bims-flamet 2024-10-13 papers

bims-flamet

Biomed News

on Cytokines and immunometabolism in metastasis

Issue of 2024–10–13
twenty papers selected by
Peio Azcoaga, Biodonostia HRI

Lipids in the tumor microenvironment: immune modulation and metastasis.
Metabolism and macrophages in the tumor microenvironment.
Transforming growth factor-β in tumor microenvironment: Understanding its impact on monocytes and macrophages for its targeting.
P2 purinergic receptor expression and function in tumor-related immune cells.
Unlocking Apoptotic Pathways: Overcoming Tumor Resistance in CAR-T-Cell Therapy.
The Immune Microenvironment in Prostate Cancer: A Comprehensive Review.
The axis of tumor-associated macrophages, extracellular matrix proteins, and cancer-associated fibroblasts in oncogenesis.
Chemoresistance and the tumor microenvironment: the critical role of cell-cell communication.
Role of indoleamine 2, 3-dioxygenase 1 in immunosuppression of breast cancer.
MALT1 protease inhibition restrains glioblastoma progression by reversing tumor-associated macrophage-dependent immunosuppression.
Characterization of the breast cancer liver metastasis microenvironment via machine learning analysis of the primary tumor microenvironment.
CD8+ T cell exhaustion and its regulatory mechanisms in the tumor microenvironment: key to the success of immunotherapy.
The sympathetic nervous system shapes the tumor microenvironment to impair chemotherapy response.
CXCL12+ Tumor-associated Endothelial Cells Promote Immune Resistance in Hepatocellular Carcinoma.
The expression patterns of different cell types and their interactions in the tumor microenvironment are predictive of breast cancer patient response to neoadjuvant chemotherapy.
CX3CR1+CD8+ T cells: Key players in antitumor immunity.
Tumor-Selective Nano-Dispatcher Enforced Cancer Immunotherapeutic Effects via Regulating Lactate Metabolism and Activating Toll-Like Receptors.
Effects of intratumoral microbiota on tumorigenesis, anti-tumor immunity, and microbe-based cancer therapy.
Siglec-G Suppresses CD8+ T Cells Responses through Metabolic Rewiring and Can be Targeted to Enhance Tumor Immunotherapy.
The role of short-chain fatty acids in cancer prevention and cancer treatment.

Front Oncol. 2024 ;14 1435480

Lipids in the tumor microenvironment: immune modulation and metastasis.

Gloria Pascual, Salvador Aznar Benitah.

  Tumor cells can undergo metabolic adaptations that support their growth, invasion, and metastasis, such as reprogramming lipid metabolism to meet their energy demands and to promote survival in harsh microenvironmental conditions, including hypoxia and acidification. Metabolic rewiring, and especially alterations in lipid metabolism, not only fuel tumor progression but also influence immune cell behavior within the tumor microenvironment (TME), leading to immunosuppression and immune evasion. These processes, in turn, may contribute to the metastatic spread of cancer. The diverse metabolic profiles of immune cell subsets, driven by the TME and tumor-derived signals, contribute to the complex immune landscape in tumors, affecting immune cell activation, differentiation, and effector functions. Understanding and targeting metabolic heterogeneity among immune cell subsets will be crucial for developing effective cancer immunotherapies that can overcome immune evasion mechanisms and enhance antitumor immunity.

Keywords:  cancer immunotherapy; lipid metabolism; metabolic adaptations; tumor metabolism; tumor micreoenvironment (TME)

DOI:  https://doi.org/10.3389/fonc.2024.1435480
Curr Opin Immunol. 2024 Oct 04. pii: S0952-7915(24)00081-5. [Epub ahead of print]91 102491

Metabolism and macrophages in the tumor microenvironment.

Hannah Yang, Chan Kim, Weiping Zou.

Tumor-associated macrophages (TAMs) constitute the primary subset of immune cells within the tumor microenvironment (TME). Exhibiting both phenotypic and functional heterogeneity, TAMs play distinct roles in tumor initiation, progression, and responses to therapy in patients with cancer. In response to various immune and metabolic cues within the TME, TAMs dynamically alter their metabolic profiles to adapt. Changes in glucose, amino acid, and lipid metabolism in TAMs, as well as their interaction with oncometabolites, not only sustain their energy demands but also influence their impact on tumor immune responses. Understanding the molecular mechanisms underlying the metabolic reprogramming of TAMs and their orchestration of metabolic processes can offer insights for the development of novel cancer immunotherapies targeting TAMs. Here, we discuss how metabolism reprograms macrophages in the TME and review clinical trials aiming to normalize metabolic alterations in TAMs and alleviate TAM-mediated immune suppression and protumor activity.

DOI: https://doi.org/10.1016/j.coi.2024.102491
Int Rev Immunol. 2024 Oct 08. 1-16

Transforming growth factor-β in tumor microenvironment: Understanding its impact on monocytes and macrophages for its targeting.

Tetiana Hourani, Amit Sharma, Rodney B Luwor, Adrian A Achuthan.

  TGF-β is a pivotal cytokine that orchestrates various aspects of cancer progression, including tumor growth, metastasis, and immune evasion. In this review, we present a comprehensive overview of the multifaceted role of transforming growth factor β (TGF-β) in cancer biology, focusing on its intricate interactions with monocytes and macrophages within the tumor microenvironment (TME). We specifically discuss how TGF-β modulates monocyte and macrophage activities, leading to immunosuppression and tumor progression. We conclude with the current translational and clinical efforts targeting TGF-β, recognizing the promising role of this strategy in immunooncology.

Keywords:  Inflammation; TGF-β; macrophages; monocytes; signaling; tumor microenvironment

DOI:  https://doi.org/10.1080/08830185.2024.2411998
Purinergic Signal. 2024 Oct 10.

P2 purinergic receptor expression and function in tumor-related immune cells.

Vahinipriya Manoharan, Oluwafemi O Adegbayi, Janielle P Maynard.

  P2 purinergic receptor expression is dysregulated in multiple cancer subtypes and is associated with worse outcomes. Studies identify roles for P2 purinergic receptors in tumor cells that drive disease aggressiveness. There is also sufficient evidence that P2 purinergic receptor expression within the tumor microenvironment (TME) is critical for disease initiation and progression. Immune cells constitute a significant component of the TME and display both tumorigenic and anti-tumorigenic potential. Studies pre-dating the investigation of P2 purinergic receptors in cancer identify P2 receptor expression on multiple immune cells including macrophages, neutrophils, T-cells, and dendritic cells; all of which are implicated in tumor initiation, tumor promotion, or response to treatment. Herein, we discuss P2 purinergic receptor expression and function in tumor-related immune cells. We provide a rationale for further investigations of P2 purinergic receptors within the TME to better define the mechanistic pathways of inflammation-mediate tumorigenesis and explore P2 purinergic receptors as potential targets for novel immunotherapeutic approaches.

Keywords:  Immune cells; Macrophages; Neutrophils; P2 purinergic receptor; T-cells; Tumor microenvironment

DOI:  https://doi.org/10.1007/s11302-024-10054-7
Cancer Med. 2024 Oct;13(19): e70283

Unlocking Apoptotic Pathways: Overcoming Tumor Resistance in CAR-T-Cell Therapy.

Zhanna Zhang, Manqi Su, Panruo Jiang, Xiaoxia Wang, Xiangmin Tong, Gongqiang Wu.

   BACKGROUND: Chimeric antigen receptor (CAR)-T-cell therapy has transformed cancer treatment, leading to remarkable clinical outcomes. However, resistance continues to be a major obstacle, significantly limiting its efficacy in numerous patients.
OBJECTIVES: This review critically examines the challenges associated with CAR-T-cell therapy, with a particular focus on the role of apoptotic pathways in overcoming resistance.
METHODS: We explore various strategies to sensitize tumor cells to CAR-T-cell-mediated apoptosis, including the use of combination therapies with BH3 mimetics, Mcl-1 inhibitors, IAP inhibitors, and HDAC inhibitors. These agents inhibit anti-apoptotic proteins and activate intrinsic mitochondrial pathways, enhancing the susceptibility of tumor cells to apoptosis. Moreover, targeting the extrinsic pathway can increase the expression of death receptors on tumor cells, further promoting their apoptosis. The review also discusses the development of novel CAR constructs that enhance anti-apoptotic protein expression, such as Bcl-2, which may counteract CAR-T cell exhaustion and improve antitumor efficacy. We assess the impact of the tumor microenvironment (TME) on CAR-T cell function and propose dual-targeting CAR-T cells to simultaneously address both myeloid-derived suppressor cells (MDSCs) and tumor cells. Furthermore, we explore the potential of combining agents like PPAR inhibitors to activate the cGAS-STING pathway, thereby improving CAR-T cell infiltration into the tumor.
CONCLUSIONS: This review highlights that enhancing tumor cell sensitivity to apoptosis and increasing CAR-T cell cytotoxicity through apoptotic pathways could significantly improve therapeutic outcomes. Targeting apoptotic proteins, particularly those involved in the intrinsic mitochondrial pathway, constitutes a novel approach to overcoming resistance. The insights presented herein lay a robust foundation for future research and clinical applications aimed at optimizing CAR-T cell therapies.

Keywords:  CAR‐T‐cell therapy resistance; apoptotic pathways; tumor; tumor microenvironment

DOI:  https://doi.org/10.1002/cam4.70283
Oncology. 2024 Oct 09. 1-37

The Immune Microenvironment in Prostate Cancer: A Comprehensive Review.

Rene Novysedlak, Miray Guney, Majd Al Khouri, Robin Bartolini, Lily Koumbas Foley, Iva Benesova, Andrej Ozaniak, Vojtech Novak, Stepan Vesely, Pavel Pacas, Tomas Buchler, Zuzana Ozaniak Strizova.

BACKGROUND: Prostate cancer (PCa) is a malignancy with significant immunosuppressive properties and limited immune activation. This immunosuppression is linked to reduced cytotoxic T-cell activity, impaired antigen presentation, and elevated levels of immunosuppressive cytokines and immune checkpoint molecules. Studies demonstrate that cytotoxic CD8+ T cell infiltration correlates with improved survival, while increased regulatory T cells (Tregs) and tumor-associated macrophages (TAMs) are associated with worse outcomes and therapeutic resistance. Th1 cells are beneficial, whereas Th17 cells, producing interleukin-17 (IL-17), contribute to tumor progression. Tumor-associated neutrophils (TANs) and immune checkpoint molecules like PD-1/PD-L1 and TIM-3 are also linked to advanced stages of PCa. Chemotherapy holds promise in converting the "cold" tumor microenvironment (TME) to a "hot" one by depleting immunosuppressive cells and enhancing tumor immunogenicity.
SUMMARY: This comprehensive review examines the immune microenvironment in PCa, focusing on the intricate interactions between immune and tumor cells in the TME. It highlights how TAMs, Tregs, cytotoxic T cells, and other immune cell types contribute to tumor progression or suppression and how PCa's low immunogenicity complicates immunotherapy.
KEY MESSAGES: The infiltration of cytotoxic CD8+ T cells and Th1 cells correlates with better outcomes, while elevated Tregs and TAMs promote tumor growth, metastasis, and resistance. TANs and NK cells exhibit dual roles, with higher NK cell levels linked to better prognoses. Immune checkpoint molecules like PD-1, PD-L1, and TIM-3 are associated with advanced disease. Chemotherapy can improve tumor immunogenicity by depleting Tregs and MDSCs, offering therapeutic promise.

DOI: https://doi.org/10.1159/000541881
Cancer Cell Int. 2024 Oct 07. 24(1): 335

The axis of tumor-associated macrophages, extracellular matrix proteins, and cancer-associated fibroblasts in oncogenesis.

Shuhong Yu, Siyu Wang, Xuanyu Wang, Ximing Xu.

  The extracellular matrix (ECM) is a complex, dynamic network of multiple macromolecules that serve as a crucial structural and physical scaffold for neighboring cells. In the tumor microenvironment (TME), ECM proteins play a significant role in mediating cellular communication between cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs). Revealing the ECM modification of the TME necessitates the intricate signaling cascades that transpire among diverse cell populations and ECM proteins. The advent of single-cell sequencing has enabled the identification and refinement of specific cellular subpopulations, which has substantially enhanced our comprehension of the intricate milieu and given us a high-resolution perspective on the diversity of ECM proteins. However, it is essential to integrate single-cell data and establish a coherent framework. In this regard, we present a comprehensive review of the relationships among ECM, TAMs, and CAFs. This encompasses insights into the ECM proteins released by TAMs and CAFs, signaling integration in the TAM-ECM-CAF axis, and the potential applications and limitations of targeted therapies for CAFs. This review serves as a reliable resource for focused therapeutic strategies while highlighting the crucial role of ECM proteins as intermediates in the TME.

Keywords:  Cancer-associated fibroblasts; Extracellular matrix; Targeted therapy; Tumor microenvironment; Tumor-associated macrophages

DOI:  https://doi.org/10.1186/s12935-024-03518-8
Cell Commun Signal. 2024 Oct 10. 22(1): 486

Chemoresistance and the tumor microenvironment: the critical role of cell-cell communication.

Bartosz Wilczyński, Alicja Dąbrowska, Julita Kulbacka, Dagmara Baczyńska.

  Resistance of cancer cells to anticancer drugs remains a major challenge in modern medicine. Understanding the mechanisms behind the development of chemoresistance is key to developing appropriate therapies to counteract it. Nowadays, with advances in technology, we are paying more and more attention to the role of the tumor microenvironment (TME) and intercellular interactions in this process. We also know that important elements of the TME are not only the tumor cells themselves but also other cell types, such as mesenchymal stem cells, cancer-associated fibroblasts, stromal cells, and macrophages. TME elements can communicate with each other indirectly (via cytokines, chemokines, growth factors, and extracellular vesicles [EVs]) and directly (via gap junctions, ligand-receptor pairs, cell adhesion, and tunnel nanotubes). This communication appears to be critical for the development of chemoresistance. EVs seem to be particularly interesting structures in this regard. Within these structures, lipids, proteins, and nucleic acids can be transported, acting as signaling molecules that interact with numerous biochemical pathways, thereby contributing to chemoresistance. Moreover, drug efflux pumps, which are responsible for removing drugs from cancer cells, can also be transported via EVs.

Keywords:  Cancer; Cell–cell communication; Chemoresistance; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12964-024-01857-7
Cancer Pathog Ther. 2024 Oct;2(4): 246-255

Role of indoleamine 2, 3-dioxygenase 1 in immunosuppression of breast cancer.

Pratyasha Sarangi.

  Breast cancer (BC) contributes greatly to global cancer incidence and is the main cause of cancer-related deaths among women globally. It is a complex disease characterized by numerous subtypes with distinct clinical manifestations. Immune checkpoint inhibitors (ICIs) are not effective in all patients and have been associated with tumor resistance and immunosuppression. Because amino acid (AA)-catabolizing enzymes have been shown to regulate immunosuppressive effects, this review investigated the immunosuppressive roles of indoleamine 2,3-dioxygenase 1 (IDO1), a tryptophan (Trp)-catabolizing enzyme, which is overexpressed in various metastatic tumors. It promotes immunomodulatory effects by depleting Trp in the regional microenvironment. This leads to a reduction in the number of immunogenic immune cells, such as effector T and natural killer (NK) cells, and an increase in tolerogenic immune cells, such as regulatory T (Treg) cells. The BC tumor microenvironment (TME) establishes a supportive niche where cancer cells can interact with immune cells and neighboring endothelial cells and is thus a feasible target for cancer therapy. In many immunological contexts, IDO1 regulates immune control by causing regional metabolic changes in the TME and tissue environment, which may further affect the maturation of systemic immunological tolerance. In the development of effective treatment targets and approaches, it is essential to understand the immunomodulatory effects exerted by AA-catabolizing enzymes, such as IDO1, on the components of the TME.

Keywords:  Breast cancer; IDO1; IDO1 inhibitor; Immunosuppression; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.cpt.2023.11.001
bioRxiv. 2024 Sep 27. pii: 2024.09.26.614808. [Epub ahead of print]

MALT1 protease inhibition restrains glioblastoma progression by reversing tumor-associated macrophage-dependent immunosuppression.

Juliana Hofstätter Azambuja, Saigopalakrishna S Yerneni, Lisa M Maurer, Hannah E Crentsil, Gabriela N Debom, Linda Klei, Mei Smyers, Chaim T Sneiderman, Kristina E Schwab, Rajesh Acharya, Yijen Lin Wu, Prasanna Ekambaram, Dong Hu, Pete J Gough, John Bertin, Ari Melnick, Gary Kohanbash, Riyue Bao, Peter C Lucas, Linda M McAllister-Lucas.

MALT1 protease is an intracellular signaling molecule that promotes tumor progression via cancer cell-intrinsic and cancer cell-extrinsic mechanisms. MALT1 has been mostly studied in lymphocytes, and little is known about its role in tumor-associated macrophages. Here, we show that MALT1 plays a key role in glioblastoma (GBM)-associated macrophages. Mechanistically, GBM tumor cells induce a MALT1-NF-κB signaling axis within macrophages, leading to macrophage migration and polarization toward an immunosuppressive phenotype. Inactivation of MALT1 protease promotes transcriptional reprogramming that reduces migration and restores a macrophage "M1-like" phenotype. Preclinical in vivo analysis shows that MALT1 inhibitor treatment results in increased immuno-reactivity of GBM-associated macrophages and reduced GBM tumor growth. Further, the addition of MALT1 inhibitor to temozolomide reduces immunosuppression in the tumor microenvironment, which may enhance the efficacy of this standard-of-care chemotherapeutic. Together, our findings suggest that MALT1 protease inhibition represents a promising macrophage-targeted immunotherapeutic strategy for the treatment of GBM.
Graphical abstract:

DOI: https://doi.org/10.1101/2024.09.26.614808
Cancer Res Commun. 2024 Oct 07.

Characterization of the breast cancer liver metastasis microenvironment via machine learning analysis of the primary tumor microenvironment.

Dylan A Goodin, Eric Chau, Junjun Zheng, Cailin O'Connell, Anjana Tiwari, Yitian Xu, Polly Niravath, Shu-Hsia Chen, Biana Godin, Hermann B Frieboes.

Breast cancer liver metastases (BCLM) are hypovascular lesions that resist intravenously administered therapies and have grim prognosis. Immunotherapeutic strategies targeting BCLM critically depend on the tumor microenvironment (TME), including tumor-associated macrophages (TAM). However, a priori characterization of the BCLM TME to optimize therapy is challenging since BCLM tissue is rarely collected. In contrast to primary breast tumors for which tissue is usually obtained and histological analysis performed, biopsies or resections of BCLM are generally discouraged due to potential complications. This study tested the novel hypothesis that BCLM TME characteristics could be inferred from the primary tumor tissue. Matched primary and metastatic human breast cancer samples were analyzed by imaging mass cytometry (IMC), identifying 20 shared marker clusters denoting macrophages (CD68, CD163, CD206), monocytes (CD14), immune response (CD56, CD4, CD8a), Programmed Cell Death protein 1 (PD1), Programmed Death Ligand 1 (PD-L1), tumor tissue (Ki-67, pERK), cell adhesion (E-cad), hypoxia (HIF1α), vascularity (CD31), and ECM (αSMA, collagen, MMP9). A machine learning (ML) workflow was implemented and trained on primary tumor clusters to classify each metastatic cluster density as being either above or below median values. The proposed approach achieved robust classification of BCLM marker data from matched primary tumor samples (AUROC ≥0.75, 95% CI ≥0.7, on the validation subsets). Top clusters for prediction included CD68+, E-cad+, CD8a+PD1+, CD206+, and CD163+MMP9+. We conclude that the proposed workflow using primary breast tumor marker data offers the potential to predict BCLM TME characteristics, with the longer term goal to inform personalized immunotherapeutic strategies targeting BCLM.

DOI: https://doi.org/10.1158/2767-9764.CRC-24-0263
Front Immunol. 2024 ;15 1476904

CD8+ T cell exhaustion and its regulatory mechanisms in the tumor microenvironment: key to the success of immunotherapy.

Biao Zhang, Jinming Liu, Yuying Mo, Kexin Zhang, Bingqian Huang, Dong Shang.

  A steady dysfunctional state caused by chronic antigen stimulation in the tumor microenvironment (TME) is known as CD8+ T cell exhaustion. Exhausted-like CD8+ T cells (CD8+ Tex) displayed decreased effector and proliferative capabilities, elevated co-inhibitory receptor generation, decreased cytotoxicity, and changes in metabolism and transcription. TME induces T cell exhaustion through long-term antigen stimulation, upregulation of immune checkpoints, recruitment of immunosuppressive cells, and secretion of immunosuppressive cytokines. CD8+ Tex may be both the reflection of cancer progression and the reason for poor cancer control. The successful outcome of the current cancer immunotherapies, which include immune checkpoint blockade and adoptive cell treatment, depends on CD8+ Tex. In this review, we are interested in the intercellular signaling network of immune cells interacting with CD8+ Tex. These findings provide a unique and detailed perspective, which is helpful in changing this completely unpopular state of hypofunction and intensifying the effect of immunotherapy.

Keywords:  CD8 + T cell; T cell exhaustion; adoptive T cell treatment; immune checkpoint blockade; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2024.1476904
Front Oncol. 2024 ;14 1460493

The sympathetic nervous system shapes the tumor microenvironment to impair chemotherapy response.

Annabel V Manoleras, Erica K Sloan, Aeson Chang.

  The tumor microenvironment influences cancer progression and response to treatments, which ultimately impacts the survival of patients with cancer. The sympathetic nervous system (SNS) is a core component of solid tumors that arise in the body. In addition to influencing cancer progression, a role for the SNS in the effectiveness of cancer treatments is beginning to emerge. This review explores evidence that the SNS impairs chemotherapy efficacy. We review findings of studies that evaluated the impact of neural ablation on chemotherapy outcomes and discuss plausible mechanisms for the impact of neural signaling on chemotherapy efficacy. We then discuss implications for clinical practice, including opportunities to block neural signaling to improve response to chemotherapy.

Keywords:  beta-blocker; cancer; chemotherapy; metastasis; neuron; sympathetic nervous system

DOI:  https://doi.org/10.3389/fonc.2024.1460493
J Hepatol. 2024 Oct 09. pii: S0168-8278(24)02618-7. [Epub ahead of print]

CXCL12+ Tumor-associated Endothelial Cells Promote Immune Resistance in Hepatocellular Carcinoma.

Yajie Lu, Yunpeng Liu, Xiaoshuang Zuo, Guodong Li, Jianlin Wang, Jianshan Liu, Xiangxu Wang, Shuning Wang, Wangqian Zhang, Kuo Zhang, Xiaoying Lei, Qiang Hao, Weina Li, Lei Liu, Meng Li, Cun Zhang, Hongmei Zhang, Yingqi Zhang, Yuan Gao.

   BACKGROUND: The tumor microenvironment (TME) plays a crucial role in the limited efficacy of existing treatments for hepatocellular carcinoma (HCC), with tumor-associated endothelial cells (TECs) serving as fundamental TME components that substantially influence tumor progression and treatment efficacy. However, the precise roles and mechanisms of TECs in HCC remain inadequately understood.
METHODS: We employed a multi-omics profiling strategy to investigate the single-cell and spatiotemporal evolution of TECs within the microenvironment of HCC tumors showcasing varied responses to immunotherapy. Through an analysis of a clinical cohort of HCC patients, we explored the correlation between TEC subpopulations and immunotherapy outcomes. The influence of TEC subsets on the immune microenvironment was confirmed through comprehensive in vitro and in vivo studies. To further explore the mechanisms of distinct TEC subpopulations in microenvironmental modulation and their impact on immunotherapy, we utilized TEC subset-specific knockout mouse models as well as humanized mouse models.
RESULTS: In this research, we identified a new subset of CXCL12+ TECs that exert a crucial role in immune suppression within the HCC TME. Functionally, CXCL12+ TECs impede the differentiation of CD8+ naïve T cells into CD8+ cytotoxic T cells by secreting CXCL12. Furthermore, they attract myeloid-derived suppressor cells (MDSCs). A bispecific antibody was developed to target both CXCL12 and PD1 specifically, showing significant promise in bolstering anti-tumor immune responses and advancing HCC therapy.
CONCLUSIONS: CXCL12+ TECs are pivotal in mediating immunosuppression within HCC microenvironment and targeting CXCL12+ TECs presents a promising approach to augment the efficacy of immunotherapies in HCC patients.
IMPACT AND IMPLICATION: This investigation reveals a pivotal mechanism in the HCC TME, where CXCL12+ TECs emerge as crucial modulators of immune suppression. The discovery of CXCL12+ TECs as inhibitors of CD8+ naïve T cell activation and recruiters of MDSCs significantly advances our grasp of the dynamic between HCC and immune regulation. Moreover, the development and application of a bispecific antibody precisely targeting CXCL12 and PD1 has proven to enhance immune responses in a humanized mouse HCC model. This finding underscores a promising therapeutic direction for HCC, offering the potential to amplify the impact of current immunotherapies.

Keywords:  CXCL12; Hepatocellular carcinoma; Immunosuppression; Immunotherapy; Tumor microenvironment; Tumor-associated endothelial cells

DOI:  https://doi.org/10.1016/j.jhep.2024.09.044
bioRxiv. 2024 Jun 14. pii: 2024.06.14.598770. [Epub ahead of print]

The expression patterns of different cell types and their interactions in the tumor microenvironment are predictive of breast cancer patient response to neoadjuvant chemotherapy.

Saugato Rahman Dhruba, Sahil Sahni, Binbin Wang, Di Wu, Padma Sheila Rajagopal, Yael Schmidt, Eldad D Shulman, Sanju Sinha, Stephen-John Sammut, Carlos Caldas, Kun Wang, Eytan Ruppin.

The tumor microenvironment (TME) is a complex ecosystem of diverse cell types whose interactions govern tumor growth and clinical outcome. While the TME's impact on immunotherapy has been extensively studied, its role in chemotherapy response remains less explored. To address this, we developed DECODEM ( DE coupling C ell-type-specific O utcomes using DE convolution and M achine learning), a generic computational framework leveraging cellular deconvolution of bulk transcriptomics to associate the gene expression of individual cell types in the TME with clinical response. Employing DECODEM to analyze the gene expression of breast cancer (BC) patients treated with neoadjuvant chemotherapy, we find that the gene expression of specific immune cells ( myeloid , plasmablasts , B-cells ) and stromal cells ( endothelial , normal epithelial , CAFs ) are highly predictive of chemotherapy response, going beyond that of the malignant cells. These findings are further tested and validated in a single-cell cohort of triple negative breast cancer. To investigate the possible role of immune cell-cell interactions (CCIs) in mediating chemotherapy response, we extended DECODEM to DECODEMi to identify such CCIs, validated in single-cell data. Our findings highlight the importance of active pre-treatment immune infiltration for chemotherapy success. The tools developed here are made publicly available and are applicable for studying the role of the TME in mediating response from readily available bulk tumor expression in a wide range of cancer treatments and indications.

DOI: https://doi.org/10.1101/2024.06.14.598770
Cancer Sci. 2024 Oct 08.

CX3CR1+CD8+ T cells: Key players in antitumor immunity.

Jiajin Ma, Yue Wu, Shaoxian Wu, Zhang Fang, Lujun Chen, Jingting Jiang, Xiao Zheng.

  CX3CR1 functions as the specific receptor for the chemokine CX3CL1, demonstrating expression across a broad spectrum of immune cells. This underscores its pivotal role in communication and response mechanisms within the immune system. Upon engagement with CX3CL1, CX3CR1 initiates a cascade of downstream signaling pathways that regulate various biological functions. In the context of tumor progression, the intricate and inhibitory nature of the tumor microenvironment presents a significant challenge to current clinical treatment techniques. This review aims to comprehensively explore the tumor-destructive potential shown by CX3CR1+CD8+ T cells. Simultaneously, it investigates the promising prospects of utilizing CX3CR1 in future tumor immunotherapies.

Keywords:  CD8+ T cell; CX3CR1; immunotherapy; tumor microenvironment

DOI:  https://doi.org/10.1111/cas.16359
Small. 2024 Oct 10. e2406870

Tumor-Selective Nano-Dispatcher Enforced Cancer Immunotherapeutic Effects via Regulating Lactate Metabolism and Activating Toll-Like Receptors.

Yang Liu, Hui Li, Yan-Yun Hao, Ling-Ling Huang, Xia Li, Jing Zou, Shi-Ying Zhang, Xiao-Yue Yang, Hong-Fei Chen, Yi-Xuan Guo, Yun-Yan Guan, Zhi-Yue Zhang.

  The development of tumors relies on lactate metabolic reprogramming to facilitate their unchecked growth and evade immune surveillance. This poses a significant challenge to the efficacy of antitumor immunity. To address this, a tumor-selective nano-dispatcher, PIMDQ/Syro-RNP, to enforce the immunotherapeutic effect through regulation of lactate metabolism and activation of toll-like receptors is developed. By using the tumor-targeting properties of c-RGD, the system can effectively deliver monocarboxylate transporters 4 (MCT4) inhibitor (Syro) to inhibit lactate efflux in tumor cells, leading to decreased lactate levels in the tumor microenvironment (TME) and increased accumulation within tumor cells. The reduction of lactate in TME will reduce the nutritional support for regulatory T cells (Tregs) and promote the effector function of T cells. The accumulation of lactate in tumor cells will lead to tumor death due to cellular acidosis. In addition, it will also reduce the uptake of glucose by tumor cells, reduce nutrient plunder, and further weaken the inhibition of T cell function. Furthermore, the pH-responsive release of Toll-like receptors (TLR) 7/8 agonist IMDQ within the TME activates dendritic cells (DCs) and promotes the infiltration of T cells. These findings offer a promising approach for enhancing tumor immune response through targeted metabolic interventions.

Keywords:  TLR7/8; immune therapy; lactate metabolism; monocarboxylate transporters 4 (MCT4); nano‐dispatcher

DOI:  https://doi.org/10.1002/smll.202406870
Front Oncol. 2024 ;14 1429722

Effects of intratumoral microbiota on tumorigenesis, anti-tumor immunity, and microbe-based cancer therapy.

Jingwei Zheng, Hao Chen.

  Intratumoral microbiota (IM) has emerged as a significant component of the previously thought sterile tumor microenvironment (TME), exerting diverse functions in tumorigenesis and immune modulation. This review outlines the historical background, classification, and diversity of IM, elucidating its pivotal roles in oncogenicity, cancer development, and progression, alongside its influence on anti-tumor immunity. The signaling pathways through which IM impacts tumorigenesis and immunity, including reactive oxygen species (ROS), β-catenin, stimulator of interferon genes (STING), and other pathways [NF-κB, Toll-like receptor (TLR), complement, RhoA/ROCK, PKR-like ER kinase (PERK)], are discussed comprehensively. Furthermore, we briefly introduce the clinical implications of IM, emphasizing its potential as a target for novel cancer therapies, diagnostic biomarkers, and prognostic indicators. Notably, microbe-based therapeutic strategies such as fecal microbiome transplantation (FMT), probiotics regulation, bacteriotherapy, bacteriophage therapy, and oncolytic virotherapy are highlighted. These strategies hold promise for enhancing the efficacy of current cancer treatments and warrant further exploration in clinical settings.

Keywords:  bacteriophage; engineered bacteria; fecal microbiome transplantation (FMT); intratumoral microbiota (IM); oncolytic virus; tumor microenvironment (TME)

DOI:  https://doi.org/10.3389/fonc.2024.1429722
Adv Sci (Weinh). 2024 Oct 07. e2403438

Siglec-G Suppresses CD8+ T Cells Responses through Metabolic Rewiring and Can be Targeted to Enhance Tumor Immunotherapy.

Shenhui Yin, Chunzhen Li, Xin Shen, Guanyu Yu, Likun Cui, Yunyang Wu, Yixian He, Shu Yu, Jie Chen, Shaoteng Lu, Guifang Qiu, Mengqi Song, Cheng Qian, Zui Zou, Yizhi Yu, Sheng Xu.

  CD8+ T cells play a critical role in cancer immune-surveillance and pathogen elimination. However, their effector function can be severely impaired by inhibitory receptors such as programmed death-1 (PD-1) and T cell immunoglobulin domain and mucin domain-3 (Tim-3). Here Siglec-G is identified as a coinhibitory receptor that limits CD8+ T cell function. Siglec-G is highly expressed on tumor-infiltrating T cells and is enriched in the exhausted T cell subset. Ablation of Siglec-G enhances the efficacy of adoptively transferred T cells and chimeric antigen receptor (CAR) T cells in suppressing solid tumors growth. Mechanistically, sialoglycan ligands, such as CD24 on tumor cells, activate the Siglec-G-SHP2 axis in CD8+ T cells, impairing metabolic reprogramming from oxidative phosphorylation to glycolysis, which dampens cytotoxic T lymphocyte (CTL) activation, expansion, and cytotoxicity. These findings discover a critical role for Siglec-G in inhibiting CD8+ T cell responses, suggesting its potential therapeutic effect in adoptive T cell therapy and tumor immunotherapy.

Keywords:  CD8+ T cells; Siglec‐G; metabolic rewiring; tumor immunotherapy

DOI:  https://doi.org/10.1002/advs.202403438
Arch Biochem Biophys. 2024 Oct 04. pii: S0003-9861(24)00294-7. [Epub ahead of print] 110172

The role of short-chain fatty acids in cancer prevention and cancer treatment.

Balaraman Kalyanaraman, Gang Cheng, Micael Hardy.

  Short-chain fatty acids (SCFAs) are microbial metabolites in the gut that may play a role in cancer prevention and treatment. They affect the metabolism of both normal and cancer cells, regulating various cellular energetic processes. SCFAs also inhibit histone deacetylases, which are targets for cancer therapy. The three main SCFAs are acetate, propionate, and butyrate, which are transported into cells through specific transporters. SCFAs may enhance the efficacy of chemotherapeutic agents and modulate immune cell metabolism, potentially reprogramming the tumor microenvironment. Although SCFAs and SCFA-generating microbes enhance therapeutic efficacy of several forms of cancer therapy, published data also support the opposing viewpoint that SCFAs mitigate the efficacy of some cancer therapies. Therefore, the relationship between SCFAs and cancer is more complex, and this review discusses some of these aspects. Clearly, further research is needed to understand the role of SCFAs, their mechanisms and applications in cancer prevention and treatment.

Keywords:  cancer prevention; chemotherapy; epigenetics; ferroptosis; immunotherapy; oxidative stress

DOI:  https://doi.org/10.1016/j.abb.2024.110172