bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2023‒05‒28
thirty-two papers selected by
Peio Azcoaga
Biodonostia HRI

  1. Cancer Cell Int. 2023 May 23. 23(1): 101
      Oral cancers are among the common head and neck malignancies. Different anticancer therapy modalities such as chemotherapy, immunotherapy, radiation therapy, and also targeted molecular therapy may be prescribed for targeting oral malignancies. Traditionally, it has been assumed that targeting malignant cells alone by anticancer modalities such as chemotherapy and radiotherapy suppresses tumor growth. In the last decade, a large number of experiments have confirmed the pivotal role of other cells and secreted molecules in the tumor microenvironment (TME) on tumor progression. Extracellular matrix and immunosuppressive cells such as tumor-associated macrophages, myeloid-derived suppressor cells (MDSCs), cancer-associated fibroblasts (CAFs), and regulatory T cells (Tregs) play key roles in the progression of tumors like oral cancers and resistance to therapy. On the other hand, infiltrated CD4 + and CD8 + T lymphocytes, and natural killer (NK) cells are key anti-tumor cells that suppress the proliferation of malignant cells. Modulation of extracellular matrix and immunosuppressive cells, and also stimulation of anticancer immunity have been suggested to treat oral malignancies more effectively. Furthermore, the administration of some adjuvants or combination therapy modalities may suppress oral malignancies more effectively. In this review, we discuss various interactions between oral cancer cells and TME. Furthermore, we also review the basic mechanisms within oral TME that may cause resistance to therapy. Potential targets and approaches for overcoming the resistance of oral cancers to various anticancer modalities will also be reviewed. The findings for targeting cells and potential therapeutic targets in clinical studies will also be reviewed.
    Keywords:  CD8 + T lymphocytes; Cancer-Associated fibroblasts; Immunotherapy; Oral Cancer; Tumor Microenvironment; Tumor-Associated Macrophages
  2. Front Cell Infect Microbiol. 2023 ;13 1141034
      Glioblastoma is a highly aggressive form of brain cancer characterized by the abundance of myeloid lineage cells in the tumor microenvironment. Tumor-associated macrophages and microglia (TAM) and myeloid-derived suppressor cells (MDSCs), play a pivotal role in promoting immune suppression and tumor progression. Oncolytic viruses (OVs) are self-amplifying cytotoxic agents that can stimulate local anti-tumor immune responses and have the potential to suppress immunosuppressive myeloid cells and recruit tumor-infiltrating T lymphocytes (TILs) to the tumor site, leading to an adaptive immune response against tumors. However, the impact of OV therapy on the tumor-resident myeloid population and the subsequent immune responses are not yet fully understood. This review provides an overview of how TAM and MDSC respond to different types of OVs, and combination therapeutics that target the myeloid population to promote anti-tumor immune responses in the glioma microenvironment.
    Keywords:  MDSCs; glioblastoma; glioma; immunosuppressive; macrophages; microglia; oncolytic virus; tumor microenvironment
  3. Front Oncol. 2023 ;13 1114042
      Although previous studies have shed light on the etiology of cervical cancer, metastasis of advanced cervical cancer remains the main reason for the poor outcome and high cancer-related mortality rate. Cervical cancer cells closely communicate with immune cells recruited to the tumor microenvironment (TME), such as lymphocytes, tumor-associated macrophages, and myeloid-derived suppressor cells. The crosstalk between tumors and immune cells has been clearly shown to foster metastatic dissemination. Therefore, unraveling the mechanisms of tumor metastasis is crucial to develop more effective therapies. In this review, we interpret several characteristics of the TME that promote the lymphatic metastasis of cervical cancer, such as immune suppression and premetastatic niche formation. Furthermore, we summarize the complex interactions between tumor cells and immune cells within the TME, as well as potential therapeutic strategies to target the TME.
    Keywords:  cervical cancer; immune cells; lymphangiogenesis; lymphatic metastasis; tumor microenvironment
  4. Genes (Basel). 2023 Apr 28. pii: 1008. [Epub ahead of print]14(5):
      Over the past decade, immunotherapy has emerged as one of the most promising approaches to cancer treatment. The use of immune checkpoint inhibitors has resulted in impressive and durable clinical responses in the treatment of various cancers. Additionally, immunotherapy utilizing chimeric antigen receptor (CAR)-engineered T cells has produced robust responses in blood cancers, and T cell receptor (TCR)-engineered T cells are showing promising results in the treatment of solid cancers. Despite these noteworthy advancements in cancer immunotherapy, numerous challenges remain. Some patient populations are unresponsive to immune checkpoint inhibitor therapy, and CAR T cell therapy has yet to show efficacy against solid cancers. In this review, we first discuss the significant role that T cells play in the body's defense against cancer. We then delve into the mechanisms behind the current challenges facing immunotherapy, starting with T cell exhaustion due to immune checkpoint upregulation and changes in the transcriptional and epigenetic landscapes of dysfunctional T cells. We then discuss cancer-cell-intrinsic characteristics, including molecular alterations in cancer cells and the immunosuppressive nature of the tumor microenvironment (TME), which collectively facilitate tumor cell proliferation, survival, metastasis, and immune evasion. Finally, we examine recent advancements in cancer immunotherapy, with a specific emphasis on T-cell-based treatments.
    Keywords:  CAR T/TCR T/TIL; CRISPR; T cells; alterations; antibody; cancer; cell therapy; signaling; vaccine
  5. Int J Biol Sci. 2023 ;19(8): 2382-2393
      Metastasis is an important cause of cancer-related death. Immunotherapy may be an effective way to prevent and treat tumor metastasis in the future. Currently, many studies have focused on T cells, whereas fewer have focused on B cells and their subsets. B cells play an important role in tumor metastasis. They not only secrete antibodies and various cytokines but also function in antigen presentation to directly or indirectly participate in tumor immunity. Furthermore, B cells are involved in both inhibiting and promoting tumor metastasis, which demonstrates the complexity of B cells in tumor immunity. Moreover, different subgroups of B cells have distinct functions. The functions of B cells are also affected by the tumor microenvironment, and the metabolic homeostasis of B cells is also closely related to their function. In this review, we summarize the role of B cells in tumor metastasis, analyze the mechanisms of B cells, and discuss the current status and prospects of B cells in immunotherapy.
    Keywords:  B cell; immunotherapy; mechanism; metabolism; tumor metastasis
  6. Genes Dis. 2023 Mar;10(2): 447-456
      Autophagy, as a special programmed cell death, is a critical degradative process that eliminates intracellular abnormal proteins or damage organelles to balance cell energy and favor cell metabolism with autophagy-related (ATG) proteins. Autophagy activation is being increasingly recognized as an essential hallmark in tumorigenesis through influencing the metabolism of stromal cells in the tumor microenvironment (TME) which comprises of tumor cells, cancer-associated fibroblasts (CAFs), cancer-associated endothelial cells (CAEs), immune cells and adipocytes. Tumor cells can reuse autophagy-involved recycling to maintain mitochondrial function and energy supply to meet the metabolic demand of their growth and proliferation. However, the mechanism through which autophagy can promote a crosstalk between tumor and stroma cells is not clear. Reprogramed metabolism is one of the main characteristics of TME leading to higher adaptability of tumor cells with diverse mechanisms. The activation of autophagy has expanded our understanding on the interaction between tumor metabolism and TME. The aim of this review is to report recent advances on the metabolic cross-talk between stromal cells and solid tumor cells induced by autophagy in TME and revealed potential therapeutic targets.
    Keywords:  Autophagy; Metabolism; Therapeutic targets; Tumor; Tumor microenvironment
  7. Mol Med. 2023 05 22. 29(1): 66
      Cancer-associated fibroblasts (CAFs) are the most abundant stromal cells within the tumor microenvironment (TME). They extensively communicate with the other cells. Exosome-packed bioactive molecules derived from CAFs can reshape the TME by interacting with other cells and the extracellular matrix, which adds a new perspective for their clinical application in tumor targeted therapy. An in-depth understanding of the biological characteristics of CAF-derived exosomes (CDEs) is critical for depicting the detailed landscape of the TME and developing tailored therapeutic strategies for cancer treatment. In this review, we have summarized the functional roles of CAFs in the TME, particularly focusing on the extensive communication mediated by CDEs that contain biological molecules such as miRNAs, proteins, metabolites, and other components. In addition, we have also highlighted the prospects for diagnostic and therapeutic applications based on CDEs, which could guide the future development of exosome-targeted anti-tumor drugs.
    Keywords:  Cancer-associated fibroblasts; Diagnosis; Exosomes; Therapy; Tumor microenvironment
  8. Int J Mol Sci. 2023 May 17. pii: 8871. [Epub ahead of print]24(10):
      The tumor microenvironment regulates many aspects of cancer progression and anti-tumor immunity. Cancer cells employ a variety of immunosuppressive mechanisms to dampen immune cell function in the tumor microenvironment. While immunotherapies that target these mechanisms, such as immune checkpoint blockade, have had notable clinical success, resistance is common, and there is an urgent need to identify additional targets. Extracellular adenosine, a metabolite of ATP, is found at high levels in the tumor microenvironment and has potent immunosuppressive properties. Targeting members of the adenosine signaling pathway represents a promising immunotherapeutic modality that can potentially synergize with conventional anti-cancer treatment strategies. In this review, we discuss the role of adenosine in cancer, present preclinical and clinical data on the efficacy adenosine pathway inhibition, and discuss possible combinatorial approaches.
    Keywords:  adenosine; clinical trial; immunotherapy; treatment combination
  9. Biol Cell. 2023 May 24.
      Although it is well-known that cancer-associated fibroblasts (CAFs) play a key role in regulating tumor progression, the effects of mechanical tissue changes on CAFs are understudied. Myofibroblastic CAFs (myCAFs), in particular, are known to alter tumor matrix architecture and composition, heavily influencing the mechanical forces in the tumor microenvironment, but much less is known about how these mechanical changes initiate and maintain the myCAF phenotype. Additionally, recent studies have pointed to the existence of CAFs in circulating tumor cell clusters, indicating that CAFs may be subject to mechanical forces beyond the primary tumor microenvironment. Due to their pivotal role in cancer progression, targeting CAF mechanical regulation may provide therapeutic benefit. Here, we will discuss current knowledge and summarize existing gaps in how CAFs regulate and are regulated by matrix mechanics, including through stiffness, solid and fluid stresses, and fluid shear stress. This article is protected by copyright. All rights reserved.
  10. Int J Mol Sci. 2023 May 09. pii: 8470. [Epub ahead of print]24(10):
      One of the most frequent solid tumors in children is neuroblastoma, which has a variety of clinical behaviors that are mostly influenced by the biology of the tumor. Unique characteristics of neuroblastoma includes its early age of onset, its propensity for spontaneous tumor regression in newborns, and its high prevalence of metastatic disease at diagnosis in individuals older than 1 year of age. Immunotherapeutic techniques have been added to the previously enlisted chemotherapeutic treatments as therapeutic choices. A groundbreaking new treatment for hematological malignancies is adoptive cell therapy, specifically chimeric antigen receptor (CAR) T cell therapy. However, due to the immunosuppressive nature of the tumor microenvironment (TME) of neuroblastoma tumor, this treatment approach faces difficulties. Numerous tumor-associated genes and antigens, including the MYCN proto-oncogene (MYCN) and disialoganglioside (GD2) surface antigen, have been found by the molecular analysis of neuroblastoma cells. The MYCN gene and GD2 are two of the most useful immunotherapy findings for neuroblastoma. The tumor cells devise numerous methods to evade immune identification or modify the activity of immune cells. In addition to addressing the difficulties and potential advancements of immunotherapies for neuroblastoma, this review attempts to identify important immunological actors and biological pathways involved in the dynamic interaction between the TME and immune system.
    Keywords:  high-risk neuroblastoma; immunotherapy; tumor microenvironment
  11. Diagnostics (Basel). 2023 May 12. pii: 1724. [Epub ahead of print]13(10):
      Immune cell infiltration into the tumor microenvironment is associated with cancer prognosis. Tumor-associated macrophages play essential roles in tumor initiation, progression, and metastasis. Follistatin-like protein 1 (FSTL1), a widely expressed glycoprotein in human and mouse tissues, is a tumor suppressor in various cancers and a regulator of macrophage polarization. However, the mechanism by which FSTL1 affects crosstalk between breast cancer cells and macrophages remains unclear. By analyzing public data, we found that FSTL1 expression was significantly low in breast cancer tissues compared to normal breast tissues, and high expression of FSTL1 in patients indicated prolonged survival. Using flow cytometry, we found that total and M2-like macrophages dramatically increased in the metastatic lung tissues during breast cancer lung metastasis in Fstl1+/- mice. Transwell assay in vitro and q-PCR experimental results showed that FSTL1 inhibited macrophage migration toward 4T1 cells by decreasing CSF1, VEGF-α, and TGF-β secretion in 4T1 cells. We demonstrated that FSTL1 inhibited M2-like tumor-associated macrophage recruitment toward the lungs by suppressing CSF1, VEGF-α, and TGF-β secretion in 4T1 cells. Therefore, we identified a potential therapeutic strategy for triple-negative breast cancer.
    Keywords:  M2-like tumor-associated macrophages; breast cancer lung metastasis; follistatin-like 1 (FSTL1); triple-negative breast cancer; tumor microenvironment
  12. Int Immunopharmacol. 2023 May 19. pii: S1567-5769(23)00669-0. [Epub ahead of print]120 110346
      Triple-negative breast cancer (TNBC) is a specific type of breast cancer that exhibits poor prognosis and complex tumor heterogeneity. The unique immune tumor microenvironment reveals great potential of immunotherapy in TNBC. Triptolide, a potential regulator of immune-related signaling, has shown potent antitumor activity in TNBC. However, the molecular mechanism of triptolide in TNBC is still controversial. This study identified interferon-γ (IFN-γ) as a therapeutical target of triptolide based on the analysis of prognostic biomarkers in TNBC. IFN-γ is an important component of immunotherapy and contributes to antitumor immune activation. Triptolide was found to significantly reverse the IFN-γ-inducible programmed death-ligand 1 (PD-L1) in TNBC. The combined treatment of triptolide and IFN-γ in a hydrogel delivery system remarkably induced the cytotoxic CD8 + T lymphocytes activation, showing a synergistic effect on the potent tumor inhibition.
    Keywords:  Antitumor immunity; IFN-γ; PD-L1; Triple-negative breast cancer; Triptolide
  13. J Cell Biol. 2023 Jun 05. pii: e202305044. [Epub ahead of print]222(6):
      Gina DeNicola investigates the metabolism of cancer cells in vivo with a focus on NRF2 and the tumor microenvironment.
  14. Front Immunol. 2023 ;14 1118637
      The tumor microenvironment (TME) is modified by its cellular or acellular components throughout the whole period of tumor development. The dynamic modulation can reprogram tumor initiation, growth, invasion, metastasis, and response to therapies. Hence, the focus of cancer research and intervention has gradually shifted to TME components and their interactions. Accumulated evidence indicates neural and immune factors play a distinct role in modulating TME synergistically. Among the complicated interactions, neurotransmitters, the traditional neural regulators, mediate some crucial regulatory functions. Nevertheless, knowledge of the exact mechanisms is still scarce. Meanwhile, therapies targeting the TME remain unsatisfactory. It holds a great prospect to reveal the molecular mechanism by which the interplay between the nervous and immune systems regulate cancer progression for laying a vivid landscape of tumor development and improving clinical treatment.
    Keywords:  cancer immunology; immune modulator; neuroimmune interaction; neurotransmitter; tumor microenvironment
  15. Small. 2023 May 21. e2301749
      Low infiltration of cytotoxic T lymphocytes and their exhaustion manifest the two concurrent main hurdles for achieving effective tumor immunotherapy of triple-negative breast cancer. It is found that Galectin-9 blockage can revise the exhaustion of effector T cells, meanwhile the repolarization of protumoral M2 tumor-associated macrophages (TAMs) into tumoricidal M1-like ones can recruit effector T cells infiltrating into tumor to boost immune responses. Herein, a sheddable PEG-decorated and M2-TAMs targeted nanodrug incorporating Signal Transducer and Activator of Transcription 6 inhibitor (AS) and anti-Galectin-9 antibody (aG-9) is prepared. The nanodrug responds to acidic tumor microenvironment (TME) with the shedding of PEG corona and the release of aG-9, exerting local blockade of PD-1/Galectin-9/TIM-3 interaction to augment effector T cells via exhaustion reversing. Synchronously, targeted repolarization of M2-TAMs into M1 phenotype by AS-loaded nanodrug is achieved, which promotes tumor infiltration of effector T cells and thus synergizes with aG-9 blockade to boost the therapeutic efficacy. Besides, the PEG-sheddable approach endows nanodrug with stealth ability to reduce immune-related adverse effects caused by AS and aG-9. This PEG sheddable nanodrug holds the potential to reverse the immunosuppressive TME and increase effector T cell infiltration, which dramatically enhances immunotherapy in highly malignant breast cancer.
    Keywords:  PEG-sheddable nanodrug; galectin-9 blockage; tumor immunotherapy; tumor-associated macrophage repolarization
  16. Curr Issues Mol Biol. 2023 May 22. 45(5): 4495-4517
      It is well-established that tumor antigens and molecules expressed and secreted by cancer cells trigger innate and adaptive immune responses. These two types of anti-tumor immunity lead to the infiltration of the tumor's microenvironment by immune cells with either regulatory or cytotoxic properties. Whether this response is associated with tumor eradication after radiotherapy and chemotherapy or regrowth has been a matter of extensive research through the years, mainly focusing on tumor-infiltrating lymphocytes and monocytes and their subtypes, and the expression of immune checkpoint and other immune-related molecules by both immune and cancer cells in the tumor microenvironment. A literature search has been conducted on studies dealing with the immune response in patients with rectal cancer treated with neoadjuvant radiotherapy or chemoradiotherapy, assessing its impact on locoregional control and survival and underlying the potential role of immunotherapy in the treatment of this cancer subtype. Here, we provide an overview of the interactions between local/systemic anti-tumor immunity, cancer-related immune checkpoint, and other immunological pathways and radiotherapy, and how these affect the prognosis of rectal cancer patients. Chemoradiotherapy induces critical immunological changes in the tumor microenvironment and cancer cells that can be exploited for therapeutic interventions in rectal cancer.
    Keywords:  HLA; aminoacid metabolism; immune checkpoint; prognosis; radiotherapy; rectal cancer
  17. J Immunother Cancer. 2023 May;pii: e006230. [Epub ahead of print]11(5):
      BACKGROUND: Tumor-associated macrophages (TAMs) are a major component of the tumor microenvironment (TME) and exert an important role in tumor progression. Due to the heterogeneity and plasticity of TAMs, modulating the polarization states of TAMs is considered as a potential therapeutic strategy for tumors. Long noncoding RNAs (lncRNAs) have been implicated in various physiological and pathological processes, yet the underlying mechanism on how lncRNAs manipulate the polarization states of TAMs is still unclear and remains to be further investigated.METHODS: Microarray analyses were employed to characterize the lncRNA profile involved in THP-1-induced M0, M1 and M2-like macrophage. Among those differentially expressed lncRNAs, NR_109 was further studied, for its function in M2-like macrophage polarization and the effects of the condition medium or macrophages mediated by NR_109 on tumor proliferation, metastasis and TME remodeling both in vitro and in vivo. Moreover, we revealed how NR_109 interacted with far upstream element-binding protein 1 (FUBP1) to regulate the protein stability through hindering ubiquitination modification by competitively binding with JVT-1. Finally, we examined sections of tumor patients to probe the correlation among the expression of NR_109 and related proteins, showing the clinical significance of NR_109.
    RESULTS: We found that lncRNA NR_109 was highly expressed in M2-like macrophages. Knockdown NR_109 impeded IL-4 induced M2-like macrophage polarization and significantly reduced the activity of M2-like macrophages to support the proliferation and metastasis of tumor cells in vitro and in vivo. Mechanistically, NR_109 competed with JVT-1 to bind FUBP1 at its C-terminus domain, impeded the ubiquitin-mediated degradation of FUBP1, activated c-Myc transcription and thus promoted M2-like macrophages polarization. Meanwhile, as a transcription factor, c-Myc could bind to the promoter of NR_109 and enhance the transcription of NR_109. Clinically, high NR_109 expression was found in CD163+ TAMs from tumor tissues and was positively correlated with poor clinical stages of patients with gastric cancer and breast cancer.
    CONCLUSIONS: Our work revealed for the first time that NR_109 exerted a crucial role in regulating the phenotype-remodeling and function of M2-like macrophages via a NR_109/FUBP1/c-Myc positive feedback loop. Thus, NR_109 has great translational potentials in the diagnosis, prognosis and immunotherapy of cancer.
    Keywords:  immunotherapy; macrophages; tumor microenvironment
  18. Signal Transduct Target Ther. 2023 May 22. 8(1): 210
      Over decades, researchers have focused on the epigenetic control of DNA-templated processes. Histone modification, DNA methylation, chromatin remodeling, RNA modification, and noncoding RNAs modulate many biological processes that are crucial to the development of cancers. Dysregulation of the epigenome drives aberrant transcriptional programs. A growing body of evidence suggests that the mechanisms of epigenetic modification are dysregulated in human cancers and might be excellent targets for tumor treatment. Epigenetics has also been shown to influence tumor immunogenicity and immune cells involved in antitumor responses. Thus, the development and application of epigenetic therapy and cancer immunotherapy and their combinations may have important implications for cancer treatment. Here, we present an up-to-date and thorough description of how epigenetic modifications in tumor cells influence immune cell responses in the tumor microenvironment (TME) and how epigenetics influence immune cells internally to modify the TME. Additionally, we highlight the therapeutic potential of targeting epigenetic regulators for cancer immunotherapy. Harnessing the complex interplay between epigenetics and cancer immunology to develop therapeutics that combine thereof is challenging but could yield significant benefits. The purpose of this review is to assist researchers in understanding how epigenetics impact immune responses in the TME, so that better cancer immunotherapies can be developed.
  19. Front Immunol. 2023 ;14 1161628
      Colorectal cancer (CRC) is a common malignant tumor of the digestive system, and its morbidity rates are increasing worldwide. Cancer-associated fibroblasts (CAFs), as part of the tumor microenvironment (TME), are not only closely linked to normal fibroblasts, but also can secrete a variety of substances (including exosomes) to participate in the regulation of the TME. Exosomes can play a key role in intercellular communication by delivering intracellular signaling substances (e.g., proteins, nucleic acids, non-coding RNAs), and an increasing number of studies have shown that non-coding RNAs of exosomal origin from CAFs are not only closely associated with the formation of the CRC microenvironment, but also increase the ability of CRC to grow in metastasis, mediate tumor immunosuppression, and are involved in the mechanism of drug resistance in CRC patients receiving. It is also involved in the mechanism of drug resistance after radiotherapy in CRC patients. In this paper, we review the current status and progress of research on CAFs-derived exosomal non-coding RNAs in CRC.
    Keywords:  cancer-associated fibroblasts (CAFs); colorectal cancer (CRC); exosomal noncoding RNAs (ncRNAs); exosomes; tumor microenvironment (TME)
  20. Curr Mol Med. 2023 May 10.
      Natural killer (NK) cells are among the most important cells in innate immune defense. In contrast to T cells, the effector function of NK cells does not require prior stimulation and is not MHC restricted. Therefore, chimeric antigen receptor (CAR)-NK cells are superior to CAR-T cells. The complexity of the tumor microenvironment (TME) makes it necessary to explore various pathways involved in NK cell negative regulation. CAR-NK cell effector function can be improved by inhibiting the negative regulatory mechanisms. In this respect, the E3 ubiquitin ligase tripartite motif containing 29 (TRIM29) is known to be involved in reducing NK cell cytotoxicity and cytokine production. Also, targeting TRIM29 may enhance the antitumor efficacy of CAR-NK cells. The present study discusses the negative effects of TRIM29 on NK cell activity and genomic deletion or suppression of the expression of TRIM29 as a novel approach to optimize CAR-NK cell-based immunotherapy.
    Keywords:  CAR-NK cell; CAR-T cell; TRIM29; Tumor microenvironment; chemotherapy; immunotherapy.
  21. Front Oncol. 2023 ;13 1171794
      Endothelial cells and immune cells are major regulators of cancer progression and prognosis. Endothelial cell proliferation and angiogenesis are required for providing nutrients and oxygen to the nascent tumor and infiltration of immune cells to the tumor is dependent on endothelial cell activation. Myeloid cells and innate lymphocytes have an important role in shaping the tumor microenvironment by crosstalking with cancer cells and structural cells, including endothelial cells. Innate immune cells can modulate the activation and functions of tumor endothelial cells, and, in turn, endothelial cell expression of adhesion molecules can affect immune cell extravasation. However, the mechanisms underlying this bidirectional crosstalk are not fully understood. In this review, we will provide an overview of the current knowledge on the pathways regulating the crosstalk between innate immune cells and endothelial cells during tumor progression and discuss their potential contribution to the development of novel anti-tumor therapeutic approaches.
    Keywords:  angiogenesis; cancer; endothelial cells; innate lymphocytes; myeloid cells
  22. Discov Oncol. 2023 May 23. 14(1): 77
      MDSCs are immature myeloid immune cells, which accumulate in models of liver cancer to reduce effector immune cell activity, contribute to immune escape and treatment resistance. The accumulation of MDSCs suppresses the role of CTL and the killing effects of NK cells, induces the accumulation of Treg cells, and blocks the antigen presentation of DCs, thus promoting the progression of liver cancer. Recently, immunotherapy has emerged a valuable approach following chemoradiotherapy in the therapy of advanced liver cancer. A considerable increasing of researches had proved that targeting MDSCs has become one of the therapeutic targets to enhance tumor immunity. In preclinical study models, targeting MDSCs have shown encouraging results in both alone and in combination administration. In this paper, we elaborated immune microenvironment of the liver, function and regulatory mechanisms of MDSCs, and therapeutic approaches to target MDSCs. We also expect these strategies to supply new views for future immunotherapy for the treatment of liver cancer.
  23. Int J Mol Sci. 2023 May 20. pii: 9038. [Epub ahead of print]24(10):
      There is a medical need to develop new and effective therapies against triple-negative breast cancer (TNBC). Chimeric antigen receptor (CAR) natural killer (NK) cells are a promising alternative to CAR-T cell therapy for cancer. A search for a suitable target in TNBC identified CD44v6, an adhesion molecule expressed in lymphomas, leukemias and solid tumors that is implicated in tumorigenesis and metastases. We have developed a next-generation CAR targeting CD44v6 that incorporates IL-15 superagonist and checkpoint inhibitor molecules. We could show that CD44v6 CAR-NK cells demonstrated effective cytotoxicity against TNBC in 3D spheroid models. The IL-15 superagonist was specifically released upon recognition of CD44v6 on TNBC and contributed to the cytotoxic attack. PD1 ligands are upregulated in TNBC and contribute to the immunosuppressive tumor microenvironment (TME). Competitive inhibition of PD1 neutralized inhibition by PD1 ligands expressed on TNBC. In total, CD44v6 CAR-NK cells are resistant to TME immunosuppression and offer a new therapeutic option for the treatment of BC, including TNBC.
    Keywords:  CAR; CAR-NK; CD44v6; TNBC; cancer; immunotherapy
  24. Front Oncol. 2023 ;13 1155511
      Ferroptosis is a type of lipid peroxidation-induced, iron-dependent programmed cell death. Emerging evidence suggests that ferroptosis is intimately connected to tumorigenesis, development, treatment and plays a major role in tumor immune regulation. This study focused on the connection between ferroptosis and immune regulation, which may offer a theoretical basis for targeting ferroptosis and tumor immunotherapy.
    Keywords:  ferroptosis; lipid peroxidation; micro RNA; tumor immunotherapy; tumor microenvironment
  25. Signal Transduct Target Ther. 2023 May 22. 8(1): 207
      Macrophages exist in various tissues, several body cavities, and around mucosal surfaces and are a vital part of the innate immune system for host defense against many pathogens and cancers. Macrophages possess binary M1/M2 macrophage polarization settings, which perform a central role in an array of immune tasks via intrinsic signal cascades and, therefore, must be precisely regulated. Many crucial questions about macrophage signaling and immune modulation are yet to be uncovered. In addition, the clinical importance of tumor-associated macrophages is becoming more widely recognized as significant progress has been made in understanding their biology. Moreover, they are an integral part of the tumor microenvironment, playing a part in the regulation of a wide variety of processes including angiogenesis, extracellular matrix transformation, cancer cell proliferation, metastasis, immunosuppression, and resistance to chemotherapeutic and checkpoint blockade immunotherapies. Herein, we discuss immune regulation in macrophage polarization and signaling, mechanical stresses and modulation, metabolic signaling pathways, mitochondrial and transcriptional, and epigenetic regulation. Furthermore, we have broadly extended the understanding of macrophages in extracellular traps and the essential roles of autophagy and aging in regulating macrophage functions. Moreover, we discussed recent advances in macrophages-mediated immune regulation of autoimmune diseases and tumorigenesis. Lastly, we discussed targeted macrophage therapy to portray prospective targets for therapeutic strategies in health and diseases.
  26. J Exp Clin Cancer Res. 2023 May 20. 42(1): 129
      BACKGROUND: Emerging studies have identified chronic psychological stress as an independent risk factor influencing breast cancer growth and metastasis. However, the effects of chronic psychological stress on pre-metastatic niche (PMN) formation and the underlying immunological mechanisms remain largely unknown.METHODS: The effects and molecular mechanisms of chronic unpredictable mild stress (CUMS) on modulating tumor-associated macrophages (TAMs) and PMN formation were clarified by multiplex immunofluorescence technique, cytokine array, chromatin immunoprecipitation, the dual-luciferase reporter assay, and breast cancer xenografts. Transwell and CD8+ T cytotoxicity detection were used to analyze the mobilization and function of myeloid-derived suppressor cells (MDSCs). mCherry-labeled tracing strategy and bone marrow transplantation were applied to explore the crucial role of splenic CXCR2+/+ MDSCs facilitating PMN formation under CUMS.
    RESULTS: CUMS significantly promoted breast cancer growth and metastasis, accompanied by TAMs accumulation in the microenvironment. CXCL1 was identified as a crucial chemokine in TAMs facilitating PMN formation in a glucocorticoid receptor (GR)-dependent manner. Interestingly, the spleen index was significantly reduced under CUMS, and splenic MDSCs were validated as a key factor mediating CXCL1-induced PMN formation. The molecular mechanism study revealed that TAM-derived CXCL1 enhanced the proliferation, migration, and anti-CD8+ T cell functions of MDSCs via CXCR2. Moreover, CXCR2 knockout and CXCR2-/-MDSCs transplantation significantly impaired CUMS-mediated MDSC elevation, PMN formation, and breast cancer metastasis.
    CONCLUSION: Our findings shed new light on the association between chronic psychological stress and splenic MDSC mobilization, and suggest that stress-related glucocorticoid elevation can enhance TAM/CXCL1 signaling and subsequently recruit splenic MDSCs to promote PMN formation via CXCR2.
    Keywords:  Breast cancer; CXCL1/CXCR2; Chronic psychological stress; Myeloid-derived suppressor cells; Pre-metastatic niche
  27. J Immunother Precis Oncol. 2023 May;6(2): 91-102
      Immune checkpoint inhibitors have revolutionized the treatment paradigm of several cancers. However, not all patients respond to treatment. Tumor cells reprogram metabolic pathways to facilitate growth and proliferation. This shift in metabolic pathways creates fierce competition with immune cells for nutrients in the tumor microenvironment and generates by-products harmful for immune cell differentiation and growth. In this review, we discuss these metabolic alterations and the current therapeutic strategies to mitigate these alterations to metabolic pathways that can be used in combination with checkpoint blockade to offer a new path forward in cancer management.
    Keywords:  adenosine pathway; amino acid metabolism; glucose metabolism; immune checkpoint inhibitors; lipid metabolism
  28. Crit Rev Oncol Hematol. 2023 May 24. pii: S1040-8428(23)00125-7. [Epub ahead of print] 104037
      Metabolic reprogramming is one of the important characteristics of cancer and is a key process leading to malignant proliferation, tumor development and treatment resistance. A variety of therapeutic drugs targeting metabolic reaction enzymes, transport receptors, and special metabolic processes have been developed. In this review, we investigate the characteristics of multiple metabolic changes in cancer cells, including glycolytic pathways, lipid metabolism, and glutamine metabolism changes, describe how these changes promote tumor development and tumor resistance, and summarize the progress and challenges of therapeutic strategies targeting various links of tumor metabolism in combination with current study data.
    Keywords:  Cancer; Glycolysis; Metabolism; Oxidative Phosphorylation; Treatment Resistance
  29. Pathol Res Pract. 2023 May 18. pii: S0344-0338(23)00240-6. [Epub ahead of print]247 154540
      BACKGROUND: In recent years, several studies focused on the process of reprogramming of seminoma (S) cells, which regulates the transition from pure S (P-S) to S component (S-C) of mixed germ cell tumors of the testis (GCTT) and finally to embryonal carcinoma (EC) and other nonseminomatous GCTT (NS-GCTT). The accepted pathogenetic model is driven and regulated by cells (macrophages, B- and T-lymphocytes) and molecules of the tumor microenvironment (TME). Herein, we tested a series of GCTT with double staining (DS) for CD68-PD-L1 to evaluate tumor-associated macrophages (TAMs) expressing programmed death-ligand 1 (PD-L1) [TAMs PD-L1(+)] and clarify if these cells may be involved in establishing the fate of GCTT.METHODS: We collected 45 GCTT (comprising a total of 62 different components of GCTT). TAMs PD-L1(+) were evaluated with three different scoring systems [TAMs PD-L1(+)/mm2, TAMs PD-L1(+)/mm2H-score, TAMs PD-L1(+) %], and compared using pertinent statistic tests (Student's t-test and Mann-Whitney U test).
    RESULTS: We found that TAMs PD-L1(+) values were higher in S rather than EC (p = 0.001, p = 0.015, p = 0.022) and NS-GCTT (p < 0.001). P-S showed statistically significant differences in TAMs PD-L1(+) values compared to S-C (p < 0.001, p = 0.006, p = 0.015), but there were no differences between S-C and EC (p = 0.107, p = 0.408, p = 0.800). Finally, we found statistically significant differences also in TAMs PD-L1(+) values between EC and other NS-GCTT (p < 0.001).
    CONCLUSIONS: TAMs PD-L1(+) levels gradually decrease during the reprogramming of S cells {P-S [(high values of TAMs PD-L1(+)] → S-C and EC [(intermediate values of TAMs PD-L1(+)] → other NS-GCTT [(low values of TAMs PD-L1(+)], supporting a complex pathogenetic model where the interactions between tumor cells and TME components [and specifically TAMs PD-L1(+)] play a key role in determining the fate of GCTT.
    Keywords:  Germ cell tumors of the testis; PD-L1; Reprogramming; TAMs; Tumor-associated macrophages
  30. Expert Opin Drug Discov. 2023 May 23. 1-16
      INTRODUCTION: Identifying effective cancer drugs remains an inefficient process. Drug efficacy in traditional preclinical cancer models translates poorly into therapy in the clinic. Implementation of preclinical models that incorporate the tumor microenvironment (TME) is needed to improve selection of active drugs prior to clinical trials.AREAS COVERED: Progression of cancer results from the behavior of cancer cells in concert with the host's histopathological background. Nonetheless, complex preclinical models with a relevant microenvironment have yet to become an integral part of drug development. This review discusses existing models and provides a synopsis of active areas of cancer drug development where implementation would be of value. Their contribution to finding therapeutics in immune oncology, angiogenesis, regulated cell death and targeting tumor fibroblasts as well as optimization of drug delivery, combination therapy, and biomarkers of efficacy is considered.
    EXPERT OPINION: Complex tumor models in vitro (CTMIVs) that mimic the organotypic architecture of neoplastic tumors have boosted research into TME influence on traditional cytoreductive chemotherapy as well as the detection of specific TME targets. Despite advances in technical prowess, CTMIVs can only address specific aspects of cancer pathophysiology.
    Keywords:  Tumor models; cancer therapy; microenvironment; precision medicine; preclinical disease prediction