bims-flamet 2023-12-10 papers

bims-flamet

Biomed News

on Cytokines and immunometabolism in metastasis

Issue of 2023–12–10
27 papers selected by
Peio Azcoaga, Biodonostia HRI

Radiation Therapy and Myeloid-derived Suppressor Cells: Breaking Down Their Cancerous Partnership.
Blockade of EP4 by ASP7657 Modulates Myeloid Cell Differentiation In Vivo and Enhances the Antitumor Effect of Radiotherapy.
Targeting dysregulated lipid metabolism in the tumor microenvironment.
Fibrinogen-like protein 2 promotes tumor immune suppression by regulating cholesterol metabolism in myeloid-derived suppressor cells.
Cancer-associated Fibroblasts in Neoadjuvant Setting for Solid Cancers.
ACAT1 deficiency in myeloid cells promotes glioblastoma progression by enhancing the accumulation of myeloid-derived suppressor cells.
Targeting beta-adrenergic receptor pathways in melanoma: how stress modulates oncogenic immunity.
Similarities and divergences in the metabolism of immune cells in cancer and helminthic infections.
Eliciting the antitumor immune response with a conditionally activated PD-L1 targeting antibody analyzed with a quantitative systems pharmacology model.
Emerging role of cancer-associated fibroblasts in esophageal squamous cell carcinoma.
Chimeric antigen receptor natural killer cells: a promising antitumor immunotherapy.
VEGF-C-expressing TAMs rewire the metastatic fate of breast cancer cells.
The role of ROS in tumor infiltrating immune cells and cancer immunotherapy.
Integrated transcriptomics, proteomics, and functional analysis to characterize the tissue-specific small extracellular vesicle network of breast cancer.
Anti-PD-1/PD-L1 therapy for colorectal cancer: Clinical implications and future considerations.
Scientific and clinical relevance of non-cellular tumor microenvironment components in ovarian cancer chemotherapy resistance.
Role of γδ T Cells in Cancer Progression and Therapy.
Polysaccharides regulate Th1/Th2 balance: A new strategy for tumor immunotherapy.
High dose Vitamin C inhibits PD-L1 by ROS-pSTAT3 signal pathway and enhances T cell function in TNBC.
Innate Lymphoid Cells in Bladder Cancer: From Mechanisms of Action to Immune Therapies.
The posttranslational regulation of amino acid transporters is critical for their function in the tumor microenvironment.
Phytochemicals in regulating PD-1/PD-L1 and immune checkpoint blockade therapy.
Chimerization of the Anti-Viral CD8+ T Cell Response with A Broad Anti-Tumor T Cell Response Reverses Inhibition of Checkpoint Blockade Therapy by Oncolytic Virotherapy.
Down-regulation of COL1A1 inhibits tumor-associated fibroblast activation and mediates matrix remodeling in the tumor microenvironment of breast cancer.
Advanced Generation Therapeutics: Biomimetic Nanodelivery System for Tumor Immunotherapy.
Peripheral blood inflammatory indexes in breast cancer: A review.
ΔNp63 is regulated by insulin/IGF-1 signaling in normal basal/progenitor mammary cells and in luminal-type breast cancer cells.

Int J Radiat Oncol Biol Phys. 2023 Nov 30. pii: S0360-3016(23)08174-9. [Epub ahead of print]

Radiation Therapy and Myeloid-derived Suppressor Cells: Breaking Down Their Cancerous Partnership.

Kyra M Boorsma Bergerud, Matthew Berkseth, Drew M Pardoll, Sudipto Ganguly, Lawrence R Kleinberg, Jessica Lawrence, David J Odde, David A Largaespada, Stephanie A Terezakis, Lindsey Sloan.

Radiation therapy (RT) has been a primary treatment modality in cancer for decades. Increasing evidence suggests RT can induce an immunosuppressive shift via upregulation of cells such as tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSC). MDSC inhibit anti-tumor immunity through potent immunosuppressive mechanisms and have the potential to be crucial tools for cancer prognosis and treatment. MDSC interact with many different pathways, desensitizing tumor tissue and interacting with tumor cells to promote therapeutic resistance. Vascular damage induced by RT triggers an inflammatory signaling cascade and potentiates hypoxia in the tumor microenvironment (TME). RT can also drastically modify cytokine and chemokine signaling in the TME to promote the accumulation of MDSC. RT activation of the STING/cGAS cytosolic DNA sensing pathway recruits MDSC through a CCR2-mediated mechanism, inhibiting the production of type 1 IFNs, hampering anti-tumor activity and immune surveillance in the TME. The upregulation of hypoxia-inducible factor-1 (HIF-1) and vascular endothelial growth factor (VEGF) mobilize MDSC to the TME. Following recruitment, MDSC promote immunosuppression by releasing reactive oxygen species (ROS), and upregulating nitric oxide (NO) production through inducible nitric oxide synthase (iNOS) expression to inhibit cytotoxic activity. Overexpression of arginase-1 on subsets of MDSC degrades L-arginine and downregulates CD3ζ, inhibiting T cell receptor reactivity. This review will discuss how radiation promotes tumor resistance through activation of immunosuppressive MDSC in the TME. It will explain current research targeting MDSC, which could serve as a promising clinical treatment strategy in the future.

DOI: https://doi.org/10.1016/j.ijrobp.2023.11.050
Biomed Res Int. 2023 ;2023 7133726

Blockade of EP4 by ASP7657 Modulates Myeloid Cell Differentiation In Vivo and Enhances the Antitumor Effect of Radiotherapy.

Toshihide Nishibata, Nobuaki Amino, Ruriko Tanaka-Kado, Susumu Tsujimoto, Tomoko Kawashima, Satoshi Konagai, Tomoyuki Suzuki, Masahiro Takeuchi.

The tumor microenvironment (TME) is thought to influence the antitumor efficacy of immuno-oncology agents through various products of both tumor and stromal cells. One immune-suppressive factor is prostaglandin E2 (PGE2), a lipid mediator whose biosynthesis is regulated by ubiquitously expressed cyclooxygenase- (COX-) 1 and inducible COX-2. By activating its receptors, PGE2 induces immune suppression to modulate differentiation of myeloid cells into myeloid-derived suppressor cells (MDSCs) rather than dendritic cells (DCs). Pharmacological blockade of prostaglandin E receptor 4 (EP4) causes a decrease in MDSCs, reprogramming of macrophage polarization, and increase in tumor-infiltrated T cells, leading to enhancement of antitumor immunity in preclinical models. Here, we report the effects of the highly potent EP4 antagonist ASP7657 on the DC population in tumor and antitumor immune activation in an immunocompetent mouse tumor model. Oral administration of ASP7657 inhibited tumor growth, which was accompanied by an increase in intratumor DC and CD8+ T cell populations and a decrease in the M-MDSC population in a CT26 immunocompetent mouse model. The antitumor activity of ASP7657 was dependent on CD8+ T cells and enhanced when combined with an antiprogrammed cell death-1 (PD-1) antibody. Notably, ASP7657 also significantly enhanced the antitumor efficacy of radiotherapy in an anti-PD-1 antibody refractory model. These results indicate that the therapeutic potential of ASP7657 arises via upregulation of DCs and subsequent CD8+ T cell activation in addition to suppression of MDSCs in mouse models and that combining EP4 antagonists with radiotherapy or an anti-PD-1 antibody can improve antitumor efficacy.

DOI: https://doi.org/10.1155/2023/7133726
Arch Pharm Res. 2023 Dec 07.

Targeting dysregulated lipid metabolism in the tumor microenvironment.

Do-Hee Kim, Na-Young Song, Hyungshin Yim.

  The reprogramming of lipid metabolism and its association with oncogenic signaling pathways within the tumor microenvironment (TME) have emerged as significant hallmarks of cancer. Lipid metabolism is defined as a complex set of molecular processes including lipid uptake, synthesis, transport, and degradation. The dysregulation of lipid metabolism is affected by enzymes and signaling molecules directly or indirectly involved in the lipid metabolic process. Regulation of lipid metabolizing enzymes has been shown to modulate cancer development and to avoid resistance to anticancer drugs in tumors and the TME. Because of this, understanding the metabolic reprogramming associated with oncogenic progression is important to develop strategies for cancer treatment. Recent advances provide insight into fundamental mechanisms and the connections between altered lipid metabolism and tumorigenesis. In this review, we explore alterations to lipid metabolism and the pivotal factors driving lipid metabolic reprogramming, which exacerbate cancer progression. We also shed light on the latest insights and current therapeutic approaches based on small molecular inhibitors and phytochemicals targeting lipid metabolism for cancer treatment. Further investigations are worthwhile to fully understand the underlying mechanisms and the correlation between altered lipid metabolism and carcinogenesis.

Keywords:  Cholesterol transport; Lipid uptake; Lipogenesis; Lipolysis; Phytochemical; Tumor microenvironment

DOI:  https://doi.org/10.1007/s12272-023-01473-y
J Immunother Cancer. 2023 Dec 06. pii: e008081. [Epub ahead of print]11(12):

Fibrinogen-like protein 2 promotes tumor immune suppression by regulating cholesterol metabolism in myeloid-derived suppressor cells.

Lei Wu, Xudong Liu, Juan Lei, Nan Zhang, Huakan Zhao, Jiangang Zhang, Huan Deng, Yongsheng Li.

   BACKGROUND: Myeloid-derived suppressor cells (MDSCs) are crucial mediators of tumor-associated immune suppression. Targeting the accumulation and activation of MDSCs has been recognized as a promising approach to enhance the effectiveness of immunotherapies for different types of cancer.
METHODS: The MC38 and B16 tumor-bearing mouse models were established to investigate the role of Fgl2 during tumor progression. Fgl2 and FcγRIIB-deficient mice, adoptive cell transfer, RNA-sequencing and flow cytometry analysis were used to assess the role of Fgl2 on immunosuppressive activity and differentiation of MDSCs.
RESULTS: Here, we show that fibrinogen-like protein 2 (Fgl2) regulates the differentiation and immunosuppressive functions of MDSCs. The absence of Fgl2 leads to an increase in antitumor CD8+ T-cell responses and a decrease in granulocytic MDSC accumulation. The regulation mechanism involves Fgl2 modulating cholesterol metabolism, which promotes the accumulation of MDSCs and immunosuppression through the production of reactive oxygen species and activation of XBP1 signaling. Inhibition of Fgl2 or cholesterol metabolism in MDSCs reduces their immunosuppressive activity and enhances differentiation. Targeting Fgl2 could potentially enhance the therapeutic efficacy of anti-PD-1 antibody in immunotherapy.
CONCLUSION: These results suggest that Fgl2 plays a role in promoting immune suppression by modulating cholesterol metabolism and targeting Fgl2 combined with PD-1 checkpoint blockade provides a promising therapeutic strategy for antitumor therapy.

Keywords:  Immune Checkpoint Inhibitors; Immunotherapy; Metabolic Networks and Pathways; Tumor Microenvironment

DOI:  https://doi.org/10.1136/jitc-2023-008081
Crit Rev Oncol Hematol. 2023 Dec 04. pii: S1040-8428(23)00314-1. [Epub ahead of print] 104226

Cancer-associated Fibroblasts in Neoadjuvant Setting for Solid Cancers.

Yanan Gu, Qiangda Chen, Hanlin Yin, Mengsu Zeng, Shanshan Gao, Xiaolin Wang.

  Therapeutic approaches for cancer have become increasingly diverse in recent times. A comprehensive understanding of the tumor microenvironment (TME) holds great potential for enhancing the precision of tumor therapies. Neoadjuvant therapy offers the possibility of alleviating patient symptoms and improving overall quality of life. Additionally, it may facilitate the reduction of inoperable tumors and prevent potential preoperative micrometastases. Within the TME, cancer-associated fibroblasts (CAFs) play a prominent role as they generate various elements that contribute to tumor progression. Particularly, extracellular matrix (ECM) produced by CAFs prevents immune cell infiltration into the TME, hampers drug penetration, and diminishes therapeutic efficacy. Therefore, this review provides a summary of the heterogeneity and interactions of CAFs within the TME, with a specific focus on the influence of neoadjuvant therapy on the microenvironment, particularly CAFs. Finally, we propose several potential and promising therapeutic strategies targeting CAFs, which may efficiently eliminate CAFs to decrease stroma density and impair their functions.

Keywords:  cancer-associated fibroblasts; chemotherapy; immunotherapy; neoadjuvant therapy; radiotherapy; solid cancer; targeted therapy

DOI:  https://doi.org/10.1016/j.critrevonc.2023.104226
Acta Pharm Sin B. 2023 Dec;13(12): 4733-4747

ACAT1 deficiency in myeloid cells promotes glioblastoma progression by enhancing the accumulation of myeloid-derived suppressor cells.

Mingjin Wang, Weida Wang, Shen You, Zhenyan Hou, Ming Ji, Nina Xue, Tingting Du, Xiaoguang Chen, Jing Jin.

  Glioblastoma (GBM) is a highly aggressive and lethal brain tumor with an immunosuppressive tumor microenvironment (TME). In this environment, myeloid cells, such as myeloid-derived suppressor cells (MDSCs), play a pivotal role in suppressing antitumor immunity. Lipometabolism is closely related to the function of myeloid cells. Here, our study reports that acetyl-CoA acetyltransferase 1 (ACAT1), the key enzyme of fatty acid oxidation (FAO) and ketogenesis, is significantly downregulated in the MDSCs infiltrated in GBM patients. To investigate the effects of ACAT1 on myeloid cells, we generated mice with myeloid-specific (LyzM-cre) depletion of ACAT1. The results show that these mice exhibited a remarkable accumulation of MDSCs and increased tumor progression both ectopically and orthotopically. The mechanism behind this effect is elevated secretion of C-X-C motif ligand 1 (CXCL1) of macrophages (Mφ). Overall, our findings demonstrate that ACAT1 could serve as a promising drug target for GBM by regulating the function of MDSCs in the TME.

Keywords:  Acetyl-CoA acetyltransferase 1; CXCL1; Glioblastoma; Lipid metabolism; Macrophages; Myeloid cells; Myeloid-derived suppressor cells; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.apsb.2023.09.005
Melanoma Res. 2023 Dec 04.

Targeting beta-adrenergic receptor pathways in melanoma: how stress modulates oncogenic immunity.

Benjamin Switzer, Igor Puzanov, Shipra Gandhi, Elizabeth A Repasky.

The intricate pathways of the sympathetic nervous system hold an inherently protective role in the setting of acute stress. This is achieved through dynamic immunomodulatory and neurobiological networks. However, excessive and chronic exposure to these stress-induced stimuli appears to cause physiologic dysfunction through several mechanisms that may impair psychosocial, neurologic, and immunologic health. Numerous preclinical observations have identified the beta-2 adrenergic receptor (β2-AR) subtype to possess the strongest impact on immune dysfunction in the setting of chronic stressful stimuli. This prolonged expression of β2-ARs appears to suppress immune surveillance and promote tumorigenesis within multiple cancer types. This occurs through several pathways, including (1) decreasing the frequency and function of CD8 + T-cells infiltrating the tumor microenvironment (TME) via inhibition of metabolic reprogramming during T cell activation, and (2) establishing an immunosuppressive profile within the TME including promotion of an exhausted T cell phenotype while simultaneously enhancing local and paracrine metastatic potential. The use of nonselective β-AR antagonists appears to reverse many chronic stress-induced tumorigenic pathways and may also provide an additive therapeutic benefit for various immune checkpoint modulating agents including commonly utilized immune checkpoint inhibitors. Here we review the translational and clinical observations highlighting the foundational hypotheses that chronic stress-induced β-AR signaling promotes a pro-tumoral immunophenotype and that blockade of these pathways may augment the therapeutic response of immune checkpoint inhibition within the scope of melanoma.

DOI: https://doi.org/10.1097/CMR.0000000000000943
Front Oncol. 2023 ;13 1251355

Similarities and divergences in the metabolism of immune cells in cancer and helminthic infections.

Diego Esperante, Mónica Itzel Martínez Gutiérrez, Mark E Issa, Alejandro Schcolnik-Cabrera, Fela Mendlovic.

  Energetic and nutritional requirements play a crucial role in shaping the immune cells that infiltrate tumor and parasite infection sites. The dynamic interaction between immune cells and the microenvironment, whether in the context of tumor or helminth infection, is essential for understanding the mechanisms of immunological polarization and developing strategies to manipulate them in order to promote a functional and efficient immune response that could aid in the treatment of these conditions. In this review, we present an overview of the immune response triggered during tumorigenesis and establishment of helminth infections, highlighting the transition to chronicity in both cases. We discuss the energetic demands of immune cells under normal conditions and in the presence of tumors and helminths. Additionally, we compare the metabolic changes that occur in the tumor microenvironment and the infection site, emphasizing the alterations that are induced to redirect the immune response, thereby promoting the survival of cancer cells or helminths. This emerging discipline provides valuable insights into disease pathogenesis. We also provide examples of novel strategies to enhance immune activity by targeting metabolic pathways that shape immune phenotypes, with the aim of achieving positive outcomes in cancer and helminth infections.

Keywords:  Th1 and Th2 response; antitumoral response; helminth infection; immune evasion; immunometabolism

DOI:  https://doi.org/10.3389/fonc.2023.1251355
CPT Pharmacometrics Syst Pharmacol. 2023 Dec 07.

Eliciting the antitumor immune response with a conditionally activated PD-L1 targeting antibody analyzed with a quantitative systems pharmacology model.

Alberto Ippolito, Hanwen Wang, Yu Zhang, Vahideh Vakil, Hojjat Bazzazi, Aleksander S Popel.

Conditionally activated molecules, such as Probody therapeutics (PbTx), have recently been investigated to improve antitumoral response while reducing systemic toxicity. PbTx are engineered to be proteolytically activated by proteases that are preferentially active locally in the tumor microenvironment (TME). Here, we perform an exploratory study using our recently published quantitative systems pharmacology model, previously validated for other drugs, to evaluate the effectiveness and targeting specificity of an anti-PD-L1 PbTx compared to the non-modified antibody. We have informed the model using the PbTx dynamics and pharmacokinetics published in the literature for anti-PD-L1 in patients with triple-negative breast cancer (TNBC). Our results suggest masking of the antibody slightly decreases its efficacy, while increasing the localization of active therapeutic component in the TME. We also perform a parameter optimization for the PbTx design and drug dosing regimens to maximize the response rate. Although our results are specific to the case of TNBC, our findings are generalizable to any conditionally activated PbTx molecule in solid tumors and suggest that design of a highly effective and selective PbTx is feasible.

DOI: https://doi.org/10.1002/psp4.13060
Pathol Res Pract. 2023 Nov 30. pii: S0344-0338(23)00703-3. [Epub ahead of print]253 155002

Emerging role of cancer-associated fibroblasts in esophageal squamous cell carcinoma.

Wenqing Li, Tianqi Xu, Hai Jin, Mingyang Li, Qingge Jia.

  Esophageal carcinoma is the sixth leading cause of cancer death globally and the majority of global cases are esophageal squamous cell carcinoma (ESCC). Difficulty in diagnosis exists as more than 70% of ESCC patients are diagnosed at the intermediate or advanced stage. Cancer-associated fibroblasts (CAFs) have been considered one of the crucial components in the process of tumor growth, promoting communications between cancer cells and the tumor microenvironment (TME). CAFs grow alongside malignancies dynamically and interact with ESCC cells to promote their progression, proliferation, invasion, tumor escape, chemo- and radio-resistance, etc. It is believed that CAFs qualify as a promising direction for treatment. Analyzing CAFs' subtypes and functions will elucidate the involvement of CAFs in ESCC and aid in therapeutics. This review summarizes current information on CAFs in ESCC and focuses on the latest interaction between CAFs and ESCC cancer cell discoveries. The origin of CAFs and their communication with ESCC cells and TME are also demonstrated. On the foundation of a thorough analysis, we highlight the clinical prospects and CAFs-related therapies in ESCC in the future.

Keywords:  Cancer-associated fibroblasts; Esophageal squamous cell carcinoma; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.prp.2023.155002
MedComm (2020). 2023 Dec;4(6): e422

Chimeric antigen receptor natural killer cells: a promising antitumor immunotherapy.

Yan Wang, Shengjie Jin, Qiqi Zhuang, Na Liu, Ruyi Chen, Sofia Abdulkadir Adam, Jie Jin, Jie Sun.

  Chimeric antigen receptor (CAR) T cells have been successfully used in adoptive cell therapy for malignancies. However, some obstacles, including side effects such as graft-versus-host disease and cytokine release syndrome, therapy resistance, limited sources, as well as high cost, limited the application of CAR T cells. Recently, CAR natural killer (NK) cells have been pursued as the effector cells for adoptive immunotherapy for their attractive merits of strong intrinsic antitumor activity and relatively mild side effects. Additionally, CAR NK cells can be available from various sources and do not require strict human leukocyte antigen matching, which suggests them as promising "off-the-shelf" products for clinical application. Although the use of CAR NK cells is restrained by the limited proliferation and impaired efficiency within the immunosuppressive tumor microenvironment, further investigation in optimizing CAR structure and combination therapies will overcome these challenges. This review will summarize the advancement of CAR NK cells, CAR NK cell manufacture, the clinical outcomes of CAR NK therapy, the challenges in the field, and prospective solutions. Besides, we will discuss the emerging application of other immune cells for CAR engineering. Collectively, this comprehensive review will provide a valuable and informative summary of current progress and evaluate challenges and future opportunities of CAR NK cells in tumor treatment.

Keywords:  NK cell; cancer; chimeric antigen receptor; hematologic malignancies; immunotherapy; leukemia; tumor microenvironment

DOI:  https://doi.org/10.1002/mco2.422
Cell Rep. 2023 Dec 01. pii: S2211-1247(23)01519-X. [Epub ahead of print]42(12): 113507

VEGF-C-expressing TAMs rewire the metastatic fate of breast cancer cells.

Kaveri Banerjee, Thomas Kerzel, Tove Bekkhus, Sabrina de Souza Ferreira, Tatjana Wallmann, Majken Wallerius, Laura-Sophie Landwehr, Dennis Alexander Agardy, Nele Schauer, Anna Malmerfeldt, Jonas Bergh, Margarita Bartish, Johan Hartman, Arne Östman, Mario Leonardo Squadrito, Charlotte Rolny.

  The expression of pro-lymphangiogenic VEGF-C in primary tumors is associated with sentinel lymph node metastasis in most solid cancer types. However, the impact of VEGF-C on distant organ metastasis remains unclear. Perivascular tumor-associated macrophages (TAMs) play a crucial role in guiding hematogenous spread of cancer cells by establishing metastatic pathways within the tumor microenvironment. This process supports breast cancer cell intravasation and metastatic dissemination. We show here that VEGF-C-expressing TAMs reduce the dissemination of mammary cancer cells to the lungs while concurrently increasing lymph node metastasis. These TAMs express podoplanin and interact with normalized tumor blood vessels expressing VEGFR3. Moreover, clinical data suggest inverse association between VEGF-C-expressing TAMs and breast cancer malignancy. Thus, our study elucidates the paradoxical role of VEGF-C-expressing TAMs in redirecting cancer cells to preferentially disseminate to lymph nodes rather than to lungs, partially achieved by normalizing tumor blood vessels and promoting lymphangiogenesis.

Keywords:  CP: Cancer; VEGFR3; breast cancer; hematogenous cancer cell spreading; hypoxia; lymph node metastases; podoplanin; tumor microenvironment of metastasis; tumor-associated macrophages; vascular endothelial growth factor-C; vascular normalization

DOI:  https://doi.org/10.1016/j.celrep.2023.113507
Metabolism. 2023 Nov 30. pii: S0026-0495(23)00351-7. [Epub ahead of print]151 155747

The role of ROS in tumor infiltrating immune cells and cancer immunotherapy.

Rushil Shah, Betul Ibis, Monisha Kashyap, Vassiliki A Boussiotis.

  Reactive oxygen species (ROS) are a group of short-lived highly reactive molecules formed intracellularly from molecular oxygen. ROS can alter biochemical, transcriptional, and epigenetic programs and have an indispensable role in cellular function. In immune cells, ROS are mediators of specialized functions such as phagocytosis, antigen presentation, activation, cytolysis, and differentiation. ROS have a fundamental role in the tumor microenvironment (TME) where they are produced by immune cell-intrinsic and -extrinsic mechanisms. ROS can act as a double-edged sword with short exposures leading to activation in various innate and adaptative immune cells, and prolonged exposures, unopposed by redox balancing antioxidants leading to exhaustion, immunosuppression, and unresponsiveness to cancer immunotherapy. Due to its plasticity and impact on the anti-tumor function of immune cells, attempts are currently in process to harness ROS biology with the purpose to improve contemporary strategies of cancer immunotherapy. Here, we provide a short overview how ROS and various antioxidant systems impact on the function of innate and adaptive immune system cells with emphasis on the TME and immune-based therapies for cancer.

Keywords:  Immune cells; Reactive oxygen species; cancer immunotherapy; cancer microenvironment

DOI:  https://doi.org/10.1016/j.metabol.2023.155747
MedComm (2020). 2023 Dec;4(6): e433

Integrated transcriptomics, proteomics, and functional analysis to characterize the tissue-specific small extracellular vesicle network of breast cancer.

Lesang Shen, Huanhuan Huang, Zichen Wei, Wuzhen Chen, Jiaxin Li, Yao Yao, Jun Zhou, Jian Liu, Shanshan Sun, Wenjie Xia, Ting Zhang, Xiuyan Yu, Jun Shen, Weilan Wang, Jingxin Jiang, Jian Huang, Ming Jiang, Chao Ni.

  Small extracellular vesicles (sEVs) are essential mediators of intercellular communication within the tumor microenvironment (TME). Although the biological features of sEVs have been characterized based on in vitro culture models, recent evidence indicates significant differences between sEVs derived from tissue and those derived from in vitro models in terms of both content and biological function. However, comprehensive comparisons and functional analyses are still limited. Here, we collected sEVs from breast cancer tissues (T-sEVs), paired normal tissues (N-sEVs), corresponding plasma (B-sEVs), and tumor organoids (O-sEVs) to characterize their transcriptomic and proteomic profiles. We identified the actual cancer-specific sEV signatures characterized by enriched cell adhesion and immunomodulatory molecules. Furthermore, we revealed the significant contribution of cancer-associated fibroblasts in the sEV network within the TME. In vitro model-derived sEVs did not entirely inherit the extracellular matrix- and immunity regulation-related features of T-sEVs. Also, we demonstrated the greater immunostimulatory ability of T-sEVs on macrophages and CD8+ T cells compared to O-sEVs. Moreover, certain sEV biomarkers derived from noncancer cells in the circulation exhibited promising diagnostic potential. This study provides valuable insights into the functional characteristics of tumor tissue-derived sEVs, highlighting their potential as diagnostic markers and therapeutic agents for breast cancer.

Keywords:  breast cancer tissues; immunoregulation; multiomics profiling; organoids; small extracellular vesicles

DOI:  https://doi.org/10.1002/mco2.433
Transl Oncol. 2023 Dec 01. pii: S1936-5233(23)00237-1. [Epub ahead of print]40 101851

Anti-PD-1/PD-L1 therapy for colorectal cancer: Clinical implications and future considerations.

Xiang Chen, Ling-Juan Chen, Xiao-Fei Peng, Ling Deng, Yan Wang, Jiu-Jiang Li, Dong-Li Guo, Xiao-Hua Niu.

  Colorectal cancer (CRC) is the third most prevalent cancer in the world. The PD-1/PD-L1 pathway plays a crucial role in modulating immune response to cancer, and PD-L1 expression has been observed in tumor and immune cells within the tumor microenvironment of CRC. Thus, immunotherapy drugs, specifically checkpoint inhibitors, have been developed to target the PD-1/PD-L1 signaling pathway, thereby inhibiting the interaction between PD-1 and PD-L1 and restoring T-cell function in cancer cells. However, the emergence of resistance mechanisms can reduce the efficacy of these treatments. To counter this, monoclonal antibodies (mAbs) have been used to improve the efficacy of CRC treatments. mAbs such as nivolumab and pembrolizumab are currently approved for CRC treatment. These antibodies impede immune checkpoint receptors, including PD-1/PD-L1, and their combination therapy shows promise in the treatment of advanced CRC. This review presents a concise overview of the use of the PD-1/PD-L1 blockade as a therapeutic strategy for CRC using monoclonal antibodies and combination therapies. Additionally, this article outlines the function of PD-1/PD-L1 as an immune response suppressor in the CRC microenvironment as well as the potential advantages of administering inflammatory agents for CRC treatment. Finally, this review analyzes the outcomes of clinical trials to examine the challenges of anti-PD-1/PD-L1 therapeutic resistance.

Keywords:  Colorectal cancer; Immune checkpoint receptors; Monoclonal antibodies; Programmed cell death‐1; Programmed cell death‐ligand 1

DOI:  https://doi.org/10.1016/j.tranon.2023.101851
Biochim Biophys Acta Rev Cancer. 2023 Dec 01. pii: S0304-419X(23)00185-3. [Epub ahead of print]1879(1): 189036

Scientific and clinical relevance of non-cellular tumor microenvironment components in ovarian cancer chemotherapy resistance.

Marta Ostrowska-Lesko, Alicja Rajtak, Gema Moreno-Bueno, Marcin Bobinski.

  The tumor microenvironment (TME) components play a crucial role in cancer cells' resistance to chemotherapeutic agents. This phenomenon is exceptionally fundamental in patients with ovarian cancer (OvCa), whose outcome depends mainly on their response to chemotherapy. Until now, most reports have focused on the role of cellular components of the TME, while less attention has been paid to the stroma and other non-cellular elements of the TME, which may play an essential role in the therapy resistance. Inhibiting these components could help define new therapeutic targets and potentially restore chemosensitivity. The aim of the present article is both to summarize the knowledge about non-cellular components of the TME in the development of OvCa chemoresistance and to suggest targeting of non-cellular elements of the TME as a valuable strategy to overcome chemoresistance and to develop new therapeutic strategies in OvCA patients.

Keywords:  Chemotherapy resistance; Non-cellular components; Ovarian cancer; TME; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.bbcan.2023.189036
Crit Rev Oncog. 2023 ;28(4): 59-70

Role of γδ T Cells in Cancer Progression and Therapy.

Vasudevaraju Padmaraju, Yogitha Sankla, Rama Rao Malla.

γδ T cells signify a foundational group of immune cells that infiltrate tumors early on, engaging in combat against cancer cells. The buildup of γδ T cells as cancer advances underscores their significance. Initially, these cells infiltrate and enact cytotoxic effects within the tumor tissue. However, in later stages, the predominant phenotype of γδ T cells undergoes changes in numerous cancers, fostering tumor growth and metastasis. Different mechanisms induced by cancer cell suppress effector action of γδ T cells and even sometimes promote cancer progression. In the early stages, stopping this mechanism clears this challenge and enables γδ T cells to effectively remove cancer cells. Given this context, it becomes imperative to delve into the mechanisms of how γδ T cells function in tumor microenvironment. This review discusses γδ T cells' role across different cancer types.

DOI: https://doi.org/10.1615/CritRevOncog.2023050067
Biomed Pharmacother. 2023 Dec 02. pii: S0753-3322(23)01774-2. [Epub ahead of print]170 115976

Polysaccharides regulate Th1/Th2 balance: A new strategy for tumor immunotherapy.

Qihang Shang, Xiaoyun Yu, Qi Sun, Huayao Li, Changgang Sun, Lijuan Liu.

  T helper (Th) cells have received extensive attention owing to their indispensable roles in anti-tumor immune responses. Th1 and Th2 cells are two key subsets of Th cells that exist in relative equilibrium through the secretion of cytokines that suppress their respective immune response. When the type of cytokine in the tumor microenvironment is altered, this equilibrium may be disrupted, leading to a shift from Th1 to Th2 immune response. Th1/Th2 imbalance is one of the decisive factors in the development of malignant tumors. Therefore, focusing on the balance of Th1/Th2 anti-tumor immune responses may enable future breakthroughs in cancer immunotherapy. Polysaccharides can regulate the imbalance between Th1 and Th2 cells and their characteristic cytokine profiles, thereby improving the tumor immune microenvironment. To our knowledge, this study is the most comprehensive assessment of the regulation of the tumor Th1/Th2 balance by polysaccharides. Herein, we systematically summarized the intrinsic molecular mechanisms of polysaccharides in the regulation of Th1 and Th2 cells to provide a new perspective and potential target drugs for improved anti-tumor immunity and delayed tumor progression.

Keywords:  Cytokines; Polysaccharide; Th1/Th2 balance; Tumor immune microenvironment

DOI:  https://doi.org/10.1016/j.biopha.2023.115976
Int Immunopharmacol. 2023 Dec 01. pii: S1567-5769(23)01648-X. [Epub ahead of print]126 111321

High dose Vitamin C inhibits PD-L1 by ROS-pSTAT3 signal pathway and enhances T cell function in TNBC.

Xixi Zhao, Mengjie Liu, Chaofan Li, Xiaoxiao Liu, Jiaqi Zhao, Hongbing Ma, Shuqun Zhang, Jingkun Qu.

  Vitamin C (VitC) presents excellent anti-tumor effect for long time. Recently, high dose VitC achieved by intravenous administration manifests superior anti-tumor effect. However, the functions and detailed mechanisms of high dose VitC's role in cancer immunity are not fully understood. This study investigates the effect of high dose VitC on PD-L1 expression in triple negative breast cancer (TNBC) and the potential mechanism. Results showed VitC inhibited PD-L1 expression in breast cancer cell lines and enhanced anti-tumor effects of T cells. Furthermore, we found VitC inhibited PD-L1 transcription through ROS-pSTAT3 signal pathways. Consistent with in vitro results, in vivo study showed VitC suppressed tumor growth in immunocompetent mice and enhanced CD8+ T cells infiltration and function in tumor microenvironment. Our findings identify the effects of high dose VitC on PD-L1 expression and provide a rationale for the use of high dose VitC as immunomodulator for cancer therapy.

Keywords:  Immunotherapy; PD-L1; TNBC; Vitamin C

DOI:  https://doi.org/10.1016/j.intimp.2023.111321
Cancer Immunol Res. 2023 Dec 07. OF1-OF12

Innate Lymphoid Cells in Bladder Cancer: From Mechanisms of Action to Immune Therapies.

Onika D V Noel, Zaineb Hassouneh, Robert S Svatek, Neelam Mukherjee.

Bladder tumors have a high mutational burden and tend to be responsive to immune therapies; however, response rates remain modest. To date, immunotherapy in bladder cancer has largely focused on enhancing T-cell immune responses in the bladder tumor microenvironment. It is anticipated that other immune cells, including innate lymphoid cells (ILC), which play an important role in bladder oncogenesis and tumor suppression, could be targeted to improve response to existing therapies. ILCs are classified into five groups: natural killer cells, ILC1s, ILC2s, ILC3s, and lymphoid tissue inducer cells. ILCs are pleiotropic and play dual and sometimes paradoxical roles in cancer development and progression. Here, a comprehensive discussion of the current knowledge and recent advancements in understanding the role of ILCs in bladder cancer is provided. We discuss the multifaceted roles that ILCs play in bladder immune surveillance, tumor protection, and immunopathology of bladder cancer. This review provides a rationale for targeting ILCs in bladder cancer, which is relevant for other solid tumors.

DOI: https://doi.org/10.1158/2326-6066.CIR-23-0414
Curr Opin Biotechnol. 2023 Dec 05. pii: S0958-1669(23)00132-5. [Epub ahead of print]85 103022

The posttranslational regulation of amino acid transporters is critical for their function in the tumor microenvironment.

Jessica C Koe, Seth J Parker.

Amino acid transporters (AATs) facilitate nutrient uptake and nutrient exchange between cancer and stromal cells. The posttranslational modification (PTM) of transporters is an important mechanism that tumor-associated cells use to dynamically regulate their function and stability in response to microenvironmental cues. In this review, we summarize recent findings that demonstrate the significance of N-glycosylation, phosphorylation, and ubiquitylation for the function of AATs. We also highlight powerful approaches that hijack the PTM machinery that could be used as therapeutics or tools to modulate transporter activity.

DOI: https://doi.org/10.1016/j.copbio.2023.103022
Phytother Res. 2023 Dec 05.

Phytochemicals in regulating PD-1/PD-L1 and immune checkpoint blockade therapy.

Qi Zhang, Chenying Yang, Xingsu Gao, Ju Dong, Caiyun Zhong.

  Clinical treatment and preclinical studies have highlighted the role of immune checkpoint blockade in cancer treatment. Research has been devoted to developing immune checkpoint inhibitors in combination with other drugs to achieve better efficacy or reduce adverse effects. Phytochemicals sourced from vegetables and fruits have demonstrated antiproliferative, proapoptotic, anti-migratory, and antiangiogenic effects against several cancers. Phytochemicals also modulate the tumor microenvironment such as T cells, regulatory T cells, and cytokines. Recently, several phytochemicals have been reported to modulate immune checkpoint proteins in in vivo or in vitro models. Phytochemicals decreased programmed cell death ligand-1 expression and synergized programmed cell death receptor 1 (PD-1) monoclonal antibody to suppress tumor growth. Combined administration of phytochemicals and PD-1 monoclonal antibody enhanced the tumor growth inhibition as well as CD4+ /CD8+ T-cell infiltration. In this review, we discuss immune checkpoint molecules as potential therapeutic targets of cancers. We further assess the impact of phytochemicals including carotenoids, polyphenols, saponins, and organosulfur compounds on cancer PD-1/programmed cell death ligand-1 immune checkpoint molecules and document their combination effects with immune checkpoint inhibitors on various malignancies.

Keywords:  PD-1/PD-L1; cancer immunotherapy; immune checkpoint; phytochemical

DOI:  https://doi.org/10.1002/ptr.8082
Res Sq. 2023 Nov 20. pii: rs.3.rs-3576281. [Epub ahead of print]

Chimerization of the Anti-Viral CD8+ T Cell Response with A Broad Anti-Tumor T Cell Response Reverses Inhibition of Checkpoint Blockade Therapy by Oncolytic Virotherapy.

Richard Vile, Mason Webb, Jacob van Vloten, Laura Evgin, Thanich Sangsuwannukul, Benjamin Kendall, Jason Tonne, Jill Thompson, Muriel Metko, Madelyn Moore, Maria Chiriboga Yerovi, Mark McNiven, Satdarshan Monga, Mitesh Borad, Lewis Roberts.

Although immune checkpoint inhibition (ICI) has produced profound survival benefits in a broad variety of tumors, a proportion of patients do not respond. Treatment failure is in part due to immune suppressive tumor microenvironments (TME), which is particularly true of hepatocellular carcinoma (HCC). Since oncolytic viruses (OV) can generate a highly immune-infiltrated, inflammatory TME, we developed a vesicular stomatitis virus expressing interferon-ß (VSV-IFNß) as a viro-immunotherapy against HCC. Since HCC standard of care atezolizumab/bevacizumab incorporates ICI, we tested the hypothesis that pro-inflammatory VSV-IFNß would recruit, prime, and activate anti-tumor T cells, whose activity anti-PD-L1 ICI would potentiate. However, in a partially anti-PD-L1-responsive model of HCC, addition of VSV-IFNß abolished anti-PD-L1 therapy. Cytometry by Time of Flight showed that VSV-IFNß expanded dominant anti-viral effector CD8 T cells with concomitant, relative disappearance of anti-tumor T cell populations which are the target of anti-PD-L1. However, by expressing a range of HCC tumor antigens within VSV, the potent anti-viral response became amalgamated with an anti-tumor T cell response generating highly significant cures compared to anti-PD-L1 ICI alone. Our data provide a cautionary message for the use of highly immunogenic viruses as tumor-specific immune-therapeutics by showing that dominant anti-viral T cell responses can inhibit sub-dominant anti-tumor T cell responses. However, by chimerizing anti-viral and anti-tumor T cell responses through encoding tumor antigens within the virus, oncolytic virotherapy can be purposed for very effective immune driven tumor clearance and can generate anti-tumor T cell populations upon which immune checkpoint blockade can effectively work.

DOI: https://doi.org/10.21203/rs.3.rs-3576281/v1
Open Life Sci. 2023 ;18(1): 20220776

Down-regulation of COL1A1 inhibits tumor-associated fibroblast activation and mediates matrix remodeling in the tumor microenvironment of breast cancer.

Bin Ma, Fangfang Li, Binlin Ma.

  We investigated the effects of collagen type I alpha 1 (COL1A1) on tumor-associated fibroblast activation and matrix remodeling in the tumor microenvironment of breast cancer. Cells were divided into the blank control, negative control, and siRNA-COL1A1 groups, or HKF control, HKF + exosomes (EXO), HKF + siRNA negative control-EXO, and HKF + siRNA-COL1A1-EXO co-culture groups. Western blot and quantitative real-time PCR detected gene expressions. COL Ⅰ, COL Ⅲ, and TGF-β1 were detected by enzyme-linked immunosorbent assay. We found that compared with blank and negative control groups, COL1A1 expression and the secretion of exosomes by breast cancer cells were inhibited in the siRNA-COL1A1 group. Compared with the HKF control group, the COL Ⅰ, COL Ⅲ, TGF-β1, α-SMA, and fibroblast activation protein (FAP) were increased, while the E-cadherin and CAV-1 were decreased in the HKF + EXO, HKF + siRNA negative control-EXO, and HKF + siRNA-COL1A1-EXO co-culture groups. Compared with HKF + EXO and HKF + siRNA negative control-EXO co-culture groups, the COL Ⅰ, COL Ⅲ, TGF-β1, α-SMA, and FAP were decreased, and the E-cadherin and CAV-1 were increased in the HKF + siRNA-COL1A1-EXO co-culture group. Collectively, COL1A1 down-regulation may inhibit exosome secretion possibly via inhibiting COL Ⅰ and upregulating CAV-1, thereby inhibiting tumor-associated fibroblast activation and matrix remodeling in the tumor microenvironment.

Keywords:  CAV-1; collagen type I A1; fibroblasts; matrix remodeling; tumor microenvironment

DOI:  https://doi.org/10.1515/biol-2022-0776
ACS Nano. 2023 Dec 06.

Advanced Generation Therapeutics: Biomimetic Nanodelivery System for Tumor Immunotherapy.

Jie Li, Huamin Zeng, Luwei Li, Qiu Yang, Lang He, Mingqing Dong.

  Tumor immunotherapy is a safe and effective strategy for precision medicine. However, immunotherapy for most cancer cases still ends in failure, with the root causes of the immunosuppressive and extraordinary heterogeneity of the solid tumors microenvironment. The emerging biomimetic nanodelivery system provides a promising tactic to improve the immunotherapy effect while reducing the adverse reactions on nontarget cells. Herein, we summarize the relationship between tumor occurrence and tumor immune microenvironment, mechanism of tumor immune escape, immunotherapy classification (including adoptive cellular therapy, cytokines, cancer vaccines, and immune checkpoint inhibitors) and recommend target cells for immunotherapy first, and then emphatically introduce the recent advances and applications of the latest biomimetic nanodelivery systems (e.g., immune cells, erythrocytes, tumor cells, platelets, bacteria) in tumor immunotherapy. Meanwhile, we separately summarize the application of tumor vaccines. Finally, the predictable challenges and perspectives in a forward exploration of biomimetic nanodelivery systems for tumor immunotherapy are also discussed.

Keywords:  biomimetic nanodelivery system; cancer vaccines; efficacy improvement strategies; immune escape mechanism; immunotherapy classification; target cells; tumor immunotherapy; tumor microenvironment

DOI:  https://doi.org/10.1021/acsnano.3c10212
Medicine (Baltimore). 2023 Dec 01. 102(48): e36315

Peripheral blood inflammatory indexes in breast cancer: A review.

Jiaqiang Xie, Zhenxi Guo, Yijing Zhu, Mingde Ma, Guangwei Jia.

Immune and inflammatory responses play an important role in tumorigenesis and metastasis. Inflammation is an important component of the tumor microenvironment, and the changes in inflammatory cells may affect the occurrence and development of tumors. Complete blood count at the time of diagnosis and treatment can reflect the inflammatory status within the tumor. Studies have shown that the number of certain inflammatory cells in peripheral blood and their ratios are important prognostic factors for many malignancies, including neutrophil, lymphocyte, monocyte, and platelet counts, as well as neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, systemic immune-inflammation index, systemic inflammation response index and pan-immune-inflammation-value. The value of peripheral blood inflammation indexes in predicting the efficacy and prognosis of breast cancer neoadjuvant therapy is worth recognizing. This review details the application of peripheral blood inflammation indexes in the evaluation of efficacy and prediction of prognosis in neoadjuvant therapy for breast cancer, aiming to provide a more comprehensive reference for the comprehensive diagnosis and treatment of breast cancer.

DOI: https://doi.org/10.1097/MD.0000000000036315
Neoplasma. 2023 Oct;pii: 230719N376. [Epub ahead of print]70(5): 621-632

ΔNp63 is regulated by insulin/IGF-1 signaling in normal basal/progenitor mammary cells and in luminal-type breast cancer cells.

Michaela Stenckova, Yajing Liu, Marta Nekulova, Jitka Holcakova, Zuzana Pokorna, Rudolf Nenutil, Alastair M Thompson, Borivoj Vojtesek, Philip John Coates.

Breast cancers are a heterogeneous group of tumors classified according to their histological growth patterns and receptor expression characteristics. Intratumor heterogeneity also exists, with subpopulations of cells with different phenotypes found in individual cancers, including cells with stem or progenitor cell properties. At least two types of breast cancer stem cells (CSCs) exist, the epithelial and the basal/mesenchymal subtypes, although how these phenotypes are controlled is unknown. ΔNp63 is a basal cell marker and regulator of stem/progenitor cell activities in the normal mammary gland and is expressed in the basal-like CSC subpopulation in some estrogen receptor-positive (ER+) and/or human epidermal growth factor receptor 2-positive (HER2+) breast adenocarcinomas. Whilst p63 is known to directly impart CSC properties in luminal breast cancer cells, how p63 is regulated and induced in these cells is unknown. We initially confirmed the existence of a small subpopulation of ΔNp63+ cells in lymph node metastases of ER+ human ductal adenocarcinomas, indicating together with previous reports that ΔNp63+ tumor cells are present in approximately 40% of these metastases. Notably, ΔNp63+ cells show a preferential location at the edge of tumor areas, suggesting possible regulation of ΔNp63 by the tumor microenvironment. Subsequently, we showed that the high levels of ΔNp63 in basal non-transformed MCF-10A mammary epithelial cells rely on insulin in their culture medium, whilst ΔNp63 levels are increased in MCF-7 ER+ luminal-type breast cancer cells treated with insulin or insulin-like growth factor 1 (IGF-1). Mechanistically, small molecule inhibitors and siRNA gene knockdown demonstrated that induction of ΔNp63 by IGF-1 requires PI3K, ERK1/2, and p38 MAPK activation, and acts through FOXO transcriptional inactivation. We also show that metformin inhibits ΔNp63 induction. These data reveal an IGF-mediated mechanism to control basal-type breast CSCs, with therapeutic implications to modify intratumor breast cancer cell heterogeneity and plasticity.

DOI: https://doi.org/10.4149/neo_2023_230719N376