bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2023‒04‒23
thirty-six papers selected by
Peio Azcoaga
Biodonostia HRI

  1. Trends Cell Biol. 2023 Apr 18. pii: S0962-8924(23)00049-1. [Epub ahead of print]
      Tumor-associated macrophages (TAMs) are critical in promoting tumor progression and therapeutic resistance. In adapting to metabolic changes in the tumor microenvironment (TME), TAMs reprogram their metabolisms and acquire immunosuppressive and pro-tumor properties. Increased glucose metabolism in TAMs leads to the accumulation of a variety of oncometabolites that exhibit potent tumor-promoting capacity via regulating gene expression and signaling transduction. Glucose uptake also fuels O-GlcNAcylation and other post-translational modifications to promote pro-tumor polarization and function of TAMs. Glucose metabolism coordinates interactions between TAMs and various types of cells in the TME, creating a complex network that facilitates tumor progression. Targeting glucose metabolism represents a promising strategy to switch TAMs from pro-tumor toward anti-tumor function for cancer therapy.
    Keywords:  O-GlcNAcylation; glucose metabolism; lactic acids; tumor metastasis; tumor-associated macrophages
  2. Adv Protein Chem Struct Biol. 2023 ;pii: S1876-1623(22)00099-2. [Epub ahead of print]135 281-311
      The vast complexity of the tumor microenvironment (TME) aggrandizes the underlying principles responsible for immune escape, therapy resistance, and treatment failure. The stromal and immune cell population circumjacent to the tumor cells affects the cancer cell cycle leading to tumor progression. Tumor-associated macrophages (TAMs) exhibiting a unique M2 polarization state constitute a significant portion of the TME. They serve as tumor suppressors at early stages and tumor promoters at advanced stages by governing various microenvironmental cues. TAMs secreted various pro-tumoral cytokines, chemokines, and matrix metalloproteases are known to regulate the different cell cycle molecules including checkpoint inhibitors in cancer cells leading to cell cycle progression with faulty cellular components. Moreover, TAMs are well-known immunosuppressors and thereby facilitating the tumor cells' evasion from immune recognition. This chapter will describe the interaction between TAMs and tumor cells, the involvement of TAMs in the regulation of cancer cell progression by controlling cell cycle checkpoints or molecular pathways, and current TAM-based therapies, including restriction of TAM recruitment, anti-survival strategies, or switching polarity. Moreover, this chapter will also emphasize recently developed drug targets and CAR-macrophage cell therapy that restricts tumor progression.
    Keywords:  CAR-M therapy; Cell cycle; Immunosuppression; Tumor progression; Tumor-associated macrophages
  3. Front Oncol. 2023 ;13 1166860
      Pancreatic cancer is one of the most malignant tumors with increased incidence rate. The effect of surgery combined with chemoradiotherapy on survival of patients is unsatisfactory. New treatment strategy such as immunotherapy need to be investigated. The accumulation of desmoplastic stroma, infiltration of immunosuppressive cells including myeloid derived suppressor cells (MDSCs), tumor associated macrophages (TAMs), cancer-associated fibroblasts (CAFs), and regulatory T cells (Tregs), as well as tumor associated cytokine such as TGF-β, IL-10, IL-35, CCL5 and CXCL12 construct an immunosuppressive microenvironment of pancreatic cancer, which presents challenges for immunotherapy. In this review article, we explore the roles and mechanism of immunosuppressive cells and lymphocytes in establishing an immunosuppressive tumor microenvironment in pancreatic cancer. In addition, immunotherapy strategies for pancreatic cancer based on tumor microenvironment including immune checkpoint inhibitors, targeting extracellular matrix (ECM), interfering with stromal cells or cytokines in TME, cancer vaccines and extracellular vesicles (EVs) are also discussed. It is necessary to identify an approach of immunotherapy in combination with other modalities to produce a synergistic effect with increased response rates in pancreatic cancer therapy.
    Keywords:  clinical trial; immunosuppression; immunotherapy; pancreatic cancer; tumor microenvironment
  4. Clin Transl Oncol. 2023 Apr 20.
      Radiotherapy is one of the main therapies for cancer. The process leading to radioresistance is still not fully understood. Cancer radiosensitivity is related to the DNA reparation of cancer cells and the tumor microenvironment (TME), which supports cancer cell survival. Factors that affect DNA reparation and the TME can directly or indirectly affect the radiosensitivity of cancer. Recent studies have shown that lipid metabolism in cancer cells, which is involved in the stability of cell membrane structure, energy supply and signal transduction of cancer cells, can also affect the phenotype and function of immune cells and stromal cells in the TME. In this review, we discussed the effects of lipid metabolism on the radiobiological characteristics of cancer cells and the TME. We also summarized recent advances in targeted lipid metabolism as a radiosensitizer and discussed how these scientific findings could be translated into clinical practice to improve the radiosensitivity of cancer.
    Keywords:  Cancer; Cholesterol; Fatty acid oxidation; Lipid metabolism; Radioresistance; Tumor microenvironment
  5. Front Pharmacol. 2023 ;14 1142374
      Introduction: Triple-negative breast cancer (TNBC) usually has a poor prognosis. Although the immunotherapy of TNBC has achieved great progress, only a few patients can benefit from the current treatment. CD47 is widely expressed on the surface of TNBC cells and may become an immune checkpoint for TNBC treatment. Nevertheless, increasingly more attention has been paid to systemic side effects since the ubiquitous expression of CD47 on normal cells. The toll-like receptor (TLR) agonist resiquimod (R848) can activate dendritic cells (DCs) and promote the maturation of immune cells in the tumor microenvironment, which further enhances the tumor inhibition ability of the immune system and synergizes with CD47 small interfering RNA (siRNA) for TNBC therapy. However, ideal delivery platforms such as nanocarriers are still needed because its weakness of hydrophobicity. Methods: In order to improve efficacy and reduce toxicity, R848 and siCD47 were entrapped in amphiphilic PEG-PLGA nanoparticles by double emulsification and stable nanoparticles NP/R848/siCD47 were generated to investigate their anti-tumor effects in a TNBC tumor-bearing mouse model. Results: Here, we show that PEG-PLGA nanoparticles are effective nanocarriers that can safely and effectively deliver siCD47 and R848 to tumor tissue, as demonstrated by retarded tumor growth. Mechanistically, downregulation of CD47 expression and activation of DCs took part in promoting the immune response of cytotoxic T cells (CTLs). Meanwhile, a decrease of myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) indicated the modulating of the tumor immune microenvironment. Discussion: To our best knowledge, our study pioneered co-delivery system for hydrophilic siCD47 and hydrophobic R848. It can maximize break tumor immune escape caused by CD47 and simultaneously enhance antigen presentation by activating DCs for effector T cell killing while regulating the tumor microenvironment as expected. Not only does it conform to the reports of previous basic research, but also it can break the bottleneck of their clinical application hopefully. Collectively, our findings could lay the foundation for future therapeutic strategies of TNBC.
    Keywords:  PEG-PLGA nanoparticles; R848; TNBC; siCD47; tumor immunotherapy
  6. Med Oncol. 2023 Apr 21. 40(5): 155
      Nowadays, one of the main challenges clinicians face is malignancies. Through the progression of technology in recent years, tumor nature and tumor microenvironment (TME) can be better understood. Because of immune system involvement in tumorigenesis and immune cell dysfunction in the tumor microenvironment, clinicians encounter significant challenges in patient treatment and normal function recovery. The tumor microenvironment can stop the development of tumor antigen-specific helper and cytotoxic T cells in the tumor invasion process. Tumors stimulate the production of proinflammatory and immunosuppressive factors and cells that inhibit immune responses. Despite the more successful outcomes, the current cancer therapeutic approaches, including surgery, chemotherapy, and radiotherapy, have not been effective enough for tumor eradication. Hence, developing new treatment strategies such as monoclonal antibodies, adaptive cell therapies, cancer vaccines, checkpoint inhibitors, and cytokines helps improve cancer treatment. Among adoptive cell therapies, the interaction between the immune system and malignancies and using molecular biology led to the development of chimeric antigen receptor (CAR) T cell therapy. CAR-modified immune cells are one of the modern cancer therapeutic methods with encouraging outcomes in most hematological and solid cancers. The current study aimed to discuss the structure, formation, subtypes, and application of CAR immune cells in hematologic malignancies and solid tumors.
    Keywords:  CAR T cell therapy; Chimeric antigen receptor; Hematological malignancy; Immunotherapy; Solid tumor
  7. Adv Biol (Weinh). 2023 Apr 21. e2300047
      Macrophages are multifunctional cells that are employed by the tumor to further its growth and adaptation. While tumor-associated macrophages (TAMs) have widely diverse phenotypes, tumors coevolve with the ones that can promote tumorigenesis. Functionally, TAMs/myeloid cells constitute the largest negative influence on the tumor microenvironment and need to be reprogrammed in order to enable successful anti-tumor response in most tumors. It is predicted that successful TAM repolarization has the potential to become a staple of immuno-oncology across most indications.
    Keywords:  TAM; cancer; immunotherapy; macrophages; tumor microenvironment
  8. Theranostics. 2023 ;13(6): 1774-1808
      Metabolic reprogramming is one of the most important hallmarks of malignant tumors. Specifically, lipid metabolic reprogramming has marked impacts on cancer progression and therapeutic response by remodeling the tumor microenvironment (TME). In the past few decades, immunotherapy has revolutionized the treatment landscape for advanced cancers. Lipid metabolic reprogramming plays pivotal role in regulating the immune microenvironment and response to cancer immunotherapy. Here, we systematically reviewed the characteristics, mechanism, and role of lipid metabolic reprogramming in tumor and immune cells in the TME, appraised the effects of various cell death modes (specifically ferroptosis) on lipid metabolism, and summarized the antitumor therapies targeting lipid metabolism. Overall, lipid metabolic reprogramming has profound effects on cancer immunotherapy by regulating the immune microenvironment; therefore, targeting lipid metabolic reprogramming may lead to the development of innovative clinical applications including sensitizing immunotherapy.
    Keywords:  immunotherapy; lipid metabolic reprogramming; therapeutic target; tumor microenvironment
  9. Front Genet. 2023 ;14 1086163
      Triple negative breast cancer (TNBC) has poor prognosis when compared to other breast cancer subtypes. Despite pre-clinical data supporting an immune targeted approach for TNBCs, immunotherapy has failed to demonstrate the impressive responses seen in other solid tumor malignancies. Additional strategies to modify the tumor immune microenvironment and potentiate response to immunotherapy are needed. In this review, we summarise phase III data supporting the use of immunotherapy for TNBC. We discuss the role of IL-1β in tumorigenesis and summarize pre-clinical data supporting IL-1β inhibition as a potential therapeutic strategy in TNBC. Finally, we present current trials evaluating IL-1β in breast cancer and other solid tumor malignancies and discuss future studies that may provide a strong scientific rationale for the combination of IL-1β and immunotherapy in the neoadjuvant and metastatic setting for people with TNBC.
    Keywords:  IL1beta; immunotherapy; inflammasome; triple negative breast cancer; tumor microenvironment
  10. Trends Biochem Sci. 2023 Apr 18. pii: S0968-0004(23)00080-4. [Epub ahead of print]
      The metabolic cross-talk between cancer cells and T cells dictates cancer formation and progression. These cells possess metabolic plasticity. Thus, they adapt their metabolic profile to meet their phenotypic requirements. However, the nutrient microenvironment of a tumor is a very hostile niche in which these cells are forced to compete for the available nutrients. The hyperactive metabolism of tumor cells often outcompetes the antitumorigenic CD8+ T cells while promoting the protumorigenic exhausted CD8+ T cells and T regulatory (Treg) cells. Thus, cancer cells elude the immune response and spread in an uncontrolled manner. Identifying the metabolic pathways necessary to shift the balance from a protumorigenic to an antitumorigenic immune phenotype is essential to potentiate antitumor immunity.
    Keywords:  antitumorigenic T cells; immunometabolism; protumorigenic T cells; tumor microenvironment
  11. Front Pharmacol. 2023 ;14 1163160
      The dysregulation of the biochemical pathways in cancer promotes oncogenic transformations and metastatic potential. Recent studies have shed light on how obesity and altered lipid metabolism could be the driving force for tumor progression. Here, in this review, we focus on liver cancer and discuss how obesity and lipid-driven metabolic reprogramming affect tumor, immune, and stroma cells in the tumor microenvironment and, in turn, how alterations in these cells synergize to influence and contribute to tumor growth and dissemination. With increasing evidence on how obesity exacerbates inflammation and immune tolerance, we also touch upon the impact of obesity and altered lipid metabolism on tumor immune escape.
    Keywords:  NASH; adipocytes; hepatocellular carcinoma; lipid; obesity
  12. Mol Ther. 2023 Apr 17. pii: S1525-0016(23)00206-X. [Epub ahead of print]
      Poor intratumoral infiltration is the major challenge for chimeric antigen receptor (CAR)-T cell therapy in solid tumors. Hypofractionated radiotherapy (HFRT) has been reported to induce immune cell infiltration and reshape the tumor immune microenvironment. Here, we showed that HFRT (5×5 Gy)-mediated an early accumulation of intratumoral myeloid-derived suppressor cells (MDSCs) and decreased infiltration of T cells in the tumor microenvironment (TME) of immunocompetent mice bearing triple-negative breast cancer (TNBC) or colon cancer, which was further confirmed in tumors from patients. RNA sequencing (RNA-seq) and cytokine profiling analysis revealed that HFRT-induced the activation and proliferation of tumor-infiltrated MDSCs, and which was mediated by the interactions of multiple chemokines and chemokine receptors. Further investigation showed that when combined with HFRT, CXCR2 blockade significantly inhibited MDSCs trafficking to tumors, and effectively enhanced the intratumoral infiltration and treatment efficacy of CAR-T cells. Our study demonstrates that MDSCs blockade combined with HFRT is promising for CAR-T cell therapy optimization in solid tumors.
  13. Crit Rev Immunol. 2022 ;42(6): 9-15
      Triple-negative breast cancer (TNBC) is a type of breast cancer (BC) with high aggressive nature, devoid of receptors for estrogen and progesterone hormones and with overexpression of the HER2/neu protein. It is more aggressive than other types of BC, common occurring in younger women. Recently, preclinical and clinical studies have investigated the use of immune therapies to treat TNBC patients. However, a subset of patients is responding to immunotherapy due to the high level of tumor mutation burden. The bidirectional communication among the tumor microenvironment (TME) cells via signal molecules modulates γδ T cells to support or impair tumor growth. This review emphasizes γδ T cell-mediated immune responses with a special focus on breast cancer. We present the cytotoxic characteristics of γδ T cells. We also present the promising role of γδ T cells in mounting pro-tumor and anti-tumor responses in the TME. Finally, our review focuses on prominent features of γδ T cells as a curse in breast cancer development.
  14. Biomater Adv. 2023 Apr 11. pii: S2772-9508(23)00148-6. [Epub ahead of print]150 213425
      The efficacy of immune checkpoint therapy is limited by the immunosuppressive tumor microenvironment (TME), and lactate, the most universal component of TME, has been rediscovered that plays important roles in the regulation of metabolic pathways, angiogenesis, and immunosuppression. Here, a therapeutic strategy of acidity modulation combined with programmed death ligand-1 (PD-L1) siRNA (siPD-L1) is proposed to synergistically enhance tumor immunotherapy. The lactate oxidase (LOx) is encapsulated into the hollow Prussian blue (HPB) nanoparticles (NPs) prepared by hydrochloric acid etching followed by the modification with polyethyleneimine (PEI) and polyethylene glycol (PEG) via sulfur bonds (HPB-S-PP@LOx), siPD-L1 is loaded via electrostatic adsorption to obtain HPB-S-PP@LOx/siPD-L1. The obtained co-delivery NPs can accumulate in tumor tissue with stable systemic circulation, and simultaneous release of LOx and siPD-L1 in intracellular high glutathione (GSH) environment after uptake by tumor cells without being destroyed by lysosome. Moreover, LOx can catalyze the decomposition of lactate in the hypoxic tumor tissue with the aid of oxygen release by the HPB-S-PP nano-vector. The results show that the acidic TME regulation via lactate consumption can improve the immunosuppressive TME, including revitalizing the exhausted CD8+ T cells and decreasing the proportion of immunosuppressive Tregs, and synergistically elevating the therapeutic effect of PD1/PD-L1 blockade therapy via siPD-L1. This work provides a novel insight for tumor immunotherapy and explores a promising therapy for triple-negative breast cancer.
    Keywords:  Acidity modulation; Co-delivery system; Tumor immunotherapy; siPD-L1
  15. Clin Transl Oncol. 2023 Apr 19.
      Chemokines are chemotactic-competent molecules composed of a family of small cytokines, playing a key role in regulating tumor progression. The roles of chemokines in antitumor immune responses are of great interest. CXCL9, CXCL10, and CXCL11 are important members of chemokines. It has been widely investigated that these three chemokines can bind to their common receptor CXCR3 and regulate the differentiation, migration, and tumor infiltration of immune cells, directly or indirectly affecting tumor growth and metastasis. Here, we summarize the mechanism of how the CXCL9/10/11-CXCR3 axis affects the tumor microenvironment, and list the latest researches to find out how this axis predicts the prognosis of different cancers. In addition, immunotherapy improves the survival of tumor patients, but some patients show drug resistance. Studies have found that the regulation of CXCL9/10/11-CXCR3 on the tumor microenvironment is involved in the process of changing immunotherapy resistance. Here we also describe new approaches to restoring sensitivity to immune checkpoint inhibitors through the CXCL9/10/11-CXCR3 axis.
    Keywords:  CXCL9/10/11; CXCR3; Immune cells; Immunotherapy resistance
  16. Int Immunopharmacol. 2023 Apr 18. pii: S1567-5769(23)00515-5. [Epub ahead of print]119 110194
      BACKGROUND: Most studies on melatonin have focused on tumor cells but have ignored the tumor microenvironment (TME), especially one of its important components, the cancer-associated fibroblasts (CAFs). Therefore, we attempted to explore the role of melatonin in TME.METHODS: We investigated the regulatory role of melatonin in the tumor-promoting effect of CAFs and its underlying mechanism by using cell and animal models.
    RESULTS: CAFs promoted tumor progression, but melatonin weakened the tumor-promoting effect of CAFs. Compared with tumor cells, IL-8 was mainly expressed in CAFs. CAFs-overexpressing IL-8 induced the epithelial-mesenchymal transition (EMT) of tumor cells, and a positive crosstalk was observed between CAFs and tumor cells undergoing EMT, thereby further promoting the IL-8 expression. Melatonin suppressed this crosstalk by inhibiting the NF-κB pathway, thereby impeding the IL-8 expression from CAFs. Importantly, melatonin reversed CAFs-derived IL-8-mediated EMT by inhibiting the AKT pathway. Melatonin was found to directly and indirectly inhibit tumor progression.
    CONCLUSION: Our research reveals the potential action mechanism of melatonin in regulating the CAF-tumor cell interaction and suggests the potential of melatonin as an adjuvant of tumor therapy.
    Keywords:  Breast cancer; Cancer-associated fibroblasts; Epithelial-mesenchymal transition; IL-8; Tumor microenvironment
  17. Immunohorizons. 2023 Apr 01. 7(4): 256-264
      The correct folding of proteins is essential for appropriate cell function and is tightly regulated within the endoplasmic reticulum (ER). Environmental challenges and cellular conditions disrupt ER homeostasis and induce ER stress, which adversely affect protein folding and activate the unfolded protein response (UPR). It is now becoming recognized that cancer cells can overcome survival challenges posed within the tumor microenvironment by activating the UPR. Furthermore, the UPR has also been found to impose detrimental effects on immune cells by inducing immunoinhibitory activity in both tumor-infiltrating innate and adaptive immune cells. This suggests that these signaling axes may be important therapeutic targets, resulting in multifaceted approaches to eradicating tumor cells. In this mini-review, we discuss the role of the UPR in driving tumor progression and modulating the immune system's ability to target cancer cells. Additionally, we highlight some of the key unanswered questions that may steer future UPR research.
  18. J Mol Cell Biol. 2023 Apr 18. pii: mjad025. [Epub ahead of print]
      Recent studies have found that cancer-associated adipocytes (CAA) in the tumor microenvironment are involved in the malignant progression of breast cancer. However, the underlying mechanism of CAA formation and its effects on the development of breast cancer are still unknown. Here, we show that CSF2 is highly expressed in both CAA and breast cancer cells. CSF2 promotes inflammatory phenotypic changes of adipocytes through the Stat3 signaling pathway leading to the secretion of multiple cytokines and proteases, particularly CXCL3. Adipocyte-derived CXCL3 binds to its specific receptor CXCR2 on breast cancer cells and activates the FAK pathway, leading to an enhanced mesenchymal phenotype, migration and invasion of breast cancer cells. In addition, we demonstrate that targeting CSF2 and CXCR2 synergistically inhibits adipocyte-induced lung metastasis of mouse 4T1 cells in vivo. These findings elucidate a novel mechanism of breast cancer metastasis and provide a potential therapeutic strategy for breast cancer metastasis.
    Keywords:  Breast cancer metastasis; CSF2; CXCL3; Cancer-associated adipocytes; FAK
  19. Endocr Relat Cancer. 2023 Apr 01. pii: ERC-23-0028. [Epub ahead of print]
      Non-pituitary GH (npGH) expression is well established in extrapituitary tissues, but understanding of the physiological role of npGH remains rather limited. Pro-tumorigenic npGH impacting the tumor microenvironment has been reviewed, and we focus here on autocrine/paracrine npGH effects in non-tumorous tissues and discuss its mechanisms of action in the normal tissue microenvironment. We address tissue-specific effects of npGH in regulating stem, endothelial, immune, and epithelial cells and highlight the related role of npGH-associated changes in tissue aging.
  20. Nat Cancer. 2023 Apr 17.
      Macroautophagy is a cellular quality-control process that degrades proteins, protein aggregates and damaged organelles. Autophagy plays a fundamental role in cancer where, in the presence of stressors (for example, nutrient starvation, hypoxia, mechanical pressure), tumor cells activate it to degrade intracellular substrates and provide energy. Cell-autonomous autophagy in tumor cells and cell-nonautonomous autophagy in the tumor microenvironment and in the host converge on mechanisms that modulate metabolic fitness, DNA integrity and immune escape and, consequently, support tumor growth. In this Review, we will discuss insights into the tumor-modulating roles of autophagy in different contexts and reflect on how future studies using physiological culture systems may help to understand the complexity and open new therapeutic avenues.
  21. Int Immunopharmacol. 2023 Apr 13. pii: S1567-5769(23)00479-4. [Epub ahead of print]119 110158
      Urothelial carcinoma (UC) is a very common malignant tumor. In the past few decades, platinum-based chemotherapy has been regarded as the standard recommended regimen for patients with metastatic urothelial carcinoma (mUC) who can receive either cisplatin or carboplatin. The emergence of immune checkpoint inhibitors (ICIs) brought some hope for possible treatments for mUC patients who were unfit for platinum therapy. ICIs drugs have emerged as new potential weapons to overcome UC in our lifetime. ICIs block the binding of programmed death-1 (PD-1) to programmed death-ligand 1 (PD-L1), leading to enhancement of the immune function of antitumor T cells. In the treatment of UC, ICIs show an apparent ascendancy and effectively enhance survival rates. With good tolerability and remarkable effects, ICIs have given thousands of patients hope. This article mainly shows the application of PD-1 and PD-L1 inhibitors in mUC.
    Keywords:  Immune checkpoint inhibitor; Immunotherapy; Metastatic urothelial carcinoma; Programmed death-1; Programmed death-ligand 1
  22. Matrix Biol. 2023 Apr 18. pii: S0945-053X(23)00050-1. [Epub ahead of print]
      Previously, impaired responses to immunotherapy in cancer had been attributed mainly to inherent tumor characteristics (tumor cell intrinsic factors) such as low immunogenicity, (low) mutational burden, weak host immune system, etc. However, mapping the responses of immunotherapeutic regimes in clinical trials for different types of cancer has pointed towards an obvious commonality - that tumors with a rich fibrotic stroma respond poorly or not at all. This has prompted a harder look on tumor cell extrinsic factors such as the surrounding tumor microenvironment (TME), and specifically, the fibrotic stroma as a potential enabler of immunotherapy failure. Indeed, the role of cancer-associated fibrosis in impeding efficacy of immunotherapy is now well-established. In fact, recent studies reveal a complex interconnection between fibrosis and treatment efficacy. Accordingly, in this review we provide a general overview of what a tumor associated fibrotic reaction is and how it interacts with the members of immune system that are frequently seen to be modulated in a failed immunotherapeutic regime.
    Keywords:  Tumor microenvironment; cancer-associated fibroblasts; extracellular matrix; matricellular proteins
  23. J Cell Physiol. 2023 Apr 16.
      In tumor microenvironment (TME), macrophages trigger and maintain inflammatory responses that promoting tumor progression. Many cellular proteins are secreted from tumors and modulate their own TME by modulating macrophage phenotypes. Recently, we reported that interferon-γ-inducible protein 16 (IFI16), which was identified as an innate immune DNA sensor recognizing foreign DNA, triggered type Ⅰ interferon responses in breast cancer (BC). However, whether IFI16 was released from BC and affects TME has not been studied. Here, we report that IFI16 and its mouse homolog Ifi202 were released from BC cells, but not from normal epithelial cells. Ifi202 induced secretion of proinflammatory cytokines such as Interleukin (IL)-1β, IL-6, and Tumor necrosis factor-α from macrophages via binding toll-like receptor 2 and activating downstream signaling pathway. Growth of allografted mouse BC 4T1 lacking Ifi202 was suppressed and accompanied with increased infiltration and cytotoxic activity of CD8+ T lymphocytes. Further, IFI16 was detected in sera of patients with BC. High expression level of IFI16 was associated with poor prognosis in patients with BC. Taken together, our findings suggest a novel role of IFI16/Ifi202 in TME, that elicits tumor promoting inflammation and thereby shaping immunosuppressive TME in BC.
    Keywords:  IFI16; Ifi202; breast cancer; macrophages; tumor microenvironment
  24. Front Immunol. 2023 ;14 1125737
      Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature cells capable of inhibiting T-cell responses. MDSCs have a crucial role in the regulation of the immune response of the body to pathogens, especially in inflammatory response and pathogenesis during anti-infection. Pathogens such as bacteria and viruses use MDSCs as their infectious targets, and even some pathogens may exploit the inhibitory activity of MDSCs to enhance pathogen persistence and chronic infection of the host. Recent researches have revealed the pathogenic significance of MDSCs in pathogens such as bacteria and viruses, despite the fact that the majority of studies on MDSCs have focused on tumor immune evasion. With the increased prevalence of viral respiratory infections, the resurgence of classical tuberculosis, and the advent of medication resistance in common bacterial pneumonia, research on MDSCs in these illnesses is intensifying. The purpose of this work is to provide new avenues for treatment approaches to pulmonary infectious disorders by outlining the mechanism of action of MDSCs as a biomarker and therapeutic target in pulmonary infectious diseases.
    Keywords:  immunotherapy; myeloid-derived suppressor cells; novel coronaviral pneumonia; other infectious lung diseases; tuberculosis
  25. Int J Pharm. 2023 Apr 19. pii: S0378-5173(23)00390-3. [Epub ahead of print] 122970
      The low level of T-lymphocyte infiltration in tumor is a key issue in cancer immunotherapy. Stimulating anti-tumor immune responses and improving the tumor microenvironment are essential for enhancing anti-PD-L1 immunotherapy. Herein, atovaquone (ATO), protoporphyrin IX (PpIX), and stabilizer (ATO/PpIX NPs) were constructed to self-assemble with hydrophobic interaction and passively targeted to tumor for the first time. The studies have indicated that PpIX-mediated photodynamic induction of immunogenic cell death combined with relieving tumor hypoxia by ATO, leading to maturation of dendritic cells, polarization of M2-type tumor-associated macrophages (TAMs) towards M1-type TAMs, infiltration of cytotoxic T lymphocytes, reduction of regulatory T cells, release of pro-inflammatory cytokines, resulting in an effective anti-tumor immune response synergized with anti-PD-L1 against primary tumor and pulmonary metastasis. Taken together, the combined nanoplatform may be a promising strategy to enhance cancer immunotherapy.
    Keywords:  Anti-PD-L1 therapy; Cancer immunotherapy; Hypoxic microenvironment; Immunogenetic cell death; Tumor-associated macrophages
  26. Theranostics. 2023 ;13(6): 1823-1825
      Gene expression network in cancer cells is orchestrated by a small number of master regulator transcription factors (MRTFs), which play a prominent role in regulating cancer intrinsic hallmarks, such as sustaining proliferative signaling, evading growth suppressors, resisting cell death, etc. A new study reports a new role of one MRTF, KLF5, in regulating tumor microenvironment in an extrinsic manner. These findings not only reveal novel mechanistic underpinnings of tumor evasion from immune destruction but also broaden our understanding of the transcriptional deregulation in cancer biology.
  27. Bone Res. 2023 Apr 21. 11(1): 22
      Myeloid-derived suppressor cells (MDSCs) are bone marrow (BM)-derived immunosuppressive cells in the tumor microenvironment, but the mechanism of MDSC mobilization from the BM remains unclear. We investigated how BM stromal cell activation by PTH1R contributes to MDSC mobilization. PTH1R activation by parathyroid hormone (PTH) or PTH-related peptide (PTHrP), a tumor-derived counterpart, mobilized monocytic (M-) MDSCs from murine BM without increasing immunosuppressive activity. In vitro cell-binding assays demonstrated that α4β1 integrin and vascular cell adhesion molecule (VCAM)-1, expressed on M-MDSCs and osteoblasts, respectively, are key to M-MDSC binding to osteoblasts. Upon PTH1R activation, osteoblasts express VEGF-A and IL6, leading to Src family kinase phosphorylation in M-MDSCs. Src inhibitors suppressed PTHrP-induced MDSC mobilization, and Src activation in M-MDSCs upregulated two proteases, ADAM-17 and MMP7, leading to VCAM1 shedding and subsequent disruption of M-MDSC tethering to osteoblasts. Collectively, our data provide the molecular mechanism of M-MDSC mobilization in the bones of tumor hosts.
  28. Transplant Cell Ther. 2023 Apr 17. pii: S2666-6367(23)01238-1. [Epub ahead of print]
      While chimeric antigen receptor (CAR) T-cell therapy has altered the treatment landscape for relapsed/refractory B-cell malignancies and multiple myeloma, only a minority of patients attain long term remissions. The underlying reasons for CAR-T resistance are multi-facetted and can be broadly divided into host-related, tumor-intrinsic, micro- and macro-environmental, and CAR T-cell related factors. Emerging host-related determinants of response to CAR-T relate to gut microbiome composition, intact hematopoietic function, body composition, and physical reserve. Emerging tumor-intrinsic resistance mechanisms include complex genomic alterations and mutations to immunomodulatory genes. Furthermore, the extent of systemic inflammation prior to CAR-T is a potent biomarker of response and reflects a pro-inflammatory tumor micromilieu characterized by infiltration of myeloid-derived suppressor cells and regulatory T-cell populations. The tumor and its surrounding micromilieu also is able to shape the response of the host to CAR T-cell infusion and the subsequent expansion and persistence of CAR T-cells, which represents a prerequisite for efficient eradication of tumor cells. Focusing on both large B-cell lymphoma (LBCL) and multiple myeloma, we review resistance mechanisms, explore therapeutic avenues to overcome resistance to CAR T-cell therapies, and discuss the management of patients who have relaped after CAR T-cell therapy.
  29. Front Bioeng Biotechnol. 2023 ;11 1122585
      Extracellular vesicles (EVs) are increasingly recognized as important intermediaries of intercellular communication. They have significant roles in many physiological and pathological processes and show great promise as novel biomarkers of disease, therapeutic agents, and drug delivery tools. Existing studies have shown that natural killer cell-derived EVs (NEVs) can directly kill tumor cells and participate in the crosstalk of immune cells in the tumor microenvironment. NEVs own identical cytotoxic proteins, cytotoxic receptors, and cytokines as NK cells, which is the biological basis for their application in antitumor therapy. The nanoscale size and natural targeting property of NEVs enable precisely killing tumor cells. Moreover, endowing NEVs with a variety of fascinating capabilities via common engineering strategies has become a crucial direction for future research. Thus, here we provide a brief overview of the characteristics and physiological functions of the various types of NEVs, focusing on their production, isolation, functional characterization, and engineering strategies for their promising application as a cell-free modality for tumor immunotherapy.
    Keywords:  cancer immunotherapy; engineering strategy; extracellular vesicles; natural killer cell; tumor microenvironment
  30. Nat Med. 2023 Apr 17.
    Keywords:  Cancer immunotherapy; Cell therapies; Clinical trials; Paediatrics
  31. Breast Cancer Res. 2023 Apr 17. 25(1): 43
      Triple-negative breast cancer (TNBC) exhibits the poorest outcomes among breast cancer subtypes due to the high heterogeneity and a lasting scarcity of effectual treatments. Targeted therapies based on molecular subtypes of TNBC are critical step toward tailoring treatments to improve clinical outcomes. Gastrointestinal cancer stem cell (CSC) marker DCLK1 was reported to be highly expressed in stem cell-rich subtype of TNBC. Here, we firstly explored the impacts of DCLK1 on tumor cells as well as their immune microenvironment in TNBC and potential therapeutic strategies for TNBC patients with high DCLK1 expression. Our results disclosed that DCLK1 overexpression promoted, while knockout of DCLK1 suppressed the CSC-like traits of TNBC cells and resistance to chemotherapeutics. Besides, DCLK1 supported immune escape by inhibiting intratumoral cytotoxic T cell infiltration in TNBC and hence limited immune checkpoint inhibitors efficacy. Mechanistically, bioinformatics analysis revealed that IL-6/STAT3 signaling was significantly enriched in high DCLK1-expressing patients, and our results further revealed that DCLK1 enhanced IL-6 expression and STAT3 activation in TNBC cells, which finally gave rise to upregulated CSC traits and suppressed CD8+ T-cell activity. Inhibiting IL-6/STAT3 pathway by IL-6R antagonist, Tocilizumab or STAT3 inhibitor, S31-201 could abolish DCLK1-promoted malignant phenotypes of TNBC cells. Finally, DCLK1 was identified to be specifically and highly expressed in the mesenchymal-like subtype of TNBC and targeting DCLK1 could improve chemotherapy efficacy and activate antitumor immunity. Overall, our study revealed the potential clinical benefits of targeting DCLK1 in TNBC treatment.
    Keywords:  CSCs; DCLK1; IL-6/STAT3 signaling; The mesenchymal-like subtype; Triple-negative breast cancer
  32. Oncoimmunology. 2023 ;12(1): 2198185
      The tumor microenvironment (TME) in ovarian cancer (OC) is characterized by immune suppression, due to an abundance of suppressive immune cells populations. To effectively enhance the activity of immune checkpoint inhibition (ICI), there is a need to identify agents that target these immunosuppressive networks while promoting the recruitment of effector T cells into the TME. To this end, we sought to investigate the effect of the immunomodulatory cytokine IL12 alone or in combination with dual-ICI (anti-PD1 + anti-CTLA4) on anti-tumor activity and survival, using the immunocompetent ID8-VEGF murine OC model. Detailed immunophenotyping of peripheral blood, ascites, and tumors revealed that durable treatment responses were associated with reversal of myeloid cell-induced immune suppression, which resulted in enhanced anti-tumor activity by T cells. Single cell transcriptomic analysis further demonstrated striking differences in the phenotype of myeloid cells from mice treated with IL12 in combination with dual-ICI. We also identified marked differences in treated mice that were in remission compared to those whose tumors progressed, further confirming a pivotal role for the modulation of myeloid cell function to allow for response to immunotherapy. These findings provide the scientific basis for the combination of IL12 and ICI to improve clinical response in OC.
    Keywords:  Interleukin 12; Ovarian cancer; checkpoint blockade; immunotherapy; myeloid cells
  33. Cancer Lett. 2023 Apr 17. pii: S0304-3835(23)00133-7. [Epub ahead of print] 216182
      Cancer treatment has been advanced with the advent of immune checkpoint inhibitors (ICIs) exemplified by anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), anti-programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) drugs. Patients have reaped substantial benefit from ICIs in many cancer types. However, few patients benefit from ICIs whereas the vast majority undergoing these treatments do not obtain survival benefit. Even for patients with initial responses, they may encounter drug resistance in their subsequent treatments, which limits the efficacy of ICIs. Therefore, a deepening understanding of drug resistance is critically important for the explorations of approaches to reverse drug resistance and to boost ICI efficacy. In the present review, different mechanisms of ICI resistance have been summarized according to the tumor intrinsic, tumor microenvironment (TME) and host classifications. We further elaborated corresponding strategies to battle against such resistance accordingly, which include targeting defects in antigen presentation, dysregulated interferon-γ (IFN-γ) signaling, neoantigen depletion, upregulation of other T cell checkpoints as well as immunosuppression and exclusion mediated by TME. Moreover, regarding the host, several additional approaches that interfere with diet and gut microbiome have also been described in reversing ICI resistance. Additionally, we provide an overall glimpse into the ongoing clinical trials that utilize these mechanisms to overcome ICI resistance. Finally, we summarize the challenges and opportunities that needs to be addressed in the investigation of ICI resistance mechanisms, with the aim to benefit more patients with cancer.
    Keywords:  Clinical trials; Combination therapy; Host; Immune checkpoint inhibitor resistance; Tumor microenvironment
  34. Cancer Immunol Res. 2023 Apr 18. OF1-OF18
      The pioneering design of chimeric antigen receptor (CAR) T-cell therapy demonstrated the potential of reprogramming the immune system. Nonetheless, T-cell exhaustion, toxicity, and suppressive microenvironments limit their efficacy in solid tumors. We previously characterized a subset of tumor-infiltrating CD4+ T cells expressing the FcγRI receptor. Herein, we detail engineering of a receptor, based on the FcγRI structure, allowing T cells to target tumor cells using antibody intermediates. These T cells showed effective and specific cytotoxicity only when an appropriate antibody was added. Only target-bound antibodies activated these cells, while free antibodies were internalized without activation. Their cytotoxic activity was correlated to target protein density, therefore targeting tumor cells with high antigen density while sparing normal cells with low or no expression. This activation mechanism prevented premature exhaustion. Furthermore, during antibody-dependent cytotoxicity these cells secreted attenuated cytokine levels compared with CAR T cells, thereby enhancing their safety profile. These cells eradicated established melanomas, infiltrated the tumor microenvironment, and facilitated host immune cell recruitment in immunocompetent mice. In NOD/SCID gamma mice the cells infiltrate, persist, and eradicate tumors. As opposed to CAR T-cell therapies, which require changing the receptor across different types of cancer, our engineered T cells remain the same across tumor types, while only the injected antibody changes. Overall, we generated a highly flexible T-cell therapy capable of binding a wide range of tumor cells with high affinity, while preserving the cytotoxic specificity only to cells expressing high density of tumor-associated antigens and using a single manufacturing process.