bims-flamet 2024-02-25 papers

bims-flamet

Biomed News

on Cytokines and immunometabolism in metastasis

Issue of 2024–02–25
thirty papers selected by
Peio Azcoaga, Biodonostia HRI

NF-κB: Governing Macrophages in Cancer.
Immunotherapy Innovations in the Fight against Osteosarcoma: Emerging Strategies and Promising Progress.
Tumor-specific activation of folate receptor beta enables reprogramming of immune cells in the tumor microenvironment.
Glioblastoma-Associated Mesenchymal Stem/Stromal Cells and Cancer-Associated Fibroblasts: Partners in Crime?
Reciprocal relationship between cancer stem cells and myeloid-derived suppressor cells: implications for tumor progression and therapeutic strategies.
The significance of targeting lysosomes in cancer immunotherapy.
Addressing the Mechanical Interaction Between Cancer-Associated Fibroblasts and Cancer Cells by Laser Ablation.
Biomaterial-Based Responsive Nanomedicines for Targeting Solid Tumor Microenvironments.
Lysine lactylation in the regulation of tumor biology.
Disruption of MerTK increases the efficacy of checkpoint inhibitor by enhancing ferroptosis and immune response in hepatocellular carcinoma.
Immunosuppressive role of BDNF in therapy-induced neuroendocrine prostate cancer.
Dietary methionine restriction in cancer development and antitumor immunity.
Enhancing CAR-T cell metabolism to overcome hypoxic conditions in the brain tumor microenvironment.
Mechanisms underlying immunosuppression by regulatory cells.
Phenotypic Heterogeneity, Bidirectionality, Universal Cues, Plasticity, Mechanics, and the Tumor Microenvironment Drive Cancer Metastasis.
Three-Dimensional Hanging Drop Spheroid Plates for Easy Chimeric Antigen Receptor (CAR) T Cytotoxicity Assay.
Tumor-resident microbes: the new kids on the microenvironment block.
Involvement of neuronal factors in tumor angiogenesis and the shaping of the cancer microenvironment.
Breaking Barriers: The Promise and Challenges of Immune Checkpoint Inhibitors in Triple-Negative Breast Cancer.
PD-L1-expressing tumor-associated macrophages are immunostimulatory and associate with good clinical outcome in human breast cancer.
How murine neutrophils are hijacked within the microenvironment of pancreatic cancer.
Effect of surface modification on the distribution of magnetic nanorings in hepatocellular carcinoma and immune cells.
Mapping spatial heterogeneity in gastric cancer microenvironment.
In situ characterization of the tumor microenvironment.
Harnessing Pyroptosis for Cancer Immunotherapy.
Tumor microenvironment in thyroid cancer: Immune cells, patterns, and novel treatments.
Restricting CAR T Cell Trafficking Expands Targetable Antigen Space.
RECQL4 Inhibits Radiation-Induced Tumor Immune Awakening via Suppressing the cGAS-STING Pathway in Hepatocellular Carcinoma.
Enhancing photodynamic immunotherapy by reprograming the immunosuppressive tumor microenvironment with hypoxia relief.
Hepatitis B virus-related hepatocellular carcinoma exhibits distinct intratumoral microbiota and immune microenvironment signatures.

Genes (Basel). 2024 Jan 31. pii: 197. [Epub ahead of print]15(2):

NF-κB: Governing Macrophages in Cancer.

Jessica Cornice, Daniela Verzella, Paola Arboretto, Davide Vecchiotti, Daria Capece, Francesca Zazzeroni, Guido Franzoso.

  Tumor-associated macrophages (TAMs) are the major component of the tumor microenvironment (TME), where they sustain tumor progression and or-tumor immunity. Due to their plasticity, macrophages can exhibit anti- or pro-tumor functions through the expression of different gene sets leading to distinct macrophage phenotypes: M1-like or pro-inflammatory and M2-like or anti-inflammatory. NF-κB transcription factors are central regulators of TAMs in cancers, where they often drive macrophage polarization toward an M2-like phenotype. Therefore, the NF-κB pathway is an attractive therapeutic target for cancer immunotherapy in a wide range of human tumors. Hence, targeting NF-κB pathway in the myeloid compartment is a potential clinical strategy to overcome microenvironment-induced immunosuppression and increase anti-tumor immunity. In this review, we discuss the role of NF-κB as a key driver of macrophage functions in tumors as well as the principal strategies to overcome tumor immunosuppression by targeting the NF-κB pathway.

Keywords:  NF-κB; tumor microenvironment (TME); tumor-associated macrophages (TAMs)

DOI:  https://doi.org/10.3390/genes15020197
Pharmaceutics. 2024 Feb 08. pii: 251. [Epub ahead of print]16(2):

Immunotherapy Innovations in the Fight against Osteosarcoma: Emerging Strategies and Promising Progress.

Shigao Cheng, Huiyuan Wang, Xuejia Kang, Hui Zhang.

  Immunosuppressive elements within the tumor microenvironment are the primary drivers of tumorigenesis and malignant advancement. The presence, as well as the crosstalk between myeloid-derived suppressor cells (MDSCs), osteosarcoma-associated macrophages (OS-Ms), regulatory T cells (Tregs), and endothelial cells (ECs) with osteosarcoma cells cause the poor prognosis of OS. In addition, the consequent immunosuppressive factors favor the loss of treatment potential. Nanoparticles offer a means to dynamically and locally manipulate immuno-nanoparticles, which present a promising strategy for transforming OS-TME. Additionally, chimeric antigen receptor (CAR) technology is effective in combating OS. This review summarizes the essential mechanisms of immunosuppressive cells in the OS-TME and the current immune-associated strategies. The last part highlights the limitations of existing therapies and offers insights into future research directions.

Keywords:  immunotherapy; nanoparticles; osteosarcoma; suppressive immune environment

DOI:  https://doi.org/10.3390/pharmaceutics16020251
Front Immunol. 2024 ;15 1354735

Tumor-specific activation of folate receptor beta enables reprogramming of immune cells in the tumor microenvironment.

Fenghua Zhang, Bo Huang, Sagar M Utturkar, Weichuan Luo, Gregory Cresswell, Seth A Herr, Suilan Zheng, John V Napoleon, Rina Jiang, Boning Zhang, Muyi Liu, Nadia Lanman, Madduri Srinivasarao, Timothy L Ratliff, Philip S Low.

  Folate receptors can perform folate transport, cell adhesion, and/or transcription factor functions. The beta isoform of the folate receptor (FRβ) has attracted considerable attention as a biomarker for immunosuppressive macrophages and myeloid-derived suppressor cells, however, its role in immunosuppression remains uncharacterized. We demonstrate here that FRβ cannot bind folate on healthy tissue macrophages, but does bind folate after macrophage incubation in anti-inflammatory cytokines or cancer cell-conditioned media. We further show that FRβ becomes functionally active following macrophage infiltration into solid tumors, and we exploit this tumor-induced activation to target a toll-like receptor 7 agonist specifically to immunosuppressive myeloid cells in solid tumors without altering myeloid cells in healthy tissues. We then use single-cell RNA-seq to characterize the changes in gene expression induced by the targeted repolarization of tumor-associated macrophages and finally show that their repolarization not only changes their own phenotype, but also induces a proinflammatory shift in all other immune cells of the same tumor mass, leading to potent suppression of tumor growth. Because this selective reprogramming of tumor myeloid cells is accompanied by no systemic toxicity, we propose that it should constitute a safe method to reprogram the tumor microenvironment.

Keywords:  folate receptor beta; myeloid derived suppressor cells; reprogramming of tumor microenvironment; single-cell RNA-seq analysis; tumor associated macrophages

DOI:  https://doi.org/10.3389/fimmu.2024.1354735
Int J Mol Sci. 2024 Feb 14. pii: 2285. [Epub ahead of print]25(4):

Glioblastoma-Associated Mesenchymal Stem/Stromal Cells and Cancer-Associated Fibroblasts: Partners in Crime?

Thibault Lootens, Bart I Roman, Christian V Stevens, Olivier De Wever, Robrecht Raedt.

  Tumor-associated mesenchymal stem/stromal cells (TA-MSCs) have been recognized as attractive therapeutic targets in several cancer types, due to their ability to enhance tumor growth and angiogenesis and their contribution to an immunosuppressive tumor microenvironment (TME). In glioblastoma (GB), mesenchymal stem cells (MSCs) seem to be recruited to the tumor site, where they differentiate into glioblastoma-associated mesenchymal stem/stromal cells (GA-MSCs) under the influence of tumor cells and the TME. GA-MSCs are reported to exert important protumoral functions, such as promoting tumor growth and invasion, increasing angiogenesis, stimulating glioblastoma stem cell (GSC) proliferation and stemness, mediating resistance to therapy and contributing to an immunosuppressive TME. Moreover, they could act as precursor cells for cancer-associated fibroblasts (CAFs), which have recently been identified in GB. In this review, we provide an overview of the different functions exerted by GA-MSCs and CAFs and the current knowledge on the relationship between these cell types. Increasing our understanding of the interactions and signaling pathways in relevant models might contribute to future regimens targeting GA-MSCs and GB-associated CAFs to inhibit tumor growth and render the TME less immunosuppressive.

Keywords:  cancer-associated fibroblasts; glioblastoma; mesenchymal stem/stromal cells; tumor microenvironment

DOI:  https://doi.org/10.3390/ijms25042285
Future Oncol. 2024 Feb;20(4): 215-228

Reciprocal relationship between cancer stem cells and myeloid-derived suppressor cells: implications for tumor progression and therapeutic strategies.

Guiqing Ding, Hua Yu, Jason Jin, Xi Qiao, Jinyun Ma, Tong Zhang, Xiaodong Cheng.

  Recently, there has been an increased focus on cancer stem cells (CSCs) due to their resilience, making them difficult to eradicate. This resilience often leads to tumor recurrence and metastasis. CSCs adeptly manipulate their surroundings to create an environment conducive to their survival. In this environment, myeloid-derived suppressor cells (MDSCs) play a crucial role in promoting epithelial-mesenchymal transition and bolstering CSCs' stemness. In response, CSCs attract MDSCs, enhancing their infiltration, expansion and immunosuppressive capabilities. This interaction between CSCs and MDSCs increases the difficulty of antitumor therapy. In this paper, we discuss the interplay between CSCs and MDSCs based on current research and highlight recent therapeutic strategies targeting either CSCs or MDSCs that show promise in achieving effective antitumor outcomes.

Keywords:  cancer stem cells; myeloid-derived suppressor cells; therapeutic strategies; tumor microenvironment; tumor progression

DOI:  https://doi.org/10.2217/fon-2023-0907
Front Immunol. 2024 ;15 1308070

The significance of targeting lysosomes in cancer immunotherapy.

Yanxin Xu, Bo Shao, Yafeng Zhang.

  Lysosomes are intracellular digestive organelles that participate in various physiological and pathological processes, including the regulation of immune checkpoint molecules, immune cell function in the tumor microenvironment, antigen presentation, metabolism, and autophagy. Abnormalities or dysfunction of lysosomes are associated with the occurrence, development, and drug resistance of tumors. Lysosomes play a crucial role and have potential applications in tumor immunotherapy. Targeting lysosomes or harnessing their properties is an effective strategy for tumor immunotherapy. However, the mechanisms and approaches related to lysosomes in tumor immunotherapy are not fully understood at present, and further basic and clinical research is needed to provide better treatment options for cancer patients. This review focuses on the research progress related to lysosomes and tumor immunotherapy in these.

Keywords:  immunotherapy; lysosomal autophagy; lysosomes; tumor immunity; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2024.1308070
Methods Mol Biol. 2024 ;2764 179-203

Addressing the Mechanical Interaction Between Cancer-Associated Fibroblasts and Cancer Cells by Laser Ablation.

Carlos Perez-Gonzalez, Jorge Barbazán.

  Cells within a tumor interact by generating, transmitting, and sensing mechanical forces. Among all the cells of the tumor microenvironment, cancer-associated fibroblasts (CAFs) are a paradigmatic example of mechanical communication. In different steps of tumor progression, CAFs pull and push on cancer cells, regulating cancer cell migration, invasion, compartmentalization, and signaling. There is thus an increasing need to experimentally address mechanical interactions within a tumor. A common technique to measure these interactions is laser ablation. Cutting a tissue region with a high-power laser triggers a sudden tissue displacement whose direction and magnitude reveal the local mechanical stresses. In this chapter, we provide a detailed protocol to perform laser ablations in vitro and ex vivo. First, we describe how to prepare cocultures of primary CAFs and cancer cells and tumor explants. Then, we explain how to perform laser ablations in these two systems and how to analyze the induced tissue displacements using particle image velocimetry (PIV). Overall, we provide a workflow to perform, analyze, and interpret laser ablations to explore tumor mechanical interactions.

Keywords:  Cancer associated fibroblasts; Cancer cells; Co-cultures; Forces; Laser ablation; Mechanical interactions; Tumor tissue slices

DOI:  https://doi.org/10.1007/978-1-0716-3674-9_13
Pharmaceutics. 2024 Jan 26. pii: 179. [Epub ahead of print]16(2):

Biomaterial-Based Responsive Nanomedicines for Targeting Solid Tumor Microenvironments.

Konstantinos Avgoustakis, Athina Angelopoulou.

  Solid tumors are composed of a highly complex and heterogenic microenvironment, with increasing metabolic status. This environment plays a crucial role in the clinical therapeutic outcome of conventional treatments and innovative antitumor nanomedicines. Scientists have devoted great efforts to conquering the challenges of the tumor microenvironment (TME), in respect of effective drug accumulation and activity at the tumor site. The main focus is to overcome the obstacles of abnormal vasculature, dense stroma, extracellular matrix, hypoxia, and pH gradient acidosis. In this endeavor, nanomedicines that are targeting distinct features of TME have flourished; these aim to increase site specificity and achieve deep tumor penetration. Recently, research efforts have focused on the immune reprograming of TME in order to promote suppression of cancer stem cells and prevention of metastasis. Thereby, several nanomedicine therapeutics which have shown promise in preclinical studies have entered clinical trials or are already in clinical practice. Various novel strategies were employed in preclinical studies and clinical trials. Among them, nanomedicines based on biomaterials show great promise in improving the therapeutic efficacy, reducing side effects, and promoting synergistic activity for TME responsive targeting. In this review, we focused on the targeting mechanisms of nanomedicines in response to the microenvironment of solid tumors. We describe responsive nanomedicines which take advantage of biomaterials' properties to exploit the features of TME or overcome the obstacles posed by TME. The development of such systems has significantly advanced the application of biomaterials in combinational therapies and in immunotherapies for improved anticancer effectiveness.

Keywords:  acidosis; biomaterials; hypoxia; nanomedicine; resistance; stimuli-responsiveness; targeting; tumor microenvironment; tumor vasculature

DOI:  https://doi.org/10.3390/pharmaceutics16020179
Trends Endocrinol Metab. 2024 Feb 22. pii: S1043-2760(24)00025-0. [Epub ahead of print]

Lysine lactylation in the regulation of tumor biology.

Zijian Yang, Yingqi Zheng, Qiang Gao.

  Lysine lactylation (Kla), a newly discovered post-translational modification (PTM) of lysine residues, is progressively revealing its crucial role in tumor biology. A growing body of evidence supports its capacity of transcriptional regulation through histone modification and modulation of non-histone protein function. It intricately participates in a myriad of events in the tumor microenvironment (TME) by orchestrating the transitions of immune states and augmenting tumor malignancy. Its preferential modification of metabolic proteins underscores its specific regulatory influence on metabolism. This review focuses on the effect and the probable mechanisms of Kla-mediated regulation of tumor metabolism, the upstream factors that determine Kla intensity, and its potential implications for the clinical diagnosis and treatment of tumors.

Keywords:  lysine lactylation; post-translational modification; precision medicine; tumor metabolism; tumor microenvironment

DOI:  https://doi.org/10.1016/j.tem.2024.01.011
Cell Rep Med. 2024 Feb 20. pii: S2666-3791(24)00038-7. [Epub ahead of print]5(2): 101415

Disruption of MerTK increases the efficacy of checkpoint inhibitor by enhancing ferroptosis and immune response in hepatocellular carcinoma.

Shun Wang, Le Zhu, Tianen Li, Xinxin Lin, Yan Zheng, Da Xu, Yu Guo, Ze Zhang, Yan Fu, Hao Wang, Xufeng Wang, Tiantian Zou, Xiaotian Shen, Lumin Zhang, Nannan Lai, Lu Lu, Lunxiu Qin, Qiongzhu Dong.

Immune checkpoint inhibitors, particularly PD-1/PD-L1 blockades, have been approved for unresectable hepatocellular carcinoma (HCC). However, high resistance rates still limit their efficacy, highlighting the urgent need to understand the underlying mechanisms and develop strategies for overcoming the resistance. In this study, we demonstrate that HCC with high MER proto-oncogene tyrosine kinase (MerTK) expression exhibits anti-PD-1/PD-L1 resistance in two syngeneic mouse models and in patients who received anti-PD-1/PD-L1 therapy. Mechanistically, MerTK renders HCC resistant to anti-PD-1/PD-L1 by limiting ferroptosis with the upregulation of SLC7A11 via the ERK/SP1 pathway and facilitating the development of an immunosuppressive tumor microenvironment (TME) with the recruitment of myeloid-derived suppressor cells (MDSCs). Sitravatinib, an inhibitor of MerTK, sensitizes resistant HCC to anti-PD-L1 therapy by promoting tumor ferroptosis and decreasing MDSC infiltration into the TME. In conclusion, we find that MerTK could serve as a predictive biomarker for patient stratification and as a promising target to overcome anti-PD-1/PD-L1 resistance in HCC.

DOI: https://doi.org/10.1016/j.xcrm.2024.101415
Mol Oncol. 2024 Feb 21.

Immunosuppressive role of BDNF in therapy-induced neuroendocrine prostate cancer.

Yen-Nien Liu, Wei-Yu Chen, Ming-Kun Liu, Hsiu-Lien Yeh, Wei-Hao Chen, Kuo-Ching Jiang, Han-Ru Li, Zi-Qing Chen, Wan-Hsin Wang, Wassim Abou-Kheir, Yu-Ching Wen.

  Prostate stromal cells play a crucial role in the promotion of tumor growth and immune evasion in the tumor microenvironment (TME) through intricate molecular alterations in their interaction with prostate cancer (PCa) cells. While the impact of these cells on establishing an immunosuppressive response and influencing PCa aggressiveness remains incompletely understood. Our study shows that the activation of the leukemia inhibitory factor (LIF)/LIF receptor (LIFR) pathway in both prostate tumor and stromal cells, following androgen deprivation therapy (ADT), leads to the development of an immunosuppressive TME. Activation of LIF/LIFR signaling in PCa cells induces neuroendocrine differentiation (NED) and upregulates immune checkpoint expression. Inhibition of LIF/LIFR attenuates these effects, underscoring the crucial role of LIF/LIFR in linking NED to immunosuppression. Prostate stromal cells expressing LIFR contribute to NED and immunosuppressive marker abundance in PCa cells, while LIFR knockdown in prostate stromal cells reverses these effects. ADT-driven LIF/LIFR signaling induces brain-derived neurotrophic factor (BDNF) expression, which, in turn, promotes NED, aggressiveness, and immune evasion in PCa cells. Clinical analyses demonstrate elevated BDNF levels in metastatic castration-resistant PCa (CRPC) and a positive correlation with programmed death-ligand 1 (PDL1) and immunosuppressive signatures. This study shows that the crosstalk between PCa cells and prostate stromal cells enhances LIF/LIFR signaling, contributing to an immunosuppressive TME and NED in PCa cells through the upregulation of BDNF.

Keywords:  androgen deprivation therapy; brain-derived neurotrophic factor; leukemia inhibitory factor; neuroendocrine differentiation; prostate cancer; tumor microenvironment

DOI:  https://doi.org/10.1002/1878-0261.13614
Trends Endocrinol Metab. 2024 Feb 20. pii: S1043-2760(24)00023-7. [Epub ahead of print]

Dietary methionine restriction in cancer development and antitumor immunity.

Ming Ji, Qing Xu, Xiaoling Li.

  Methionine restriction (MR) has been shown to suppress tumor growth and improve the responses to various anticancer therapies. However, methionine itself is required for the proliferation, activation, and differentiation of T cells that are crucial for antitumor immunity. The dual impact of methionine, that influences both tumor and immune cells, has generated concerns regarding the potential consequences of MR on T cell immunity and its possible role in promoting cancer. In this review we systemically examine current literature on the interactions between dietary methionine, cancer cells, and immune cells. Based on recent findings on MR in immunocompetent animals, we further discuss how tumor stage-specific methionine dependence of immune cells and cancer cells in the tumor microenvironment could ultimately dictate the response of tumors to MR.

Keywords:  antitumor immunity; gut microbiota; methylation; redox homeostasis; sulfur metabolism

DOI:  https://doi.org/10.1016/j.tem.2024.01.009
JCI Insight. 2024 Feb 22. pii: e177141. [Epub ahead of print]

Enhancing CAR-T cell metabolism to overcome hypoxic conditions in the brain tumor microenvironment.

Ryusuke Hatae, Keith Kyewalabye, Akane Yamamichi, Tiffany Chen, Su Phyu, Pavlina Chuntova, Takahide Nejo, Lauren S Levine, Matthew H Spitzer, Hideho Okada.

  The efficacy of chimeric antigen receptor (CAR)-T therapy has been limited against brain tumors to date. CAR-T cells infiltrating syngeneic intracerebral SB28-EGFRvIII glioma revealed impaired mitochondrial ATP production and a markedly hypoxic status compared to ones migrating to subcutaneous tumors. Drug screenings to improve metabolic states of T cells under hypoxic conditions led us to evaluate the combination of AMPK activator Metformin and the mTOR inhibitor Rapamycin (Met+Rap). Met+Rap-pretreated mouse CAR-T cells showed activated PPAR-gamma coactivator 1α (PGC-1α) through mTOR inhibition and AMPK activation, and a higher level of mitochondrial spare respiratory capacity than those pretreated with individual drugs or without pretreatment. Moreover, Met+Rap-pretreated CAR-T cells demonstrated persistent and effective anti-glioma cytotoxic activities in the hypoxic condition. Furthermore, a single intravenous infusion of Met+Rap-pretreated CAR-T cells significantly extended the survival of mice bearing intracerebral SB28-EGFRvIII gliomas. Mass cytometric analyses highlighted increased glioma-infiltrating CAR-T cells in the Met+Rap group with fewer Ly6c+ CD11b+ monocytic myeloid-derived suppressor cells in the tumors. Finally, human CAR-T cells pretreated with Met+Rap recapitulated the observations with murine CAR-T cells, demonstrating improved functions in vitro hypoxic conditions. These findings advocate for translational and clinical exploration of Met+Rap-pretreated CAR-T cells in human trials.

Keywords:  Brain cancer; Cancer immunotherapy; Hypoxia; Immunology; Otology

DOI:  https://doi.org/10.1172/jci.insight.177141
Front Immunol. 2024 ;15 1328193

Mechanisms underlying immunosuppression by regulatory cells.

Oliver Goldmann, Obiageli Vivian Nwofor, Qian Chen, Eva Medina.

  Regulatory cells, such as regulatory T cells (Tregs), regulatory B cells (Bregs), and myeloid-derived suppressor cells (MDSCs), play a crucial role in preserving immune tolerance and controlling immune responses during infections to prevent excessive immune activation. However, pathogens have developed strategies to hijack these regulatory cells to decrease the overall effectiveness of the immune response and persist within the host. Consequently, therapeutic targeting of these immunosuppressive mechanisms during infection can reinvigorate the immune response and improve the infection outcome. The suppressive mechanisms of regulatory cells are not only numerous but also redundant, reflecting the complexity of the regulatory network in modulating the immune responses. The context of the immune response, such as the type of pathogen or tissue involved, further influences the regulatory mechanisms involved. Examples of these immunosuppressive mechanisms include the production of inhibitory cytokines such as interleukin 10 (IL-10) and transforming growth factor beta (TGF-β) that inhibit the production of pro-inflammatory cytokines and dampen the activation and proliferation of effector T cells. In addition, regulatory cells utilize inhibitory receptors like cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) to engage with their respective effector cells, thereby suppressing their function. An alternative approach involves the modulation of metabolic reprogramming in effector immune cells to limit their activation and proliferation. In this review, we provide an overview of the major mechanisms mediating the immunosuppressive effect of the different regulatory cell subsets in the context of infection.

Keywords:  immunosuppressive mechanisms; infection; myeloid-derived suppressor cells; regulatory B cells; regulatory T cells

DOI:  https://doi.org/10.3389/fimmu.2024.1328193
Biomolecules. 2024 Feb 03. pii: 184. [Epub ahead of print]14(2):

Phenotypic Heterogeneity, Bidirectionality, Universal Cues, Plasticity, Mechanics, and the Tumor Microenvironment Drive Cancer Metastasis.

Claudia Tanja Mierke.

  Tumor diseases become a huge problem when they embark on a path that advances to malignancy, such as the process of metastasis. Cancer metastasis has been thoroughly investigated from a biological perspective in the past, whereas it has still been less explored from a physical perspective. Until now, the intraluminal pathway of cancer metastasis has received the most attention, while the interaction of cancer cells with macrophages has received little attention. Apart from the biochemical characteristics, tumor treatments also rely on the tumor microenvironment, which is recognized to be immunosuppressive and, as has recently been found, mechanically stimulates cancer cells and thus alters their functions. The review article highlights the interaction of cancer cells with other cells in the vascular metastatic route and discusses the impact of this intercellular interplay on the mechanical characteristics and subsequently on the functionality of cancer cells. For instance, macrophages can guide cancer cells on their intravascular route of cancer metastasis, whereby they can help to circumvent the adverse conditions within blood or lymphatic vessels. Macrophages induce microchannel tunneling that can possibly avoid mechanical forces during extra- and intravasation and reduce the forces within the vascular lumen due to vascular flow. The review article highlights the vascular route of cancer metastasis and discusses the key players in this traditional route. Moreover, the effects of flows during the process of metastasis are presented, and the effects of the microenvironment, such as mechanical influences, are characterized. Finally, the increased knowledge of cancer metastasis opens up new perspectives for cancer treatment.

Keywords:  cancer stem cells (CSCs); cancerogenesis; exosomes; fibroblasts; intravascular cancer cell dissemination; mechanotransduction; stiffness; transmigration; tumor associated macrophages (TAMs)

DOI:  https://doi.org/10.3390/biom14020184
Methods Mol Biol. 2024 ;2764 35-42

Three-Dimensional Hanging Drop Spheroid Plates for Easy Chimeric Antigen Receptor (CAR) T Cytotoxicity Assay.

Zhenzhong Chen, Sungsu Park.

  Chimeric antigen receptor (CAR) T cell therapy shows a highly effective therapeutic effect on B-cell malignancies. The tumor microenvironment (TME) of solid tumors in vivo poses a great challenge to CAR T cell therapy due to its complexity. Recently, tumor spheroids have attracted much attention because of their ability to recapitulate TME. However, the use of tumor spheroids for the CAR T cytotoxicity assay involves the difficult task of separating unbound T cells and dead tumor cells from the spheroids. Therefore, we developed a three-dimensional hanging spheroid plate (3DHSP) that facilitates spheroid formation and separation of unbound and dead cells from spheroids during cytotoxicity assays. In this work, detailed steps have been described for fabrication and operation of the 3DHSP. This new 3DHSP device is a 96-well plate in which each well consists of a hanging dripper and a spheroid separation plate. A tumor spheroid forms in a droplet hanging in the dripper and is mixed with CAR T cells. The mixture in the droplet is deposited into the spheroid separation plate by pipetting, and unbound and dead CAR T and tumor cells are detached from the spheroid and moved to the waste well in the plate by tilting the 3DHSP at 20°. The size of the spheroid can be used as a readout for CAR T cell cytotoxicity assay, suggesting that the 3DHSP does not require cumbersome fluorescent staining.

Keywords:  3D hanging drop spheroid plate; Cytotoxicity assay; HER2-CAR T cell; Tumor spheroid

DOI:  https://doi.org/10.1007/978-1-0716-3674-9_4
Trends Cancer. 2024 Feb 21. pii: S2405-8033(23)00242-X. [Epub ahead of print]

Tumor-resident microbes: the new kids on the microenvironment block.

Le Li, Vidhi Chandra, Florencia McAllister.

  Tumor-resident microbes (TRM) are an integral component of the tumor microenvironment (TME). TRM can influence tumor growth, distant dissemination, and response to therapies by interfering with molecular pathways in tumor cells as well as with other components of the TME. Novel technologies are improving the identification and visualization of cell type-specific microbes in the TME. The mechanisms that mediate the role of TRM at the primary tumors and metastatic sites are being elucidated. This knowledge is providing novel perspectives for targeting microbes or using microbial interventions for cancer interception or therapy.

Keywords:  cancer; immunity; metastasis; microenvironment; tumor-resident microbes; tumorigenesis

DOI:  https://doi.org/10.1016/j.trecan.2023.12.002
Front Immunol. 2024 ;15 1284629

Involvement of neuronal factors in tumor angiogenesis and the shaping of the cancer microenvironment.

Sharif Shalabi, Ali Belayachi, Bruno Larrivée.

  Emerging evidence suggests that nerves within the tumor microenvironment play a crucial role in regulating angiogenesis. Neurotransmitters and neuropeptides released by nerves can interact with nearby blood vessels and tumor cells, influencing their behavior and modulating the angiogenic response. Moreover, nerve-derived signals may activate signaling pathways that enhance the production of pro-angiogenic factors within the tumor microenvironment, further supporting blood vessel growth around tumors. The intricate network of communication between neural constituents and the vascular system accentuates the potential of therapeutically targeting neural-mediated pathways as an innovative strategy to modulate tumor angiogenesis and, consequently, neoplastic proliferation. Hereby, we review studies that evaluate the precise molecular interplay and the potential clinical ramifications of manipulating neural elements for the purpose of anti-angiogenic therapeutics within the scope of cancer treatment.

Keywords:  angiogenesis; growth factors (angiogenesis factors); neurovascular crosstalk; tumor microenvironment; tumorigenesis

DOI:  https://doi.org/10.3389/fimmu.2024.1284629
Biomedicines. 2024 Feb 05. pii: 369. [Epub ahead of print]12(2):

Breaking Barriers: The Promise and Challenges of Immune Checkpoint Inhibitors in Triple-Negative Breast Cancer.

Sawsan Sudqi Said, Wisam Nabeel Ibrahim.

  Triple-negative breast cancer (TNBC) is a highly aggressive malignancy with pronounced immunogenicity, exhibiting rapid proliferation and immune cell infiltration into the tumor microenvironment. TNBC's heterogeneity poses challenges to immunological treatments, inducing resistance mechanisms in the tumor microenvironment. Therapeutic modalities, including immune checkpoint inhibitors (ICIs) targeting PD-1, PD-L1, and CTLA-4, are explored in preclinical and clinical trials. Promising results emerge from combining ICIs with anti-TGF-β and VISTA, hindering TNBC tumor growth. TNBC cells employ complex evasion strategies involving interactions with stromal and immune cells, suppressing immune recognition through various cytokines, chemokines, and metabolites. The recent focus on unraveling humoral and cellular components aims to disrupt cancer crosstalk within the tumor microenvironment. This review identifies TNBC's latest resistance mechanisms, exploring potential targets for clinical trials to overcome immune checkpoint resistance and enhance patient survival rates.

Keywords:  PD-1/PD-L1/CTLA-4; TME; resistance; triple-negative breast cancer

DOI:  https://doi.org/10.3390/biomedicines12020369
Cell Rep Med. 2024 Feb 20. pii: S2666-3791(24)00043-0. [Epub ahead of print]5(2): 101420

PD-L1-expressing tumor-associated macrophages are immunostimulatory and associate with good clinical outcome in human breast cancer.

Lei Wang, Weihua Guo, Zhikun Guo, Jiangnan Yu, Jiayi Tan, Diana L Simons, Ke Hu, Xinyu Liu, Qian Zhou, Yizi Zheng, Egelston A Colt, John Yim, James Waisman, Peter P Lee.

Tumor-associated macrophages (TAMs) are the predominant cells that express programmed cell death ligand 1 (PD-L1) within human tumors in addition to cancer cells, and PD-L1+ TAMs are generally thought to be immunosuppressive within the tumor immune microenvironment (TIME). Using single-cell transcriptomic and spatial multiplex immunofluorescence analyses, we show that PD-L1+ TAMs are mature and immunostimulatory with spatial preference to T cells. In contrast, PD-L1- TAMs are immunosuppressive and spatially co-localize with cancer cells. Either higher density of PD-L1+ TAMs alone or ratio of PD-L1+/PD-L1- TAMs correlate with favorable clinical outcome in two independent cohorts of patients with breast cancer. Mechanistically, we show that PD-L1 is upregulated during the monocyte-to-macrophage maturation and differentiation process and does not require external IFN-γ stimulus. Functionally, PD-L1+ TAMs are more mature/activated and promote CD8+ T cells proliferation and cytotoxic capacity. Together, our findings reveal insights into the immunological significance of PD-L1 within the TIME.

DOI: https://doi.org/10.1016/j.xcrm.2024.101420
J Leukoc Biol. 2024 Feb 23. pii: qiae042. [Epub ahead of print]

How murine neutrophils are hijacked within the microenvironment of pancreatic cancer.

Marco Antonio Cassatella, Patrizia Scapini, Nicola Tamassia.

  Discoveries made in the last decades have brought out that, in addition to their classical primary defensive functions against infections, polymorphonuclear neutrophils play key effector roles not only in chronic inflammatory and immune-mediated diseases but also in cancer. In addition, depending on their differentiation/activation status, and/or on the physiological or pathological microenvironment in which they reside, neutrophils have been shown to behave as highly plastic cells, able to acquire new phenotypes/functional states. All these features are well manifested in cancer and modulated during tumor progression. Herein, we discuss intriguing data by Lai Ng's group, that have shed light on the origin and development of terminally differentiated, proangiogenic, tumor-associated neutrophils, facilitating tumor growth in a murine orthotopic model of pancreatic ductal adenocarcinoma. These findings help to progress toward the ambitious goal of selectively targeting only the skewed pathological neutrophil populations present within the tumor microenvironment.

Keywords:  angiogenesis; dcTRAILR1; single cell RNA sequencing; tumor-associated neutrophils (TANs)

DOI:  https://doi.org/10.1093/jleuko/qiae042
J Mater Chem B. 2024 Feb 20.

Effect of surface modification on the distribution of magnetic nanorings in hepatocellular carcinoma and immune cells.

Wangbo Jiao, Nana Wen, Siyao Wang, Guxiang Zhou, Qiaoyi Lu, Zijun Su, Xinxin Wang, Shuwei Hu, Youbang Xie, Nan Zhang, Xiaoli Liu.

Magnetic nanomaterial-mediated magnetic hyperthermia is a localized heating treatment modality that has been applied to treat aggressive cancer in clinics. In addition to being taken up by tumor cells to function in cancer therapy, magnetic nanomaterials can also be internalized by immune cells in the tumor microenvironment, which may contribute to regulating the anti-tumor immune effects. However, there exists little studies on the distribution of magnetic nanomaterials in different types of cells within tumor tissue. Herein, ferrimagnetic vortex-domain iron oxide nanorings (FVIOs) with or without the liver-cancer-targeting peptide SP94 have been successfully synthesized as a model system to investigate the effect of surface modification of FVIOs (with or without SP94) on the distribution of tumor cells and different immune cells in hepatocellular carcinoma (HCC) microenvironment of a mouse. The distribution ratio of FVIO-SP94s in tumor cells was 1.3 times more than that of FVIOs. Immune cells in the liver tumor microenvironment took up fewer FVIO-SP94s than FVIOs. In addition, myeloid cells were found to be much more amenable than lymphoid cells in terms of their ability to phagocytose nanoparticles. Specifically, the distributions of FVIOs/FVIO-SP94s in tumor-associated macrophages, dendritic cells, and myeloid-derived suppressor cells were 13.8%/12%, 3.7%/0.9%, and 6.3%/1.2%, respectively. While the distributions of FVIOs/FVIO-SP94s in T cells, B cells, and natural killer cells were 5.5%/0.7%, 3.0%/0.7%, and 0.4%/0.3%, respectively. The results described in this article enhance our understanding of the distribution of nanomaterials in the tumor microenvironment and provide a strategy for rational design of magnetic hyperthermia agents that can effectively regulate anti-tumor immune effects.

DOI: https://doi.org/10.1039/d3tb02560h
Biomed Pharmacother. 2024 Feb 20. pii: S0753-3322(24)00198-7. [Epub ahead of print]172 116317

Mapping spatial heterogeneity in gastric cancer microenvironment.

Bingyu Wang, Buyun Song, Yong Li, Qun Zhao, Bibo Tan.

  Gastric cancer (GC) is difficult to characterize due to its heterogeneity, and the complicated heterogeneity leads to the difficulty of precisely targeted therapy. The spatially heterogeneous composition plays a crucial role in GC onset, progression, treatment efficacy, and drug resistance. In recent years, the technological advancements in spatial omics has shifted our understanding of the tumor microenvironment (TME) from cancer-centered model to a dynamic and variant whole. In this review, we concentrated on the spatial heterogeneity within the primary lesions and between the primary and metastatic lesions of GC through the TME heterogeneity including the tertiary lymphoid structures (TLSs), the uniquely spatial organization. Meanwhile, the immune phenotype based on spatial distribution was also outlined. Furthermore, we recapitulated the clinical treatment in mediating spatial heterogeneity in GC, hoping to provide a systematic view of how spatial information could be integrated into anti-cancer immunity.

Keywords:  Gastric cancer; Spatial heterogeneity; Tertiary lymphoid structures; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.biopha.2024.116317
Curr Opin Biotechnol. 2024 Feb 20. pii: S0958-1669(24)00019-3. [Epub ahead of print]86 103083

In situ characterization of the tumor microenvironment.

Habib Sadeghirad, Vahid Yaghoubi Naei, Ken O'Byrne, Majid E Warkiani, Arutha Kulasinghe.

The development of new therapies for cancer is underpinned by an increasing need to comprehensively characterize the tumor microenvironment (TME). While traditional approaches have relied on bulk or single-cell approaches, these are limited in their ability to provide cellular context. Deconvolution of the complex TME is fundamental to understanding tumor dynamics and treatment resistance. Spatially resolved characterization of the TME is likely to provide greater insights into the cellular architecture, tumor-immune cell interactions, receptor-ligand interactions, and cell niches. In turn, these aid in dictating the optimal way in which to target each patient's individual cancer. In this review, we discuss a number of cutting-edge in situ spatial profiling methods giving us new insights into tumor biology.

DOI: https://doi.org/10.1016/j.copbio.2024.103083
Cells. 2024 Feb 16. pii: 346. [Epub ahead of print]13(4):

Harnessing Pyroptosis for Cancer Immunotherapy.

Christopher M Bourne, Cornelius Y Taabazuing.

  Cancer immunotherapy is a novel pillar of cancer treatment that harnesses the immune system to fight tumors and generally results in robust antitumor immunity. Although immunotherapy has achieved remarkable clinical success for some patients, many patients do not respond, underscoring the need to develop new strategies to promote antitumor immunity. Pyroptosis is an immunostimulatory type of regulated cell death that activates the innate immune system. A hallmark of pyroptosis is the release of intracellular contents such as cytokines, alarmins, and chemokines that can stimulate adaptive immune activation. Recent studies suggest that pyroptosis promotes antitumor immunity. Here, we review the mechanisms by which pyroptosis can be induced and highlight new strategies to induce pyroptosis in cancer cells for antitumor defense. We discuss how pyroptosis modulates the tumor microenvironment to stimulate adaptive immunity and promote antitumor immunity. We also suggest research areas to focus on for continued development of pyroptosis as an anticancer treatment. Pyroptosis-based anticancer therapies offer a promising new avenue for treating immunologically 'cold' tumors.

Keywords:  antitumor immunity; cancer immunotherapy; caspases; gasdermins; immune checkpoint blockade therapy; inflammasomes; pyroptosis; tumor microenvironment

DOI:  https://doi.org/10.3390/cells13040346
Head Neck. 2024 Feb 21.

Tumor microenvironment in thyroid cancer: Immune cells, patterns, and novel treatments.

Beatriz Febrero, Juan José Ruiz-Manzanera, Inmaculada Ros-Madrid, Antonio Miguel Hernández, Esteban Orenes-Piñero, José Manuel Rodríguez.

  The tumor immune microenvironment of thyroid cancer is the heterogeneous histological space in which tumor cells coexist with host cells. Published data from this review were identified by search and selection database of Pubmed, Elsevier, and Science Direct. Searching was made in two steps using different keywords. In thyroid pathology, the inflammatory response is very important, and might have a key role finding new diagnostic and therapeutic methods, particularly in thyroid cancer. Different immune cells may be more or less present in different types of thyroid cancer and may even have different functions, hence the importance of knowing their presence in different thyroid tumor pathologies. Cancer-related inflammation could be a useful target for new diagnostic and therapeutic strategies by analyzing peritumoral and intratumoral immune cells in different types of thyroid tumors. Moreover, novel strategies for thyroid cancer treatments, such as monoclonal antibodies targeting checkpoint inhibitors, are emerging as promising alternatives.

Keywords:  anaplastic thyroid carcinoma; immune cells; immune checkpoints; medullary thyroid carcinoma; papillary thyroid carcinoma; tumor microenvironment

DOI:  https://doi.org/10.1002/hed.27695
bioRxiv. 2024 Feb 11. pii: 2024.02.08.579002. [Epub ahead of print]

Restricting CAR T Cell Trafficking Expands Targetable Antigen Space.

Erin A Morales, Kenneth A Dietze, Jillian M Baker, Alexander Wang, Stephanie V Avila, Fiorella Iglesias, Sabarinath V Radhakrishnan, Erica Vander Mause, Michael L Olson, Wenxiang Sun, Ethan Rosati, Sadie L Chidester, Thierry Iraguha, Xiaoxuan Fan, Djordje Atanackovic, Tim Luetkens.

Chimeric antigen receptor (CAR) T cells are an effective treatment for some blood cancers. However, the lack of tumor-specific surface antigens limits their wider use. We identified a set of surface antigens that are limited in their expression to cancer and the central nervous system (CNS). We developed CAR T cells against one of these antigens, LINGO1, which is widely expressed in Ewing sarcoma (ES). To prevent CNS targeting, we engineered LINGO1 CAR T cells lacking integrin ⍺ 4 (A4 ko ), an adhesion molecule essential for migration across the blood-brain barrier. A4 ko LINGO1 CAR T cells were efficiently excluded from the CNS but retained efficacy against ES. We show that altering adhesion behavior expands the set of surface antigens targetable by CAR T cells.
One sentence summary: Altering integrin-mediated adhesion provides tumor selectivity to CAR T cells by preventing homing to defined normal tissues but retaining tumor trafficking and anti-tumor activity.
GRAPHICAL ABSTRACT:

DOI: https://doi.org/10.1101/2024.02.08.579002
Adv Sci (Weinh). 2024 Feb 21. e2308009

RECQL4 Inhibits Radiation-Induced Tumor Immune Awakening via Suppressing the cGAS-STING Pathway in Hepatocellular Carcinoma.

Weifeng Hong, Yang Zhang, Siwei Wang, Zongjuan Li, Danxue Zheng, Shujung Hsu, Jian Zhou, Jia Fan, Zhesheng Chen, Xiaojun Xia, Zhaochong Zeng, Qiang Gao, Min Yu, Shisuo Du.

  Many patients with hepatocellular carcinoma (HCC) respond poorly to radiotherapy despite remarkable advances in treatment. A deeper insight into the mechanism of sensitivity of HCC to this therapy is urgently required. It is demonstrated that RECQL4 is upregulated in the malignant cells of patients with HCC. Elevated RECQL4 levels reduce the sensitivity of HCC to radiotherapy by repairing radiation-induced double-stranded DNA (dsDNA) fragments. Mechanistically, the inhibitory effect of RECQL4 on radiotherapy is due to the reduced recruitment of dendritic cells and CD8+ T cells in the tumor microenvironment (TME). RECQL4 disrupts the radiation-induced transformation of the TME into a tumoricidal niche by inhibiting the cGAS-STING pathway in dendritic cells. Knocking out STING in dendritic cells can block the impact of RECQL4 on HCC radiosensitivity. Notably, high RECQL4 expressions in HCC is significantly associated with poor prognosis in multiple independent cohorts. In conclusion, this study highlights how HCC-derived RECQL4 disrupts cGAS-STING pathway activation in dendritic cells through DNA repair, thus reducing the radiosensitivity of HCC. These findings provide new perspectives on the clinical treatment of HCC.

Keywords:  DNA repair; RecQ-Like Helicase 4; cGAS-STING pathway; hepatocellular carcinoma; tumor microenvironment

DOI:  https://doi.org/10.1002/advs.202308009
J Control Release. 2024 Feb 21. pii: S0168-3659(24)00125-1. [Epub ahead of print]

Enhancing photodynamic immunotherapy by reprograming the immunosuppressive tumor microenvironment with hypoxia relief.

Mengying He, Mengyao Zhang, Tao Xu, Shujuan Xue, Dazhao Li, Yanan Zhao, Feng Zhi, Dawei Ding.

  Tumor hypoxia impairs the generation of reactive oxygen species and the induction of immunogenic cell death (ICD) for photodynamic therapy (PDT), thus impeding its efficacy and the subsequent immunotherapy. In addition, hypoxia plays a critical role in forming immunosuppressive tumor microenvironments (TME) by regulating the infiltration of immunosuppressive tumor-associated macrophages (TAMs) and the expression of programmed death ligand 1 (PD-L1). To simultaneously tackle these issues, a MnO2-containing albumin nanoplatform co-delivering IR780, NLG919, and a paclitaxel (PTX) dimer is designed to boost photodynamic immunotherapy. The MnO2-catalyzed oxygen supply bolsters the efficacy of PDT and PTX-mediated chemotherapy, collectively amplifying the induction of ICD and the expansion of tumor-specific cytotoxic T lymphocytes (CTLs). More importantly, alleviating hypoxia reshapes the immunosuppressive TME via down-regulating the intratumoral infiltration of M2-type TAMs and the PD-L1 expression of tumor cells to enhance the infiltration and efficacy of CTLs in combination with immune checkpoint inhibitor NLG919, consequently eradicating primary tumors and almost completely preventing tumor relapse and metastasis. This study sets an example of enhanced immunotherapy for breast cancers through dual ICD induction and simultaneous immunosuppression modulation via both hypoxia relief and ICB, providing a strategy for the treatment of other hypoxic and immunosuppressive cancers.

Keywords:  Hypoxia relief; Immune checkpoint blockade; Immunosuppressive tumor microenvironment; Photodynamic immunotherapy; Tumor-associated macrophages

DOI:  https://doi.org/10.1016/j.jconrel.2024.02.030
J Med Virol. 2024 Feb;96(2): e29485

Hepatitis B virus-related hepatocellular carcinoma exhibits distinct intratumoral microbiota and immune microenvironment signatures.

Yuanjie Liu, Elena S Kim, Haitao Guo.

  Emerging evidence supports a high prevalence of cancer type-specific microbiota residing within tumor tissues. The intratumoral microbiome in hepatocellular carcinoma (HCC), especially in viral (hepatitis B virus [HBV]/hepatitis C virus [HCV]) HCC, has not been well characterized for their existence, composition, distribution, and biological functions. We report herein a finding of specific microbial signature in viral HCC as compared to non-HBV/non-HCV (NBNC) HCC. However, the significantly diverse tumor microbiome was only observed in HBV-related HCC, and Cutibacterium was identified as the representative taxa biomarker. Biological function of the unique tumor microbiota in modulating tumor microenvironment (TME) was characterized by using formalin-fixed paraffin-embedded (FFPE) tissue-based multiplex immunofluorescence histochemistry (mIFH) allowing simultaneous in situ detection of the liver cancer cells surrounded with high/low density of microbiota, and the infiltrating immune cells. In HBV_HCC, the intratumoral microbiota are positively associated with increased tumor-infiltrating CD8+ T lymphocytes, but not the CD56+ NK cells. Two subtypes of myeloid-derived suppressor cells (MDSCs): monocytic MDSCs and polymorphonuclear MDSCs, were also found to be positively correlated with the intratumoral microbiota in HBV_HCC, indicating an inhibitory role of these microbial species in antitumor immunity and the contribution to the liver TME in combination of chronic viral hepatitis during HCC development.

Keywords:  HBV; HCC; HCV; TME; microbiome

DOI:  https://doi.org/10.1002/jmv.29485