bims-flamet 2024-03-03 papers

bims-flamet

Biomed News

on Cytokines and immunometabolism in metastasis

Issue of 2024–03–03
25 papers selected by
Peio Azcoaga, Biodonostia HRI

Study on the mechanism of MDSC-platelets and their role in the breast cancer microenvironment.
Cell-mediated barriers in cancer immunosurveillance.
Metabolic rewiring and communication in cancer immunity.
Circadian rhythms of macrophages are altered by the acidic pH of the tumor microenvironment.
IL-37 dampens immunosuppressive functions of MDSCs via metabolic reprogramming in the tumor microenvironment.
Immune cell networking in solid tumors: focus on macrophages and neutrophils.
From monocyte-derived macrophages to resident macrophages-how metabolism leads their way in cancer.
TGFβ-specific T cells induced by a TGFβ-derived immune modulatory vaccine both directly and indirectly modulate the phenotype of tumor-associated macrophages and fibroblasts.
Manipulating the tumor immune microenvironment to improve cancer immunotherapy: IGF1R, a promising target.
Co-delivery of doxorubicin and STING agonist cGAMP for enhanced antitumor immunity.
Effects of Tumor Microenvironment on the Primo Vascular Pattern in the Mouse Model of Metastatic Breast Cancer.
Unveiling the immune symphony: decoding colorectal cancer metastasis through immune interactions.
Targeting the activated microenvironment with endosialin (CD248)-directed CAR-T cells ablates perivascular cells to impair tumor growth and metastasis.
Arginase-1 specific CD8+ T cells react toward malignant and regulatory myeloid cells.
NETs unleashed: neutrophil extracellular traps boost chemotherapy against colorectal cancer.
Exploring the multifaceted effects of Interleukin-1 in lung cancer: From tumor development to immune modulation.
Recent advances in cancer-associated fibroblast: Biomarkers, signaling pathways, and therapeutic opportunities.
Nucleosides are overlooked fuels in central carbon metabolism.
Targeting PHGDH reverses the immunosuppressive phenotype of tumor-associated macrophages through α-ketoglutarate and mTORC1 signaling.
Involvement of CircRNAs in Regulating The "New Generation of Cancer Hallmarks": A Special Depiction on Hepatocellular Carcinoma.
Potential role of p53 deregulation in modulating immune responses in human malignancies: A paradigm to develop immunotherapy.
Dual-targeted CAR T-cell immunotherapies for hematological malignancies: latest updates from the 2023 ASH annual meeting.
PX-478, an HIF-1α inhibitor, impairs mesoCAR T cell antitumor function in cervical cancer.
Endothelial cells in tumor microenvironment: insights and perspectives.
The secretome from human-derived mesenchymal stem cells augments the activity of antitumor plant extracts in vitro.

Front Cell Dev Biol. 2024 ;12 1310442

Study on the mechanism of MDSC-platelets and their role in the breast cancer microenvironment.

Xinpu Han, Xiaotong Song, Zhigang Xiao, Guanghui Zhu, Ruike Gao, Baoyi Ni, Jie Li.

  Myeloid-derived suppressor cells (MDSCs) are key immunosuppressive cells in the tumor microenvironment (TME) that play critical roles in promoting tumor growth and metastasis. Tumor-associated platelets (TAPs) help cancer cells evade the immune system and promote metastasis. In this paper, we describe the interaction between MDSCs and TAPs, including their generation, secretion, activation, and recruitment, as well as the effects of MDSCs and platelets on the generation and changes in the immune, metabolic, and angiogenic breast cancer (BC) microenvironments. In addition, we summarize preclinical and clinical studies, traditional Chinese medicine (TCM) therapeutic approaches, and new technologies related to targeting and preventing MDSCs from interacting with TAPs to modulate the BC TME, discuss the potential mechanisms, and provide perspectives for future development. The therapeutic strategies discussed in this review may have implications in promoting the normalization of the BC TME, reducing primary tumor growth and distant lung metastasis, and improving the efficiency of anti-tumor therapy, thereby improving the overall survival (OS) and progression-free survival (PFS) of patients. However, despite the significant advances in understanding these mechanisms and therapeutic strategies, the complexity and heterogeneity of MDSCs and side effects of antiplatelet agents remain challenging. This requires further investigation in future prospective cohort studies.

Keywords:  MDSCs; breast cancer; mechanisms; microenvironment; platelets

DOI:  https://doi.org/10.3389/fcell.2024.1310442
Life Sci. 2024 Feb 24. pii: S0024-3205(24)00117-6. [Epub ahead of print]342 122528

Cell-mediated barriers in cancer immunosurveillance.

Jafar Rezaie, Leila Chodari, Shadi Mohammadpour-Asl, Abbas Jafari, Zahra Niknam.

  The immune cells within the tumor microenvironment (TME) exert multifaceted functions ranging from tumor-antagonizing or tumor-promoting activities. During the initial phases of tumor development, the tumor-antagonizing immune cells in the TME combat cancer cells in an immune surveillance process. However, with time, cancer cells can evade detection and impede the immune cells' effectiveness through diverse mechanisms, such as decreasing immunogenic antigen presentation on their surfaces and/or secreting anti-immune factors that cause tolerance in TME. Moreover, some immune cells cause immunosuppressive situations and inhibit antitumoral immune responses. Physical and cellular-mediated barriers in the TME, such as cancer-associated fibroblasts, tumor endothelium, the altered lipid composition of tumor cells, and exosomes secreted from cancer cells, also mediate immunosuppression and prevent extravasation of immune cells. Due to successful clinical outcomes of cancer treatment strategies the potential barriers must be identified and addressed. We need to figure out how to optimize cancer immunotherapy strategies, and how to combine therapeutic approaches for maximum clinical benefit. This review provides a detailed overview of various cells and molecules in the TME, their association with escaping from immune surveillance, therapeutic targets, and future perspectives for improving cancer immunotherapy.

Keywords:  Cellular barriers; Immune cells; Immune evading; Immune surveillance; Immunosuppression; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.lfs.2024.122528
Cell Chem Biol. 2024 Feb 26. pii: S2451-9456(24)00075-8. [Epub ahead of print]

Metabolic rewiring and communication in cancer immunity.

Nicole M Chapman, Hongbo Chi.

The immune system shapes tumor development and progression. Although immunotherapy has transformed cancer treatment, its overall efficacy remains limited, underscoring the need to uncover mechanisms to improve therapeutic effects. Metabolism-associated processes, including intracellular metabolic reprogramming and intercellular metabolic crosstalk, are emerging as instructive signals for anti-tumor immunity. Here, we first summarize the roles of intracellular metabolic pathways in controlling immune cell function in the tumor microenvironment. How intercellular metabolic communication regulates anti-tumor immunity, and the impact of metabolites or nutrients on signaling events, are also discussed. We then describe how targeting metabolic pathways in tumor cells or intratumoral immune cells or via nutrient-based interventions may boost cancer immunotherapies. Finally, we conclude with discussions on profiling and functional perturbation methods of metabolic activity in intratumoral immune cells, and perspectives on future directions. Uncovering the mechanisms for metabolic rewiring and communication in the tumor microenvironment may enable development of novel cancer immunotherapies.

DOI: https://doi.org/10.1016/j.chembiol.2024.02.001
bioRxiv. 2024 Feb 16. pii: 2024.02.14.580339. [Epub ahead of print]

Circadian rhythms of macrophages are altered by the acidic pH of the tumor microenvironment.

Amelia M Knudsen-Clark, Daniel Mwangi, Juliana Cazarin, Lauren M Hablitz, Minsoo Kim, Brian J Altman.

Macrophages are prime therapeutic targets due to their pro-tumorigenic and immunosuppressive functions in tumors, but varying efficacy of therapeutic approaches targeting macrophages highlights our incomplete understanding of how the tumor microenvironment (TME) can influence regulation of macrophages. The circadian clock is a key internal regulator of macrophage function, but how circadian rhythms of macrophages may be influenced by the tumor microenvironment remains unknown. We found that conditions associated with the TME such as polarizing stimuli, acidic pH, and elevated lactate concentrations can each alter circadian rhythms in macrophages. Circadian rhythms were enhanced in pro-resolution macrophages but suppressed in pro-inflammatory macrophages, while acidic pH had divergent effects on circadian rhythms depending on macrophage phenotype. While cyclic AMP (cAMP) has been reported to play a role in macrophage response to acidic pH, our results indicate that pH-driven changes in circadian rhythms are not mediated solely by the cAMP signaling pathway. Remarkably, clock correlation distance analysis of tumor-associated macrophages (TAMs) revealed evidence of circadian disorder in TAMs. This is the first report providing evidence that circadian rhythms of macrophages are altered within the TME. Our data suggest that heterogeneity in circadian rhythms at the population level may underlie this circadian disorder. Finally, we sought to determine how circadian regulation of macrophages impacts tumorigenesis, and found that tumor growth was suppressed when macrophages had a functional circadian clock. Our work demonstrates a novel mechanism by which the tumor microenvironment can influence macrophage biology through altering circadian rhythms, and the contribution of circadian rhythms in macrophages to suppressing tumor growth.

DOI: https://doi.org/10.1101/2024.02.14.580339
Cell Rep. 2024 Feb 26. pii: S2211-1247(24)00163-3. [Epub ahead of print]43(3): 113835

IL-37 dampens immunosuppressive functions of MDSCs via metabolic reprogramming in the tumor microenvironment.

Yu Mei, Ying Zhu, Kylie Su Mei Yong, Zuhairah Binte Hanafi, Huanle Gong, Yonghao Liu, Huey Yee Teo, Muslima Hussain, Yuan Song, Qingfeng Chen, Haiyan Liu.

  Interleukin-37 (IL-37) has been shown to inhibit tumor growth in various cancer types. However, the immune regulatory function of IL-37 in the tumor microenvironment is unclear. Here, we established a human leukocyte antigen-I (HLA-I)-matched humanized patient-derived xenograft hepatocellular carcinoma (HCC) model and three murine orthotopic HCC models to study the function of IL-37 in the tumor microenvironment. We found that IL-37 inhibited HCC growth and promoted T cell activation. Further study revealed that IL-37 impaired the immunosuppressive capacity of myeloid-derived suppressor cells (MDSCs). Pretreatment of MDSCs with IL-37 before adoptive transfer attenuated their tumor-promoting function in HCC tumor-bearing mice. Moreover, IL-37 promoted both glycolysis and oxidative phosphorylation in MDSCs, resulting in the upregulation of ATP release, which impaired the immunosuppressive capacity of MDSCs. Collectively, we demonstrated that IL-37 inhibited tumor development through dampening MDSCs' immunosuppressive capacity in the tumor microenvironment via metabolic reprogramming, making it a promising target for future cancer immunotherapy.

Keywords:  ATP; CP: Cancer; CP: Immunology; Interleukin-37; hepatocellular carcinoma; metabolism; myeloid-derived suppressor cells

DOI:  https://doi.org/10.1016/j.celrep.2024.113835
Front Immunol. 2024 ;15 1341390

Immune cell networking in solid tumors: focus on macrophages and neutrophils.

Irene Di Ceglie, Silvia Carnevale, Anna Rigatelli, Giovanna Grieco, Piera Molisso, Sebastien Jaillon.

  The tumor microenvironment is composed of tumor cells, stromal cells and leukocytes, including innate and adaptive immune cells, and represents an ecological niche that regulates tumor development and progression. In general, inflammatory cells are considered to contribute to tumor progression through various mechanisms, including the formation of an immunosuppressive microenvironment. Macrophages and neutrophils are important components of the tumor microenvironment and can act as a double-edged sword, promoting or inhibiting the development of the tumor. Targeting of the immune system is emerging as an important therapeutic strategy for cancer patients. However, the efficacy of the various immunotherapies available is still limited. Given the crucial importance of the crosstalk between macrophages and neutrophils and other immune cells in the formation of the anti-tumor immune response, targeting these interactions may represent a promising therapeutic approach against cancer. Here we will review the current knowledge of the role played by macrophages and neutrophils in cancer, focusing on their interaction with other immune cells.

Keywords:  anti-tumor immunity; immune cell network; tumor microenvironment; tumor-associated macrophages; tumor-associated neutrophils

DOI:  https://doi.org/10.3389/fimmu.2024.1341390
Mol Oncol. 2024 Feb 27.

From monocyte-derived macrophages to resident macrophages-how metabolism leads their way in cancer.

Ummi Ammarah, Andreia Pereira-Nunes, Marcello Delfini, Massimiliano Mazzone.

  Macrophages are innate immune cells that play key roles during both homeostasis and disease. Depending on the microenvironmental cues sensed in different tissues, macrophages are known to acquire specific phenotypes and exhibit unique features that, ultimately, orchestrate tissue homeostasis, defense, and repair. Within the tumor microenvironment, macrophages are referred to as tumor-associated macrophages (TAMs) and constitute a heterogeneous population. Like their tissue resident counterpart, TAMs are plastic and can switch function and phenotype according to the niche-derived stimuli sensed. While changes in TAM phenotype are known to be accompanied by adaptive alterations in their cell metabolism, it is reported that metabolic reprogramming of macrophages can dictate their activation state and function. In line with these observations, recent research efforts have been focused on defining the metabolic traits of TAM subsets in different tumor malignancies and understanding their role in cancer progression and metastasis formation. This knowledge will pave the way to novel therapeutic strategies tailored to cancer subtype-specific metabolic landscapes. This review outlines the metabolic characteristics of distinct TAM subsets and their implications in tumorigenesis across multiple cancer types.

Keywords:  cancer metabolism; immunometabolism; monocyte-derived macrophages; tissue-resident macrophages; tumor microenvironment; tumor-associated macrophages

DOI:  https://doi.org/10.1002/1878-0261.13618
J Immunother Cancer. 2024 Feb 27. pii: e008405. [Epub ahead of print]12(2):

TGFβ-specific T cells induced by a TGFβ-derived immune modulatory vaccine both directly and indirectly modulate the phenotype of tumor-associated macrophages and fibroblasts.

Maria Perez-Penco, Lucia Lara de la Torre, Inés Lecoq, Evelina Martinenaite, Mads Hald Andersen.

  The tumor microenvironment (TME) of pancreatic cancer is highly immunosuppressive. We recently developed a transforming growth factor (TGF)β-based immune modulatory vaccine that controlled tumor growth in a murine model of pancreatic cancer by targeting immunosuppression and desmoplasia in the TME. We found that treatment with the TGFβ vaccine not only reduced the percentage of M2-like tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) in the tumor but polarized CAFs away from the myofibroblast-like phenotype. However, whether the immune modulatory properties of the TGFβ vaccine on TAM and CAF phenotypes are a direct consequence of the recognition and subsequent targeting of these subsets by TGFβ-specific T cells or an indirect consequence of the overall modulation induced within the TME remains unknown. Recognition of M2 macrophages and fibroblast by TGFβ-specific T cells was assessed by ELISpot and flow cytometry. The indirect and direct effects of the TGFβ vaccine on these cell subsets were evaluated by culturing M2 macrophages or fibroblasts with tumor-conditioned media or with T cells isolated from the spleen of mice treated with the TGFβ vaccine or a control vaccine, respectively. Changes in phenotype were assessed by flow cytometry and Bio-Plex multiplex system (Luminex). We found that TGFβ-specific T cells induced by the TGFβ vaccine can recognize M2 macrophages and fibroblasts. Furthermore, we demonstrated that the phenotype of M2 macrophages and CAFs can be directly modulated by TGFβ-specific T cells induced by the TGFβ vaccine, as well as indirectly modulated as a result of the immune-modulatory effects of the vaccine within the TME. TAMs tend to have tumor-promoting functions, harbor an immunosuppressive phenotype and are linked to decreased overall survival in pancreatic cancer when they harbor an M2-like phenotype. In addition, myofibroblast-like CAFs create a stiff extracellular matrix that restricts T cell infiltration, impeding the effectiveness of immune therapies in desmoplastic tumors, such as pancreatic ductal adenocarcinoma. Reducing immunosuppression and immune exclusion in pancreatic tumors by targeting TAMs and CAFs with the TGFβ-based immune modulatory vaccine emerges as an innovative strategy for the generation of a more favorable environment for immune-based therapies, such as immune checkpoint inhibitors.

Keywords:  Immunomodulation; Macrophage; Transforming Growth Factors; Tumor Microenvironment; Vaccine

DOI:  https://doi.org/10.1136/jitc-2023-008405
Front Immunol. 2024 ;15 1356321

Manipulating the tumor immune microenvironment to improve cancer immunotherapy: IGF1R, a promising target.

Marsha Pellegrino, Valerio Secli, Silvia D'Amico, Lucia Lisa Petrilli, Matteo Caforio, Valentina Folgiero, Nicola Tumino, Paola Vacca, Maria Vinci, Doriana Fruci, Emmanuel de Billy.

  Cancer immunotherapy has made impressive advances in improving the outcome of patients affected by malignant diseases. Nonetheless, some limitations still need to be tackled to more efficiently and safely treat patients, in particular for those affected by solid tumors. One of the limitations is related to the immunosuppressive tumor microenvironment (TME), which impairs anti-tumor immunity. Efforts to identify targets able to turn the TME into a milieu more auspicious to current immuno-oncotherapy is a real challenge due to the high redundancy of the mechanisms involved. However, the insulin-like growth factor 1 receptor (IGF1R), an attractive drug target for cancer therapy, is emerging as an important immunomodulator and regulator of key immune cell functions. Here, after briefly summarizing the IGF1R signaling pathway in cancer, we review its role in regulating immune cells function and activity, and discuss IGF1R as a promising target to improve anti-cancer immunotherapy.

Keywords:  IGF1R; cancer immunity; immuno-oncotherapy; immunomodulation; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2024.1356321
Int J Pharm. 2024 Feb 27. pii: S0378-5173(24)00189-3. [Epub ahead of print] 123955

Co-delivery of doxorubicin and STING agonist cGAMP for enhanced antitumor immunity.

Yi Xie, Kangkang Li, Jinxin Liang, Kaixuan Wang, Zixuan Gong, Xuehong Chen.

  Many chemotherapeutic agents can induce immunogenic cell death (ICD), which leads to the release of danger-associated molecular patterns (DAMPs) and tumor-associated antigens. This process promotes dendritic cells (DCs) maturation and cytotoxic T lymphocyte (CTL) infiltration. However, cancer cells can employ diverse mechanisms to evade the host immune system. Recent studies have shown that stimulator of interferon genes (STING) agonists, such as cGAMP, can amplify ICD-triggered immune responses and enhance the infiltration of immune cells into the tumor microenvironment (TME). Building upon these findings, we constructed a doxorubicin (DOX) and cGAMP co-delivery system (DOX/cGAMP@NPs) for melanoma and triple-negative breast cancer (TNBC) therapy. The results demonstrated that DOX could effectively destroy tumors and induce the release of DAMPs by ICD. Furthermore, in orthotopic 4T1 tumors mice model and subcutaneous B16 tumor mice model, cGAMP could promote the maturation of DCs and CD8+ T cell activation and infiltration by inducing the secretion of type I interferons and pro-inflammation cytokine, which amplified the antitumor immune response induced by DOX. This strategy also promoted the depletion of immunosuppressive cells, potentially alleviating the immunosuppressive TME. In conclusion, our study highlights the combination of DOX-induced ICD and the immune-enhancing properties of cGAMP holds significant implications for future research and clinical applications.

Keywords:  Doxorubicin; Immunotherapy; STING

DOI:  https://doi.org/10.1016/j.ijpharm.2024.123955
J Acupunct Meridian Stud. 2024 Feb 29. 17(1): 23-27

Effects of Tumor Microenvironment on the Primo Vascular Pattern in the Mouse Model of Metastatic Breast Cancer.

Amir Atashi, Mohammad Kamalabadi-Farahani, Nariman Rezaei Kolarijani.

   Background: : Tumor survival, promotion, and metastatic functions are regulated by the tumor microenvironment (TME). The primo vascular system (PVS), the third circulatory system in animals, is currently thought to be a highly effective pathway for the spread of cancer cells.
Objectives: : In the present study, we intend to determine the TME effects on the PVS pattern in breast cancer for the first time.
Methods: : Heterotopic and orthotopic metastatic triple-negative breast cancer (TNBC) mice models were created. After 35 days, the skin was retracted, and a 2 cm skin incision was made up and down from the surface of the tumor tissue. In preparation for PVS staining, the dyes (trypan blue and alamarBlue) were injected throughout the tumor tissues. Under a stereomicroscope, PVS in heterotopic and orthotopic tumors was seen.
Results: : According to our data, there are no appreciable variations in PVS patterns and density between heterotopic and orthotopic animal models. Furthermore, alamarBlue is a good option for tumor PVS staining, as demonstrated by our research.
Conclusion: : For the first time, our data gave significant new information about the PVS in TNBC. Creating new anti-cancer treatments may be made possible by a better understanding of the biological characteristics of the TME and PVS.

Keywords:  Breast cancer; Metastasis; Primo vascular system; Tumor microenvironment

DOI:  https://doi.org/10.51507/j.jams.2024.17.1.23
Front Immunol. 2024 ;15 1362709

Unveiling the immune symphony: decoding colorectal cancer metastasis through immune interactions.

Ru He, Shangke Huang, Jiaan Lu, Lanqian Su, Xinrui Gao, Hao Chi.

  Colorectal cancer (CRC), known for its high metastatic potential, remains a leading cause of cancer-related death. This review emphasizes the critical role of immune responses in CRC metastasis, focusing on the interaction between immune cells and tumor microenvironment. We explore how immune cells, through cytokines, chemokines, and growth factors, contribute to the CRC metastasis cascade, underlining the tumor microenvironment's role in shaping immune responses. The review addresses CRC's immune evasion tactics, especially the upregulation of checkpoint inhibitors like PD-1 and CTLA-4, highlighting their potential as therapeutic targets. We also examine advanced immunotherapies, including checkpoint inhibitors and immune cell transplantation, to modify immune responses and enhance treatment outcomes in CRC metastasis. Overall, our analysis offers insights into the interplay between immune molecules and the tumor environment, crucial for developing new treatments to control CRC metastasis and improve patient prognosis, with a specific focus on overcoming immune evasion, a key aspect of this special issue.

Keywords:  PD-L1; TME; immune escape mechanisms; immunization checkpoints; immunological characteristic; metastatic colorectal cancer; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2024.1362709
J Immunother Cancer. 2024 Feb 27. pii: e008608. [Epub ahead of print]12(2):

Targeting the activated microenvironment with endosialin (CD248)-directed CAR-T cells ablates perivascular cells to impair tumor growth and metastasis.

Sarah L Ash, Rebecca Orha, Holly Mole, Meg Dinesh-Kumar, Steven P Lee, Frances K Turrell, Clare M Isacke.

   BACKGROUND: Targeting of solid cancers with chimeric antigen receptor (CAR)-T cells is limited by the lack of suitable tumor-specific antigens and the immunosuppressive, desmoplastic tumor microenvironment that impedes CAR-T cell infiltration, activity and persistence. We hypothesized that targeting the endosialin (CD248) receptor, strongly expressed by tumor-associated pericytes and perivascular cancer-associated fibroblasts, would circumvent these challenges and offer an exciting antigen for CAR-T cell therapy due to the close proximity of target cells to the tumor vasculature, the limited endosialin expression in normal tissues and the lack of phenotype observed in endosialin knockout mice.
METHODS: We generated endosialin-directed E3K CAR-T cells from three immunocompetent mouse strains, BALB/c, FVB/N and C57BL/6. E3K CAR-T cell composition (CD4+/CD8+ ratio), activity in vitro against endosialin+ and endosialin- cells, and expansion and activity in vivo in syngeneic tumor models as well as in tumor-naive healthy and wounded mice and tumor-bearing endosialin knockout mice was assessed.
RESULTS: E3K CAR-T cells were active in vitro against both mouse and human endosialin+, but not endosialin-, cells. Adoptively transferred E3K CAR-T cells exhibited no activity in endosialin knockout mice, tumor-naive endosialin wildtype mice or in wound healing models, demonstrating an absence of off-target and on-target/off-tumor activity. By contrast, adoptive transfer of E3K CAR-T cells into BALB/c, FVB/N or C57BL/6 mice bearing syngeneic breast or lung cancer lines depleted target cells in the tumor stroma resulting in increased tumor necrosis, reduced tumor growth and a substantial impairment in metastatic outgrowth.
CONCLUSIONS: Together these data highlight endosialin as a viable antigen for CAR-T cell therapy and that targeting stromal cells closely associated with the tumor vasculature avoids CAR-T cells having to navigate the harsh immunosuppressive tumor microenvironment. Further, the ability of E3K CAR-T cells to recognize and target both mouse and human endosialin+ cells makes a humanized and optimized E3K CAR a promising candidate for clinical development applicable to a broad range of solid tumor types.

Keywords:  Breast Cancer; Chimeric antigen receptor - CAR; Lung Cancer; Tumor microenvironment - TME

DOI:  https://doi.org/10.1136/jitc-2023-008608
Oncoimmunology. 2024 ;13(1): 2318053

Arginase-1 specific CD8+ T cells react toward malignant and regulatory myeloid cells.

Hannah Jorinde Glöckner, Evelina Martinenaite, Thomas Landkildehus Lisle, Jacob Grauslund, Shamaila Ahmad, Özcan Met, Per Thor Straten, Mads Hald Andersen.

  Arginase-1 (Arg1) is expressed by regulatory myeloid cells in the tumor microenvironment (TME), where they play a pro-tumorigenic and T-cell suppressive role. Arg1-specific CD4+ and CD8+ memory T cells have been observed in both healthy individuals and cancer patients. However, while the function of anti-regulatory Arg1-specific CD4+ T cells has been characterized, our knowledge of CD8+ Arg1-specific T cells is only scarce. In the current study, we describe the immune-modulatory capabilities of CD8+ Arg1-specific T cells. We generated CD8+ Arg1-specific T cell clones to target Arg1-expressing myeloid cells. Our results demonstrate that these T cells recognize both malignant and nonmalignant regulatory myeloid cells in an Arg1-expression-dependent manner. Notably, Arg1-specific CD8+ T cells possess cytolytic effector capabilities. Immune modulatory vaccines (IMVs) represent a novel treatment modality for cancer. The activation of Arg1-specific CD8+ T cells through Arg1-based IMVs can contribute to the modulatory effects of this treatment strategy.

Keywords:  Arginase-1; anti-regulatory T cells; immune modulatory vaccines; myeloid cells; tumor microenvironment

DOI:  https://doi.org/10.1080/2162402X.2024.2318053
J Clin Invest. 2024 Mar 01. pii: e178344. [Epub ahead of print]134(5):

NETs unleashed: neutrophil extracellular traps boost chemotherapy against colorectal cancer.

Alexandra Mousset, Jean Albrengues.

Chemotherapy, which primarily acts on cancer cells, can influence the tumor microenvironment and the recruitment and behavior of stromal cells. In this issue of the JCI, Li et al. explored the potent anticancer effect of the combination of a glutaminase inhibitor (CB-839) and 5-FU against PIK3CA-mutant colorectal cancer tumors. This chemotherapy treatment strongly induced the recruitment of neutrophils that formed neutrophil extracellular traps in cancer, which actively killed cancer cells by inducing apoptosis. This study substantially advances our understanding of the multifaceted role of neutrophils and NETs in the outcome of anticancer treatment.

DOI: https://doi.org/10.1172/JCI178344
Life Sci. 2024 Feb 27. pii: S0024-3205(24)00128-0. [Epub ahead of print]342 122539

Exploring the multifaceted effects of Interleukin-1 in lung cancer: From tumor development to immune modulation.

Mingbo Tang, Yipeng Yin, Wei Wang, Kejian Gong, Junxue Dong, Xinliang Gao, Jialin Li, Linan Fang, Jianzun Ma, Yang Hong, Zhiqin Li, Taiyu Bi, Wenyu Zhang, Wei Liu.

  Lung cancer, acknowledged as one of the most fatal cancers globally, faces limited treatment options on an international scale. The success of clinical treatment is impeded by challenges such as late diagnosis, restricted treatment alternatives, relapse, and the emergence of drug resistance. This predicament has led to a saturation point in lung cancer treatment, prompting a rapid shift in focus towards the tumor microenvironment (TME) as a pivotal area in cancer research. Within the TME, Interleukin-1 (IL-1) is abundantly present, originating from immune cells, tissue stromal cells, and tumor cells. IL-1's induction of pro-inflammatory mediators and chemokines establishes an inflammatory milieu influencing tumor occurrence, development, and the interaction between tumors and the host immune system. Notably, IL-1 expression in the TME exhibits characteristics such as staging, tissue specificity, and functional pluripotency. This comprehensive review aims to delve into the impact of IL-1 on lung cancer, encompassing aspects of occurrence, invasion, metastasis, immunosuppression, and immune surveillance. The ultimate goal is to propose a novel treatment approach, considering the intricate dynamics of IL-1 within the TME.

Keywords:  IL-1; Immunotherapy resistance; Lung cancer; Metastasis; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.lfs.2024.122539
Chin Med J (Engl). 2024 Feb 29.

Recent advances in cancer-associated fibroblast: Biomarkers, signaling pathways, and therapeutic opportunities.

Donger Zhou, Lei Zheng.

ABSTRACT: Anti-cancer therapies usually focus on tumor cells, but non-tumor stromal components in the tumor microenvironment also play vital roles in tumor initiation and progression, which may be the prognostic factors and potential therapeutic targets. Cancer-associated fibroblasts (CAFs) are the essential component in the tumor environment, exhibiting high heterogeneity in their cell origin and phenotype with diverse functions that influence tumor angiogenesis, immune systems, and metabolism. Single-cell RNA sequencing and genetically engineered mouse models have increased our understanding of CAF diversity, and many subtypes have been defined. However, the precise functions of these subtypes need to be studied and validated. Studies of signaling pathways and epigenetic changes in CAFs facilitate understanding of the phenotypes of CAFs and the crosstalk between tumor cells and CAFs to provide potential therapeutic targets. Some clinical trials, including phase III trials targeting CAFs, have been performed recently. However, few of these trials have generated promising results, which indicates that the complexity of CAFs in the tumor microenvironment remains largely unknown, and in-depth investigations of CAFs should be performed. This review summarizes the research on CAFs, focusing on the heterogeneity of their phenotypes and functions, specific signaling pathways, and the therapeutic strategies involving CAFs. Additionally, we briefly discuss the current technologies commonly used in CAF studies and describe the challenges and future perspectives of CAF research.

DOI: https://doi.org/10.1097/CM9.0000000000003031
Trends Endocrinol Metab. 2024 Feb 29. pii: S1043-2760(24)00027-4. [Epub ahead of print]

Nucleosides are overlooked fuels in central carbon metabolism.

Abigail Strefeler, Joan Blanco-Fernandez, Alexis A Jourdain.

  From our daily nutrition and synthesis within cells, nucleosides enter the bloodstream and circulate throughout the body and tissues. Nucleosides and nucleotides are classically viewed as precursors of nucleic acids, but recently they have emerged as a novel energy source for central carbon metabolism. Through catabolism by nucleoside phosphorylases, the ribose sugar group is released and can provide substrates for lower steps in glycolysis. In environments with limited glucose, such as at sites of infection or in the tumor microenvironment (TME), cells can use, and may even require, this alternative energy source. Here, we discuss the implications of these new findings in health and disease and speculate on the potential new roles of nucleosides and nucleic acids in energy metabolism.

Keywords:  Metabolism; UPP1; cancer; immunity; uridine; uridinolysis

DOI:  https://doi.org/10.1016/j.tem.2024.01.013
Cell Mol Immunol. 2024 Feb 27.

Targeting PHGDH reverses the immunosuppressive phenotype of tumor-associated macrophages through α-ketoglutarate and mTORC1 signaling.

Zhengnan Cai, Wan Li, Sonja Hager, Jayne Louise Wilson, Leila Afjehi-Sadat, Elke H Heiss, Thomas Weichhart, Petra Heffeter, Wolfram Weckwerth.

  Phosphoglycerate dehydrogenase (PHGDH) has emerged as a crucial factor in macromolecule synthesis, neutralizing oxidative stress, and regulating methylation reactions in cancer cells, lymphocytes, and endothelial cells. However, the role of PHGDH in tumor-associated macrophages (TAMs) is poorly understood. Here, we found that the T helper 2 (Th2) cytokine interleukin-4 and tumor-conditioned media upregulate the expression of PHGDH in macrophages and promote immunosuppressive M2 macrophage activation and proliferation. Loss of PHGDH disrupts cellular metabolism and mitochondrial respiration, which are essential for immunosuppressive macrophages. Mechanistically, PHGDH-mediated serine biosynthesis promotes α-ketoglutarate production, which activates mTORC1 signaling and contributes to the maintenance of an M2-like macrophage phenotype in the tumor microenvironment. Genetic ablation of PHGDH in macrophages from tumor-bearing mice results in attenuated tumor growth, reduced TAM infiltration, a phenotypic shift of M2-like TAMs toward an M1-like phenotype, downregulated PD-L1 expression and enhanced antitumor T-cell immunity. Our study provides a strong basis for further exploration of PHGDH as a potential target to counteract TAM-mediated immunosuppression and hinder tumor progression.

Keywords:  PHGDH; de novo serine synthesis; mTORC1; protumorigenic; tumor-associated macrophages, metabolomics; α-ketoglutarate

DOI:  https://doi.org/10.1038/s41423-024-01134-0
Crit Rev Oncol Hematol. 2024 Feb 28. pii: S1040-8428(24)00055-6. [Epub ahead of print] 104312

Involvement of CircRNAs in Regulating The "New Generation of Cancer Hallmarks": A Special Depiction on Hepatocellular Carcinoma.

Alyaa Dawoud, Rawan Amr Elmasri, Adham H Mohamed, Abdelhamid Mahmoud, Monica Mosaad Rostom, Rana A Youness.

  The concept of 'Hallmarks of Cancer' is an approach of reducing the enormous complexity of cancer to a set of guiding principles. As the underlying mechanism of cancer are portrayed, we find that we gain insight and additional aspects of the disease arise. The understanding of the tumor microenvironment (TME) brought a new dimension and led to the discovery of novel hallmarks such as senescent cells, non-mutational epigenetic reprogramming, polymorphic microbiomes and unlocked phenotypic plasticity. Circular RNAs (circRNAs) are single-stranded, covalently closed RNA molecules that are ubiquitous across all species. Recent studies on the circRNAs have highlighted their crucial function in regulating the formation of human malignancies through a range of biological processes. The primary goal of this review is to clarify the role of circRNAs in the most common form of liver cancer, hepatocellular carcinoma (HCC). This review also addressed the topic of how circRNAs affect HCC hallmarks, including the new generation hallmarks. Finally, the enormous applications that these rapidly expanding ncRNA molecules serve in the functional and molecular development of effective HCC diagnostic biomarkers and therapeutic targets.

Keywords:  Cancer Hallmarks; HCC; Non-mutational epigenetic; Polymorphic microbiomes; Senescent cells; Unlocked phenotypic plasticity; circRNAs; reprogramming

DOI:  https://doi.org/10.1016/j.critrevonc.2024.104312
Cancer Lett. 2024 Feb 24. pii: S0304-3835(24)00159-9. [Epub ahead of print] 216766

Potential role of p53 deregulation in modulating immune responses in human malignancies: A paradigm to develop immunotherapy.

Shivi Chauhan, Shivani Jaiswal, Vibhuti Jakhmola, Bhavana Singh, Sujata Bhattacharya, Manoj Garg, Shinjinee Sengupta.

  The crucial role played by the oncogenic expression of TP53, stemming from mutation or amyloid formation, in various human malignancies has been extensively studied over the past two decades. Interestingly, the potential role of TP53 as a crucial player in modulating immune responses has provided new insight into the field of cancer biology. The loss of p53's transcriptional functions and/or the acquisition of tumorigenic properties can efficiently modulate the recruitment and functions of myeloid and lymphoid cells, ultimately leading to the evasion of immune responses in human tumors. Consequently, the oncogenic nature of the tumor suppressor p53 can dynamically alter the function of immune cells, providing support for tumor progression and metastasis. This review comprehensively explores the dual role of p53 as both the guardian of the genome and an oncogenic driver, especially in the context of regulation of autophagy, apoptosis, the tumor microenvironment, immune cells, innate immunity, and adaptive immune responses. Additionally, the focus of this review centers on how p53 status in the immune response can be harnessed for the development of tailored therapeutic strategies and their potential application in immunotherapy against human malignancies.

Keywords:  Anti-Tumor immune response; Immunotherapy; TP53; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.canlet.2024.216766
Exp Hematol Oncol. 2024 Feb 27. 13(1): 25

Dual-targeted CAR T-cell immunotherapies for hematological malignancies: latest updates from the 2023 ASH annual meeting.

Jingyi Yang, Hao Guo, Lu Han, Yongping Song, Keshu Zhou.

  Over the past few years, dual-targeted chimeric antigen receptor (CAR) T-cell therapy has been employed in the management of hematological malignancies to mitigate treatment failure, particularly in cases of antigen escape. The most widely used approaches include CD19/CD20, CD20/CD22, and BCMA/CD19 CAR T-cells. Alternative immune cells, including natural killer T cells and invariant natural killer T cells, exhibit innate anti-tumor activity and reduced toxicity. This review summarizes several recent clinical trial reports and preclinical studies from the 2023 American Society of Hematology (ASH) annual meeting on dual-targeted CAR T-cell immunotherapy for hematological malignancies.

Keywords:  Chimeric antigen receptor; Clinical trial; Dual-targeted; Hematological malignancy

DOI:  https://doi.org/10.1186/s40164-024-00485-8
Front Oncol. 2024 ;14 1357801

PX-478, an HIF-1α inhibitor, impairs mesoCAR T cell antitumor function in cervical cancer.

Ahmad Reza Panahi Meymandi, Behnia Akbari, Tahereh Soltantoyeh, Zahra Shahosseini, Mina Hosseini, Jamshid Hadjati, Hamid Reza Mirzaei.

   Introduction: Chimeric Antigen Receptor (CAR) T cell therapy has demonstrated remarkable success in treating hematological malignancies. However, its efficacy against solid tumors, including cervical cancer, remains a challenge. Hypoxia, a common feature of the tumor microenvironment, profoundly impacts CAR T cell function, emphasizing the need to explore strategies targeting hypoxia-inducible factor-1α (HIF-1α).
Methods: In this study, we evaluated the effects of the HIF-1α inhibitor PX-478 on mesoCAR T cell function through in-silico and in vitro experiments. We conducted comprehensive analyses of HIF-1α expression in cervical cancer patients and examined the impact of PX-478 on T cell proliferation, cytokine production, cytotoxicity, and exhaustion markers.
Results: Our in-silico analyses revealed high expression of HIF-1α in cervical cancer patients, correlating with poor prognosis. PX-478 effectively reduced HIF-1α levels in T and HeLa cells. While PX-478 exhibited dose-dependent inhibition of antigen-nonspecific T and mesoCAR T cell proliferation, it had minimal impact on antigen-specific mesoCAR T cell proliferation. Notably, PX-478 significantly impaired the cytotoxic function of mesoCAR T cells and induced terminally exhausted T cells.
Discussion: Our results underscore the significant potential and physiological relevance of the HIF-1α pathway in determining the fate and function of both T and CAR T cells. However, we recognize the imperative for further molecular investigations aimed at unraveling the intricate downstream targets associated with HIF-1α and its influence on antitumor immunity, particularly within the context of hypoxic tumors. These insights serve as a foundation for the careful development of combination therapies tailored to counter immunosuppressive pathways within hypoxic environments and fine-tune CAR T cell performance in the intricate tumor microenvironment.

Keywords:  CAR T cell therapy; HIF-1α; PX-478; T cell exhaustion; cervical cancer; pharmacological targeting

DOI:  https://doi.org/10.3389/fonc.2024.1357801
Front Immunol. 2024 ;15 1367875

Endothelial cells in tumor microenvironment: insights and perspectives.

Patrizia Leone, Eleonora Malerba, Nicola Susca, Elvira Favoino, Federico Perosa, Giuliano Brunori, Marcella Prete, Vito Racanelli.

  The tumor microenvironment is a highly complex and dynamic mixture of cell types, including tumor, immune and endothelial cells (ECs), soluble factors (cytokines, chemokines, and growth factors), blood vessels and extracellular matrix. Within this complex network, ECs are not only relevant for controlling blood fluidity and permeability, and orchestrating tumor angiogenesis but also for regulating the antitumor immune response. Lining the luminal side of vessels, ECs check the passage of molecules into the tumor compartment, regulate cellular transmigration, and interact with both circulating pathogens and innate and adaptive immune cells. Thus, they represent a first-line defense system that participates in immune responses. Tumor-associated ECs are involved in T cell priming, activation, and proliferation by acting as semi-professional antigen presenting cells. Thus, targeting ECs may assist in improving antitumor immune cell functions. Moreover, tumor-associated ECs contribute to the development at the tumor site of tertiary lymphoid structures, which have recently been associated with enhanced response to immune checkpoint inhibitors (ICI). When compared to normal ECs, tumor-associated ECs are abnormal in terms of phenotype, genetic expression profile, and functions. They are characterized by high proliferative potential and the ability to activate immunosuppressive mechanisms that support tumor progression and metastatic dissemination. A complete phenotypic and functional characterization of tumor-associated ECs could be helpful to clarify their complex role within the tumor microenvironment and to identify EC specific drug targets to improve cancer therapy. The emerging therapeutic strategies based on the combination of anti-angiogenic treatments with immunotherapy strategies, including ICI, CAR T cells and bispecific antibodies aim to impact both ECs and immune cells to block angiogenesis and at the same time to increase recruitment and activation of effector cells within the tumor.

Keywords:  T cells; endothelial cells; microenvironment; tumor; tumor immune evasion

DOI:  https://doi.org/10.3389/fimmu.2024.1367875
Histochem Cell Biol. 2024 Feb 24.

The secretome from human-derived mesenchymal stem cells augments the activity of antitumor plant extracts in vitro.

J A Ramirez, M C Jiménez, V Ospina, B S Rivera, S Fiorentino, A Barreto, L M Restrepo.

  Cancer is understood as a multifactorial disease that involve multiple cell types and phenotypes in the tumor microenvironment (TME). The components of the TME can interact directly or via soluble factors (cytokines, chemokines, growth factors, extracellular vesicles, etc.). Among the cells composing the TME, mesenchymal stem cells (MSCs) appear as a population with debated properties since it has been seen that they can both promote or attenuate tumor progression. For various authors, the main mechanism of interaction of MSCs is through their secretome, the set of molecules secreted into the extracellular milieu, recruiting, and influencing the behavior of other cells in inflammatory environments where they normally reside, such as wounds and tumors. Natural products have been studied as possible cancer treatments, appealing to synergisms between the molecules in their composition; thus, extracts obtained from Petiveria alliacea (Anamu-SC) and Caesalpinia spinosa (P2Et) have been produced and studied previously on different models, showing promising results. The effect of plant extracts on the MSC secretome has been poorly studied, especially in the context of the TME. Here, we studied the effect of Anamu-SC and P2Et extracts in the human adipose-derived MSC (hAMSC)-tumor cell interaction as a TME model. We also investigated the influence of the hAMSC secretome, in combination with these natural products, on tumor cell hallmarks such as viability, clonogenicity, and migration. In addition, hAMSC gene expression and protein synthesis were evaluated for some key factors in tumor progression in the presence of the extracts by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Multiplex, respectively. It was found that the presence of the hAMSC secretome did not affect the cytotoxic or clonogenicity-reducing activities of the natural extracts on cancer cells, and even this secretome can inhibit the migration of these tumor cells, in addition to the fact that the profile of molecules can be modified by natural products. Overall, our findings demonstrate that hAMSC secretome participation in TME interactions can favor the antitumor activities of natural products.

Keywords:  Adipose-derived mesenchymal stem cell; Breast neoplasms; Melanoma; Plant extracts; Secretome; Tumor microenvironment

DOI:  https://doi.org/10.1007/s00418-024-02265-1