At the forefront of the tumor microenvironment (TME) orchestrating the initiation and advancement of HCC are cancer-associated fibroblasts (CAFs). TGF-β, widely recognized as a potent activator of CAFs, not only regulates their activity but also assumes a pivotal role in the metastatic journey of the tumor. In our recent study, drawing from the GEO database, we identified two fibroblast subtypes in HCC through single-cell RNA sequencing (scRNA-seq) and explore the expression and distribution of TGF-β and its receptors in the TME of HCC. Subsequently, we investigated the interactions between tumor cells expressing high levels (TGFB1high) and low levels (TGFB1low) of TGF-β in the HCC TME and the two subtypes of CAFs. We also employed multi-color immunohistochemistry (mIHC) technology to examine the expressions of FAP, α-SMA, CD4, Foxp3, and TGF-β in HCC tissues within a tissue microarray. Additionally, we analyzed clinical associations, prognostic values, and the correlation of these molecules. These insights advance our understanding of the molecular mechanisms driving HCC progression and underscore the intricate interplay between tumor cells and the stromal components of the TME.

Keywords:  Hepatocellular carcinoma; Multi-color immunohistochemistry; TGF-β; iCAF; myCAF

DOI:  https://doi.org/10.1186/s12885-025-13435-2
Vaccines (Basel). 2025 Jan 13. pii: 69. [Epub ahead of print]13(1):

Efficacy of Anti-Cancer Immune Responses Elicited Using Tumor-Targeted IL-2 Cytokine and Its Derivatives in Combined Preclinical Therapies.

Sahar Balkhi, Giorgia Bilato, Andrea De Lerma Barbaro, Paola Orecchia, Alessandro Poggi, Lorenzo Mortara.

  Effective cancer therapies must address the tumor microenvironment (TME), a complex network of tumor cells and stromal components, including endothelial, immune, and mesenchymal cells. Durable outcomes require targeting both tumor cells and the TME while minimizing systemic toxicity. Interleukin-2 (IL-2)-based therapies have shown efficacy in cancers such as metastatic melanoma and renal cell carcinoma but are limited by severe side effects. Innovative IL-2-based immunotherapeutic approaches include immunotoxins, such as antibody-drug conjugates, immunocytokines, and antibody-cytokine fusion proteins that enhance tumor-specific delivery. These strategies activate cytotoxic CD8+ T lymphocytes and natural killer (NK) cells, eliciting a potent Th1-mediated anti-tumor response. Modified IL-2 variants with reduced Treg cell activity further improve specificity and reduce immunosuppression. Additionally, IL-2 conjugates with peptides or anti-angiogenic agents offer improved therapeutic profiles. Combining IL-2-based therapies with immune checkpoint inhibitors (ICIs), anti-angiogenic agents, or radiotherapy has demonstrated synergistic potential. Preclinical and clinical studies highlight reduced toxicity and enhanced anti-tumor efficacy, overcoming TME-driven immune suppression. These approaches mitigate the limitations of high-dose soluble IL-2 therapy, promoting immune activation and minimizing adverse effects. This review critically explores advances in IL-2-based therapies, focusing on immunotoxins, immunocytokines, and IL-2 derivatives. Emphasis is placed on their role in combination strategies, showcasing their potential to target the TME and improve clinical outcomes effectively. Also, the use of IL-2 immunocytokines in "in situ" vaccination to relieve the immunosuppression of the TME is discussed.

Keywords:  IL-2; immunocytokines; immunotoxins

DOI:  https://doi.org/10.3390/vaccines13010069