bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2023‒07‒16
thirty-two papers selected by
Peio Azcoaga
Biodonostia HRI

  1. Cell Mol Immunol. 2023 Jul 10.
      Macrophages are critical regulators of tissue homeostasis but are also abundant in the tumor microenvironment (TME). In both primary tumors and metastases, such tumor-associated macrophages (TAMs) seem to support tumor development. While we know that TAMs are the dominant immune cells in the TME, their vast heterogeneity and associated functions are only just being unraveled. In this review, we outline the various known TAM populations found thus far and delineate their specialized roles associated with the main stages of cancer progression. We discuss how macrophages may prime the premetastatic niche to enable the growth of a metastasis and then how subsequent metastasis-associated macrophages can support secondary tumor growth. Finally, we speculate on the challenges that remain to be overcome in TAM research.
    Keywords:  Macrophages; Metastasis; Tumor associated macrophages; Tumor microenvironment
  2. Front Immunol. 2023 ;14 1157291
      Tumor-associated macrophages (TAMs) are a dynamic and heterogeneous cell population of the tumor microenvironment (TME) that plays an essential role in tumor formation and progression. Cancer cells have a high metabolic demand for their rapid proliferation, survival, and progression. A comprehensive interpretation of pro-tumoral and antitumoral metabolic changes in TAMs is crucial for comprehending immune evasion mechanisms in cancer. The metabolic reprogramming of TAMs is a novel method for enhancing their antitumor effects. In this review, we provide an overview of the recent research on metabolic alterations of TAMs caused by TME, focusing primarily on glucose, amino acid, and fatty acid metabolism. In addition, this review discusses antitumor immunotherapies that influence the activity of TAMs by limiting their recruitment, triggering their depletion, and re-educate them, as well as metabolic profiles leading to an antitumoral phenotype. We highlighted the metabolic modulational roles of TAMs and their potential to enhance immunotherapy for cancer.
    Keywords:  amino acid metabolism; fatty acid metabolism; glucose metabolism; immunotherapy; tumor microenvironment; tumor-associated macrophages
  3. Cell Mol Gastroenterol Hepatol. 2023 Jul 12. pii: S2352-345X(23)00130-3. [Epub ahead of print]
      Emerging evidence has revealed the importance of tumor microenvironment (TME) in tumorigenesis and progression. Cancer-associated fibroblasts (CAFs) are one of the most infiltrated stroma cells of TME in gastrointestinal tumors. CAFs play crucial roles in tumor development and therapeutic response by biologically secreting soluble factors or structurally remodeling the extracellular matrix (ECM). Conceivably, CAFs may become excellent targets for tumor prevention and treatment. However, the limited knowledge of the heterogeneity of CAFs represents a huge challenge for clinically targeting CAFs. In this Review, we summarize the newest understanding of gastrointestinal CAFs with a special focus on their origin, differentiation, and function. We also discuss the current understanding of CAFs subpopulations as revealed by single-cell technologies.
    Keywords:  Cancer-associated fibroblasts; Gastrointestinal tumors; Single-cell technologies; Tumor microenvironment
  4. Front Oncol. 2023 ;13 1200646
      The efficacy of cancer therapies is limited to a great extent by immunosuppressive mechanisms within the tumor microenvironment (TME). Numerous immune escape mechanisms have been identified. These include not only processes associated with tumor, immune or stromal cells, but also humoral, metabolic, genetic and epigenetic factors within the TME. The identification of immune escape mechanisms has enabled the development of small molecules, nanomedicines, immune checkpoint inhibitors, adoptive cell and epigenetic therapies that can reprogram the TME and shift the host immune response towards promoting an antitumor effect. These approaches have translated into series of breakthroughs in cancer therapies, some of which have already been implemented in clinical practice. In the present article the authors provide an overview of some of the most important mechanisms of immunosuppression within the TME and the implications for targeted therapies against different cancers.
    Keywords:  cancer; immune escape mechanisms; immunosuppression mechanisms; immunotherapy; tumor microenvironment
  5. Front Cell Dev Biol. 2023 ;11 1220376
      Tumor is one of the biggest threats to human health. Though tumor therapy has been dramatically advanced by the progress of technology and research in recent decades, it is still far from expectations. Thus, it is of great significance to explore the mechanisms of tumor growth, metastasis, and resistance. Screen based on Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-CRISPR-associated protein (Cas) 9 gene editing technology are powerful tools for exploring the abovementioned facets. This review summarizes the recent screen performed in cancer cells and immune cells in the tumor microenvironment. The screens in cancer cells mainly focus on exploring the mechanisms underlying cancer cells' growth, metastasis, and how cancer cells escape from the FDA approved drugs or immunotherapy. And the studies in tumor-associated immune cells are primarily aimed at identifying signaling pathways that can enhance the anti-tumor function of cytotoxic T lymphocytes (CTLs), CAR-T cells, and macrophages. Moreover, we discuss the limitations, merits of the CRISPR screen, and further its future application in tumor studies. Importantly, recent advances in high throughput tumor related CRISPR screen have deeply contributed to new concepts and mechanisms underlying tumor development, tumor drug resistance, and tumor immune therapy, all of which will eventually potentiate the clinical therapy for tumor patients.
    Keywords:  CRISPR screen; gene edited; tumor development and progression; tumor microenvironment (TME); tumor therapeutic
  6. Am J Cancer Res. 2023 ;13(6): 2376-2391
      This study aimed to investigate whether CKAP2 could promote cervical cancer (CC) progression by modulating the tumor microenvironment (TME) via NF-κB signaling. The communication between cervical cancer cells and the TME, including THP-1 and HUVECs, was tested. Gain- and loss-of-function assays were performed to elucidate the role of CKAP2 in cervical cancer progression. Western blot analysis was exploited to investigate the potential involved mechanism involved. Here, we reported that cervical cancer tissues were enriched with macrophages and microvessels. CKAP2 increased the tumor-promoting macrophage population. The overexpression of CKAP2 not only promoted endothelial cell viability and tube formation but also increased vascular permeability, and vice versa. Moreover, CKAP2 promoted cervical cancer progression via NF-κB signaling. This effect could be blocked by the NF-κB signaling inhibitor JSH-23. Our findings indicated that CKAP2 could promote cervical cancer progression by modulating the TME via NF-κB signaling.
    Keywords:  CKAP2; HUVEC; TAM; Tumor microenvironment; angiogenesis; metastasis
  7. Front Immunol. 2023 ;14 1238698
    Keywords:  cancer immunology; cancer immunotherapy; immune regulation; immunosuppression; tumor microenvironment
  8. Front Immunol. 2023 ;14 1153990
      The emergence of immunotherapy has profoundly changed the treatment model for triple-negative breast cancer (TNBC). But the heterogeneity of this disease resulted in significant differences in immunotherapy efficacy, and only some patients are able to benefit from this therapeutic modality. With the recent explosion in studies on the mechanism of cancer immunotherapy drug resistance, this article will focus on the processes of the immune response; summarize the immune evasion mechanisms in TNBC into three categories: loss of tumor-specific antigen, antigen presentation deficiency, and failure to initiate an immune response; together with the aberrant activation of a series of immune-critical signaling pathways, we will discuss how these activities jointly shape the immunosuppressive landscape within the tumor microenvironment. This review will attempt to elucidate the molecular mechanism of drug resistance in TNBC, identify potential targets that may assist in reversing drug resistance, and lay a foundation for research on identifying biomarkers for predicting immune efficacy and selection of breast cancer populations that may benefit from immunotherapy.
    Keywords:  antigen presentation; immunotherapy; resistance mechanism; triple-negative breast cancer; tumor microenvironment
  9. Heliyon. 2023 Jul;9(7): e17582
      Tumor-associated macrophage (TAM) affects the intrinsic properties of tumor cells and the tumor microenvironment (TME), which can stimulate tumor cell proliferation, migration, and genetic instability, and macrophage diversity includes the diversity of tumors with different functional characteristics. Macrophages are now a central drug target in various diseases, especially in the TME, which, as "tumor promoters" and "immunosuppressors", have different responsibilities during tumor development and accompany by significant dynamic alterations in various subpopulations. Remodelling immunosuppression of TME and promotion of pre-existing antitumor immune responses is critical by altering TAM polarization, which is relevant to the efficacy of immunotherapy, and uncovering the exact mechanism of action of TAMs and identifying their specific targets is vital to optimizing current immunotherapies. Hence, this review aims to reveal the triadic interactions of macrophages with programmed death and oncotherapy, and to integrate certain relationships in cancer treatment.
    Keywords:  Cancer therapy; Drug delivery; Regulated cell death (RCD); Tumor microenvironment (TME); Tumor-associated macrophage (TAM)
  10. Cancers (Basel). 2023 Jul 03. pii: 3473. [Epub ahead of print]15(13):
      Advanced prostate cancer represents the fifth leading cause of cancer death in men worldwide. Although androgen-receptor signaling is the major driver of the disease, evidence is accumulating that disease progression is supported by substantial metabolic changes. Alterations in de novo lipogenesis and fatty acid catabolism are consistently reported during prostate cancer development and progression in association with androgen-receptor signaling. Therefore, the term "lipogenic phenotype" is frequently used to describe the complex metabolic rewiring that occurs in prostate cancer. However, a new scenario has emerged in which lactate may play a major role. Alterations in oncogenes/tumor suppressors, androgen signaling, hypoxic conditions, and cells in the tumor microenvironment can promote aerobic glycolysis in prostate cancer cells and the release of lactate in the tumor microenvironment, favoring immune evasion and metastasis. As prostate cancer is composed of metabolically heterogenous cells, glycolytic prostate cancer cells or cancer-associated fibroblasts can also secrete lactate and create "symbiotic" interactions with oxidative prostate cancer cells via lactate shuttling to sustain disease progression. Here, we discuss the multifaceted role of lactate in prostate cancer progression, taking into account the influence of the systemic metabolic and gut microbiota. We call special attention to the clinical opportunities of imaging lactate accumulation for patient stratification and targeting lactate metabolism.
    Keywords:  biomarkers; lactate; metabolic imaging; monocarboxylate transporters; prostate cancer; tumor microenvironment
  11. Cells. 2023 Jun 21. pii: 1673. [Epub ahead of print]12(13):
      Monocytes are highly plastic innate immune cells that display significant heterogeneity during homeostasis, inflammation, and tumorigenesis. Tumor-induced systemic and local microenvironmental changes influence the phenotype, differentiation, and distribution of monocytes. Meanwhile, monocytes and their related cell subsets perform an important regulatory role in the development of many cancers by affecting tumor growth or metastasis. Thanks to recent advances in single-cell technologies, the nature of monocyte heterogeneity and subset-specific functions have become increasingly clear, making it possible to systematically analyze subset-specific roles of monocytes in tumorigenesis. In this review, we discuss recent discoveries related to monocytes and tumorigenesis, and new strategies for tumor biomarker identification and anti-tumor immunotherapy.
    Keywords:  immunotherapy; monocytes; myeloid-derived suppressor cells; tumor associated macrophages; tumor microenvironment; tumorigenesis
  12. JCI Insight. 2023 07 10. pii: e163518. [Epub ahead of print]8(13):
      Cutaneous T cell lymphoma (CTCL) is a disfiguring and incurable disease characterized by skin-homing malignant T cells surrounded by immune cells that promote CTCL growth through an immunosuppressive tumor microenvironment (TME). Preliminary data from our phase I clinical trial of anti-programmed cell death ligand 1 (anti-PD-L1) combined with lenalidomide in patients with relapsed/refractory CTCL demonstrated promising clinical efficacy. In the current study, we analyzed the CTCL TME, which revealed a predominant PD-1+ M2-like tumor-associated macrophage (TAM) subtype with upregulated NF-κB and JAK/STAT signaling pathways and an aberrant cytokine and chemokine profile. Our in vitro studies investigated the effects of anti-PD-L1 and lenalidomide on PD-1+ M2-like TAMs. The combinatorial treatment synergistically induced functional transformation of PD-1+ M2-like TAMs toward a proinflammatory M1-like phenotype that gained phagocytic activity upon NF-κB and JAK/STAT inhibition, altered their migration through chemokine receptor alterations, and stimulated effector T cell proliferation. Lenalidomide was more effective than anti-PD-L1 in downregulation of the immunosuppressive IL-10, leading to decreased expression of both PD-1 and PD-L1. Overall, PD-1+ M2-like TAMs play an immunosuppressive role in CTCL. Anti-PD-L1 combined with lenalidomide provides a therapeutic strategy to enhance antitumor immunity by targeting PD-1+ M2-like TAMs in the CTCL TME.
    Keywords:  Cancer immunotherapy; Dermatology; Lymphomas; Macrophages
  13. Cells. 2023 Jul 03. pii: 1770. [Epub ahead of print]12(13):
      Glioblastoma (GBM) is a highly aggressive primary brain tumor that is largely refractory to treatment and, therefore, invariably relapses. GBM patients have a median overall survival of 15 months and, given this devastating prognosis, there is a high need for therapy improvement. One of the therapeutic approaches currently tested in GBM is chimeric antigen receptor (CAR)-T cell therapy. CAR-T cells are genetically altered T cells that are redirected to eliminate tumor cells in a highly specific manner. There are several challenges to CAR-T cell therapy in solid tumors such as GBM, including restricted trafficking and penetration of tumor tissue, a highly immunosuppressive tumor microenvironment (TME), as well as heterogeneous antigen expression and antigen loss. In addition, CAR-T cells have limitations concerning safety, toxicity, and the manufacturing process. To date, CAR-T cells directed against several target antigens in GBM including interleukin-13 receptor alpha 2 (IL-13Rα2), epidermal growth factor receptor variant III (EGFRvIII), human epidermal growth factor receptor 2 (HER2), and ephrin type-A receptor 2 (EphA2) have been tested in preclinical and clinical studies. These studies demonstrated that CAR-T cell therapy is a feasible option in GBM with at least transient responses and acceptable adverse effects. Further improvements in CAR-T cells regarding their efficacy, flexibility, and safety could render them a promising therapy option in GBM.
    Keywords:  CAR-T cells; GBM; T cells; glioblastoma; glioma; immunotherapy
  14. Int Rev Cell Mol Biol. 2023 ;pii: S1937-6448(23)00030-8. [Epub ahead of print]378 137-156
      Therapeutic monoclonal antibodies blocking different immune checkpoints, have demonstrated efficacy against a wide variety of solid tumors. The exclusion or absence of lymphocytes within the tumor microenvironment (TME) is one of the main resistance mechanisms to immune checkpoint inhibitor (ICI)-based therapies. Therefore, there is a growing interest in identifying novel approaches to promote T cell infiltration on immune-deserted (cold) and immune-excluded tumors to turn them into inflamed (hot) tumors. Here, we provide a comprehensive overview of the recently published studies showing the potential of low-dose radiation (LDRT) to reprogram the TME to allow and promote T-cell infiltration and thus, improve currently approved ICI-based therapies.
    Keywords:  Abscopal effect; High-dose radiation; Immunotherapy; Low-dose radiation; Radio-combinatorial immunotherapy; T cells; Tumor immune reprogramming; Tumor-microenvironment
  15. Cancer Res Commun. 2023 Jul;3(7): 1200-1211
      The tumor suppressor TP53 is the most frequently mutated gene in cancer and is mutationally inactivated in 50% of sporadic tumors. Inactivating mutations in TP53 also occur in Li Fraumeni syndrome (LFS). In addition to germline mutations in TP53 in LFS that completely inactivate this protein, there are many more germline mutant forms of TP53 in human populations that partially inactivate this protein: we call these partially inactivating mutations "hypomorphs." One of these hypomorphs is a SNP that exists in 6%-10% of Africans and 1%-2% of African Americans, which changes proline at amino acid 47 to serine (Pro47Ser; P47S). We previously showed that the P47S variant of p53 is intrinsically impaired for tumor suppressor function, and that this SNP is associated with increased cancer risk in mice and humans. Here we show that this SNP also influences the tumor microenvironment, and the immune microenvironment profile in P47S mice is more protumorigenic. At basal levels, P47S mice show impaired memory T-cell formation and function, along with increased anti-inflammatory (so-called "M2") macrophages. We show that in tumor-bearing P47S mice, there is an increase in immunosuppressive myeloid-derived suppressor cells and decreased numbers of activated dendritic cells, macrophages, and B cells, along with evidence for increased T-cell exhaustion in the tumor microenvironment. Finally, we show that P47S mice demonstrate an incomplete response to anti-PD-L1 therapy. Our combined data suggest that the African-centric P47S variant leads to both intrinsic and extrinsic defects in tumor suppression.Significance: Findings presented here show that the P47S variant of TP53 influences the immune microenvironment, and the immune response to cancer. This is the first time that a naturally occurring genetic variant of TP53 has been shown to negatively impact the immune microenvironment and the response to immunotherapy.
  16. Front Immunol. 2023 ;14 1213629
      Dendritic cells (DCs), a class of professional antigen-presenting cells, are considered key factors in the initiation and maintenance of anti-tumor immunity due to their powerful ability to present antigen and stimulate T-cell responses. The important role of DCs in controlling tumor growth and mediating potent anti-tumor immunity has been demonstrated in various cancer models. Accordingly, the infiltration of stimulatory DCs positively correlates with the prognosis and response to immunotherapy in a variety of solid tumors. However, accumulating evidence indicates that DCs exhibit a significantly dysfunctional state, ultimately leading to an impaired anti-tumor immune response due to the effects of the immunosuppressive tumor microenvironment (TME). Currently, numerous preclinical and clinical studies are exploring immunotherapeutic strategies to better control tumors by restoring or enhancing the activity of DCs in tumors, such as the popular DC-based vaccines. In this review, an overview of the role of DCs in controlling tumor progression is provided, followed by a summary of the current advances in understanding the mechanisms by which the TME affects the normal function of DCs, and concluding with a brief discussion of current strategies for DC-based tumor immunotherapy.
    Keywords:  DC-based vaccine; dendritic cell; immune tolerance; immunosuppressive populations; tumor microenvironment
  17. Mol Oncol. 2023 Jul 15.
      Cells in the tumor microenvironment (TME) communicate via membrane-bound and secreted proteins, which are mostly glycosylated. Altered glycomes of malignant tumors influence behaviors of stromal cells. In this study, we showed that the loss of core-1 β1,3-galactosyltransferase (C1GALT1)-mediated O-glycosylation suppressed tumor growth in syngeneic head and neck cancer (HNC) mouse models. O-glycan truncation in tumor cells promoted the M1 polarization of macrophages, enhanced T-cell-mediated cytotoxicity, and reduced interleukin-6 (IL-6) levels in the secretome. Proteasomal degradation of IL-6 was controlled by the O-glycan at threonine 166. Both IL-6/IL-6R blockade and O-glycan truncation in tumor cells induced similar pro-inflammatory phenotypes in macrophages and cytotoxic T lymphocytes (CTLs). The combination of the O-glycosylation inhibitor itraconazole and anti-programmed cell death protein 1 (anti-PD-1) antibody effectively suppressed tumor growth in vivo. Collectively, our findings demonstrate that O-glycosylation in tumor cells governs their crosstalk with macrophages and CTLs. Thus, targeting O-glycosylation successfully reshapes the TME and consequently enhances the efficacy of anti-PD-1 therapy.
    Keywords:  IL-6; Itraconazole; O-glycosylation; PD-1; Tumor microenvironment (TME); core 1 β1,3-galactosyltransferase (C1GALT1); head and neck cancer (HNC); immune checkpoint inhibitor (ICI)
  18. Chin J Cancer Res. 2023 Jun 30. 35(3): 283-298
      Natural killer (NK) cells can elicit an immune response against malignantly transformed cells without recognizing antigens, and they also exhibit cytotoxic effects and immune surveillance functions in tumor immunotherapy. Although several studies have shown the promising antitumor effects of NK cells in immunotherapy, their function is often limited in the tumor microenvironment because tumor cells can easily escape NK cell-induced death. Thus, for efficient tumor immunotherapy, the mechanism by which tumor cells escape NK cell-induced cytotoxicity must be fully understood. Various novel molecules and checkpoint receptors that mediate the disruption of NK cells in the tumor microenvironment have been discovered. In this review, we analyze and detail the major activating and inhibitory receptors on the surface of NK cells to delineate the mechanism by which tumor cells suppress NKG2D ligand expression and increase tumor receptor and inhibitory receptor expression [NKG2A, programmed cell death 1 (PD-1), and T-cell immunoglobulin and immunoreceptor tyrosine inhibitory motif (TIGIT)] on the NK cell surface, and thus inhibit NK cell activity. We also reviewed the current status of treatments based on these surface molecules. By comparing the therapeutic effects related to the treatment status and bypass mechanisms, we attempt to identify optimal single or combined treatments to suggest new treatment strategies for tumor immunotherapy.
    Keywords:  Immune evasion; NKG2D; PD-1; combination therapy; natural killer cell
  19. Int Immunopharmacol. 2023 Jul 09. pii: S1567-5769(23)00905-0. [Epub ahead of print]122 110579
      The tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) poses a major obstacle to traditional and immunomodulatory cancer therapies and is closely associated with macrophage polarization. Saikosaponin d (SSd), a major active component of triterpene saponins derived from Bupleurum falcatum, has anti-inflammatory and antitumor activities. However, whether SSd can regulate immune cells during the development of the TME in PDAC remains unknown. In the present study, we aimed to analyze the role of SSd in regulating immune cells in the PDAC TME, especially the polarization of macrophages, and examine the related mechanisms. An orthotopic PDAC cancer model was used to investigate the antitumor activities and the regulation of immune cells in vivo. In vitro, bone marrow mononuclear (BM-MNC) cells and RAW 264.7 cells were used to induce the M2 macrophage phenotype and examine the effects and molecular mechanism of SSd on M2 macrophage polarization. The results revealed that SSd could directly inhibit the apoptosis and invasion of pancreatic cancer cells, modulate the immunosuppressive microenvironment and reactivate the local immune response, especially by decreasing the shift toward M2 macrophage polarization by downregulating phosphorylated STAT6 levels and the PI3K/AKT/mTOR signaling pathway. Furthermore, 740-Y-P (PI3K activator) was used to verify that SSd inhibited M2 polarization in RAW264.7 cells via the PI3K/AKT/mTOR signaling pathway. In conclusion, this study provided experimental evidence of the antitumor effect of SSd, especially in the regulation of M2 macrophage polarization, and demonstrated that SSd may be a promising therapeutic agent in PDAC.
    Keywords:  M2 macrophage; PI3K/AKT/mTOR; Pancreatic Cancer; STAT6; Saikosaponin d
  20. J Neuroimmunol. 2023 Jul 07. pii: S0165-5728(23)00132-7. [Epub ahead of print]381 578146
      Despite advancements in standard treatments, the prognosis of Glioblastoma (GBM) remains poor, prompting research for novel therapies. Immunotherapy is a promising treatment option for GBM, and many immunotherapeutic agents are currently under investigation. Chimeric antigen receptor (CAR) T cells are rapidly evolving in immunotherapy of GBM with many clinical trials showing efficacy of CAR T cells exerting anti-tumor activity following recognition of tumor-associated antigens (TAAs). Exhaustion in CAR T cells can reduce their capacity for long-term persistence and anti-tumor action. Local immunotherapy, which targets the tumor microenvironment and creates a more hospitable immunological environment for CAR T cells, has the potential to reduce CAR T cell exhaustion and increase immunity. Tertiary lymphoid structures (TLS) are ectopic lymphoid-like formations that can develop within the tumor microenvironment or in other non-lymphoid tissues. As a comprehensive local immunotherapy tool, the incorporation of TLS into an implanted biodegradable scaffold has amazing immunotherapeutic potential. The immune response to GBM can be improved even further by strategically inserting a stimulator of interferon genes (STING) agonist into the scaffold. Additionally, the scaffold's addition of glioma stem cells (GSC), which immunotherapeutic approaches may use to target, enhances the removal of cancer cells from their source. Furthermore, it has been demonstrated that GSCs have an impact on TLS formation, which helps to create a favorable tumor microenvironment. Herein, we overview local delivery of a highly specific tandem AND-gate CAR T cell along with above mentioned components. A multifaceted approach that successfully engages the immune system to mount an efficient targeted immune response against GBM is provided by the integration of CAR T cells, TLS, STING agonists, and GSCs within an implantable biodegradable scaffold. This approach offers a promising therapeutic approach for patients with GBM.
    Keywords:  Glioblastoma; Immunotherapy; Local delivery; Management
  21. Front Immunol. 2023 ;14 1212209
      The cell surface enzyme CD73 is increasingly appreciated as a pivotal non-redundant immune checkpoint (IC) in addition to PD-1/PD-L1 and CTLA-4. CD73 produces extracellular adenosine (eADO), which not only inhibits antitumor T cell activity via the adenosine receptor (AR) A2AR, but also enhances the immune inhibitory function of cancer-associated fibroblasts and myeloid cells via A2BR. Preclinical studies show that inhibition of the CD73-adenosinergic pathway in experimental models of many solid tumors either as a monotherapy or, more effectively, in combination with PD-1/PD-L1 or CTLA-4 IC blockades, improves antitumor immunity and tumor control. Consequently, approximately 50 ongoing phase I/II clinical trials targeting the CD73-adenosinergic IC are currently listed on Most of the listed trials employ CD73 inhibitors or anti-CD73 antibodies alone, in combination with A2AR antagonists, and/or with PD-1/PD-L1 blockade. Recent evidence suggests that the distribution of CD73, A2AR and A2BR in tumor microenvironments (TME) is heterogeneous, and this distribution affects CD73-adenosinergic IC function. The new insights have implications for the optimally effective, carefully tailored approaches to therapeutic targeting of this essential IC. In the mini-review, we briefly discuss the cellular and molecular mechanisms of CD73/eADO-mediated immunosuppression during tumor progression and therapy in the spatial context of the TME. We include preclinical data regarding therapeutic CD73-eADO blockade in tumor models as well as available clinical data from completed trials that targeted CD73-adenosinergic IC with or without PD-1/PD-L1 inhibitors and discuss factors that are potentially important for optimal therapeutic outcomes in cancer patients.
    Keywords:  A2AR; A2BR; CD39; CD73; NT5E; adenosine; combination therapy; immune checkpoint inhibitor
  22. Hematol Oncol Clin North Am. 2023 Jul 11. pii: S0889-8588(23)00092-8. [Epub ahead of print]
      Up to 30% of patients with acute myeloid leukemia (AML) who undergo chimeric antigen receptor (CAR) T-cell therapy have evidence of response, although trials are highly heterogeneous. These responses are rarely deep or durable. CD123, CD33, and CLL-1 have emerged as the most common targets for CAR T cells in AML. CAR T cells against myeloid antigens cause myeloablation as well as cytokine release syndrome, although neurotoxicity is rarely seen. Future efforts should focus on AML-specific antigen discovery or engineering, and on further enhancing the activity of CAR T cells.
    Keywords:  Acute myeloid leukemia; CAR T cells; CRS; Cellular immunotherapy; Myeloablation
  23. Cancer Lett. 2023 Jul 11. pii: S0304-3835(23)00257-4. [Epub ahead of print] 216306
      Bidirectional interactions between cancer cells and their microenvironment govern tumor progression. Among the stromal cells in this microenvironment, adipocytes have been reported to upregulate cancer cell migration and invasion by producing fatty acids. Conversely, cancer cells alter adipocyte phenotype notably via increased lipolysis. We aimed to identify the mechanisms through which cancer cells trigger adipocyte lipolysis and evaluate the functional consequences on cancer progression. Here, we show that cancer cell-induced acidification of the extracellular medium strongly promotes preadipocyte lipolysis through a mechanism that does not involve lipophagy but requires adipose triglyceride lipase (ATGL) activity. This increased lipolysis is triggered mainly by attenuation of the G0/G1 switch gene 2 (G0S2)-induced inhibition of ATGL. G0S2-mediated regulation in preadipocytes affects their communication with breast cancer cells, modifying the phenotype of the cancer cells and increasing their resistance to chemotherapeutic agents in vitro. Furthermore, we demonstrate that the adipocyte-specific overexpression of G0S2 impairs mammary tumor growth and lung metastasis formation in vivo. Our results highlight the importance of acidosis in cancer cell-adipocyte crosstalk and identify G0S2 as the main regulator of cancer-induced lipolysis, regulating tumor establishment and spreading.
    Keywords:  Acidosis; Adipose triglyceride lipase (ATGL); G0/G1 switch gene 2 (G0S2); Lipolysis; Tumor microenvironment
  24. Cancers (Basel). 2023 Jul 05. pii: 3507. [Epub ahead of print]15(13):
      Mounting evidence links the phenomenon of enhanced recruitment of tumor-associated macrophages towards cancer bulks to neoplastic growth, invasion, metastasis, immune escape, matrix remodeling, and therapeutic resistance. In the context of cancer progression, naïve macrophages are polarized into M1 or M2 subtypes according to their differentiation status, gene signatures, and functional roles. While the former render proinflammatory and anticancer effects, the latter subpopulation elicits an opposite impact on pancreatic ductal adenocarcinoma. M2 macrophages have gained increasing attention as they are largely responsible for molding an immune-suppressive landscape. Through positive feedback circuits involving a paracrine manner, M2 macrophages can be amplified by and synergized with neighboring neoplastic cells, fibroblasts, endothelial cells, and non-cell autonomous constituents in the microenvironmental niche to promote an advanced disease state. This review delineates the molecular cues expanding M2 populations that subsequently convey notorious clinical outcomes. Future therapeutic regimens shall comprise protocols attempting to abolish environmental niches favoring M2 polarization; weaken cancer growth typically assisted by M2; promote the recruitment of tumoricidal CD8+ T lymphocytes and dendritic cells; and boost susceptibility towards gemcitabine as well as other chemotherapeutic agents.
    Keywords:  Kras; angiogenesis; chemoresistance; epithelial–mesenchymal transition; extracellular matrix; gemcitabine; hypoxia; immune checkpoint blockades; immune suppression; metastasis; pancreatic ductal adenocarcinoma; tumor microenvironment; tumor-associated macrophages; tumor-infiltrating lymphocytes
  25. J Transl Med. 2023 07 11. 21(1): 461
      BACKGROUND: Nearly 80% of patients with pancreatic cancer suffer from glucose intolerance or diabetes. Pancreatic cancer complicated by diabetes has a more immunosuppressive tumor microenvironment (TME) and is associated with a worse prognosis. The relationship between glucose metabolism and programmed cell death-Ligand 1 (PD-L1) is close and complex. It is important to explore the regulation of high glucose on PD-L1 expression in pancreatic cancer and its effect on infiltrating immune effectors in the tumor microenvironment.METHODS: Diabetic murine models (C57BL/6) were used to reveal different immune landscape in euglycemic and hyperglycemic pancreatic tumor microenvironment. Bioinformatics, WB, iRIP [Improved RNA Binding Protein (RBP) Immunoprecipitation]-seq were used to confirm the potential regulating role of peptidyl-tRNA hydrolase 1 homolog (PTRH1) on the stability of the PD-L1 mRNA. Postoperative specimens were used to identify the expression of PD-L1 and PTRH1 in pancreatic cancer. Co-culturing T cells with pancreatic cancer cells to explore the immunosuppressive effect of pancreatic tumor cells.
    RESULTS: Our results revealed that a high dose of glucose enhanced the stability of the PD-L1 mRNA in pancreatic tumor cells by downregulating PTRH1 through RAS signaling pathway activation following epidermal growth factor receptor (EGFR) stimulation. PTRH1 overexpression significantly suppressed PD-L1 expression in pancreatic cells and improved the proportion and cytotoxic function of CD8+ T cells in the pancreatic TME of diabetic mice.
    CONCLUSIONS: PTRH1, an RBP, plays a key role in the regulation of PD-L1 by high glucose and is closely related to anti-tumor immunity in the pancreatic TME.
    Keywords:  Diabetes; PD-L1; Pancreatic ductal adenocarcinoma; RNA binding protein; Tumor microenvironment
  26. Reprod Sci. 2023 Jul 11.
      Cervical cancer (CC) remains a prevalent gynecological malignancy, posing a significant health burden among women worldwide. With the remarkable discoveries of cellular pyroptosis and cuproptosis, there has been a growing focus on exploring the intricate relationship between these two forms of cell death and their impact on tumor progression. In recent years, alternative splicing has emerged as a significant field in cancer research. Thus, the integration of alternative splicing, pyroptosis, and cuproptosis holds immense value in studying their collective impact on the occurrence and progression of cervical cancer. In this study, alternative splicing data of pyroptosis- and cuproptosis-associated genes were integrated with public databases, including TCGA, to establish a prognostic model for cervical cancer based on COX regression modeling. Subsequently, the tumor microenvironment (TME) phenotypes in the high-risk and low-risk patient groups were characterized through a comprehensive bioinformatics analysis. The findings of this study revealed that the low-risk group exhibited a predominant immune-active TME phenotype, while the high-risk group displayed a tumor-favoring metabolic phenotype. These results indicate that the alternative splicing of pyroptosis- and cuproptosis-associated genes plays a pivotal role in remodeling the phenotypic landscape of the cervical cancer TME by modulating immune responses and metabolic pathways. This study provides valuable insights into the interplay between alternative splicing variants involved in pyroptosis and cuproptosis and the TME, contributing to a deeper understanding of cervical cancer pathogenesis and potential therapeutic avenues.
    Keywords:  Alternative splicing; Cervical cancer; Cuproptosis; Immune evasion; Phenotype remodeling of tumor microenvironment; Pyroptosis; TCGA
  27. Cancer Treat Rev. 2023 Jul 08. pii: S0305-7372(23)00091-9. [Epub ahead of print]119 102598
      Inflammatory breast cancer (IBC) is the most aggressive and fatal clinical presentation of breast cancer. Despite the term "inflammatory", based on the clinical presentation, IBC is biologically driven by an immunosuppressive tumor microenvironment (TME). Whether IBC can be switched into an immune-inflamed TME by immune-checkpoint inhibitors (ICIs) is a matter of debate. Presently, measurable biomarkers of IBC-TME have never been synthetized into a comprehensive portray of the immune-milieu (i.e., an immunogram), describing the immune-vulnerability of IBC and potentially predicting the response to ICIs. We propose an immunogram for IBC, based on preclinical and clinical studies, including six parameters: the presence of immune-effector cells, of immune-suppressive cells and of immune checkpoints, the general immune status, the activation of immune-suppressive pathways, the tumor foreignness. The IBC immunogram suggests the existence of a preexisting immune TME that is suppressed by mechanisms of immune-escape but might be restored by ICIs. The combination of chemotherapy and ICIs in patients with IBC is based on a strong biological rationale. However, the design and the development of clinical trials assessing the incorporation of ICIs raise many methodological and practical issues. In parallel with the further comprehension of IBC biology, the prospective validation and integration of biomarkers predictive of response to ICIs are warranted.
    Keywords:  Biomarkers; Immune-checkpoint inhibitors; Immunogram; Inflammatory breast cancer
  28. Cancers (Basel). 2023 Jun 24. pii: 3327. [Epub ahead of print]15(13):
      Neutrophils are the most abundant myeloid cells in the blood and are a considerable immunological component of the tumor microenvironment. However, their functional importance has often been ignored, as they have always been considered a mono-dimensional population of terminally differentiated, short-living cells. During the last decade, the use of cutting-edge, single-cell technologies has revolutionized the classical view of these cells, unmasking their phenotypic and functional heterogeneity. In this review, we summarize the emerging concepts in the field of neutrophils in cancer, by reviewing the recent literature on the heterogeneity of both circulating neutrophils and tumor-associated neutrophils, as well as their possible significance in tumor prognosis and resistance to immune checkpoint inhibitors.
    Keywords:  metabolism; neutrophils; tumor microenvironment
  29. Int Rev Cell Mol Biol. 2023 ;pii: S1937-6448(23)00026-6. [Epub ahead of print]378 201-232
      Activating and recruiting the immune system is critical for successful cancer treatment. Since the discovery of immune checkpoint inhibitors, immunotherapy has become the standard of care for many types of cancers. However, many patients fail to respond to immunotherapy. Further research is needed to understand the mechanisms of resistance and adjuvant therapies that can help sensitize patients to immunotherapies. Here, we will discuss how radiotherapy can change the tumor microenvironment and work synergistically with immunotherapy. We will examine different pre-clinical models focusing on their limitations and their unique advantages in studying the efficacy of treatments and the tumor microenvironment. We will also describe emerging findings from clinical trials testing the combination of immunotherapy and radiotherapy.
    Keywords:  Clinical trials; GEMM; Immune checkpoint blockade; Immunotherapy; Preclinical models; Radiation therapy; Radiotherapy; Tumor microenvironment
  30. Int Rev Cell Mol Biol. 2023 ;pii: S1937-6448(23)00020-5. [Epub ahead of print]378 31-60
      Natural killer (NK) cells are innate lymphoid cells that play an essential role in the anti-tumor response through immunosurveillance, multiple mechanisms of cytotoxicity and the synthesis of cytokines modulating the immune tumor microenvironment (TME). After the dramatic advances in immunotherapy targeting T cells including the success of checkpoint inhibitors or autologous chimeric antigen receptor (CAR) expressing T cells in clinical practice, NK cells have gained growing interest for the development of new therapies. Although NK cells have shown promising responses in leukemia patients, the effects of NK-targeted therapies are currently limited in the treatment of solid tumors. Thus, radiotherapy could provide a valuable solution to improve treatments targeting NK cells. Indeed, ionizing radiations represent a powerful immuno-modulator that can either induce a pro-inflammatory and anti-tumor TME, or conversely lead to immunosuppression of effector immune cells in favor of tumor growth and therapeutic escape, depending on how it is delivered and tumor models. However, the effects of ionizing radiation on NK cells are only partially understood. Therefore, we review the effects of radiotherapy on the NK cell-mediated anti-tumor response, and propose potential strategies to reinvigorate NK cells by combining radiotherapy with NK cell-targeted therapies.
    Keywords:  Combinations; Immune response; Natural killer; Radiation therapy
  31. Cancer Immunol Res. 2023 Jul 11. pii: CIR-22-0536. [Epub ahead of print]
      Clec4A4 is a C-type lectin receptor (CLR) exclusively expressed on murine conventional dendritic cells (cDCs) to regulate their activation status. However, the functional role of murine Clec4A4 (mClec4A4) in antitumor immunity remains unclear. Here, we show that mClec4A4 serves as a negative immune checkpoint regulator to impair antitumor immune responses. Deficiency of mClec4A4 lead to a reduction in tumor development, accompanied by enhanced antitumor immune responses and amelioration of the immunosuppressive tumor microenvironment mediated through the enforced activation of cDCs in tumor-bearing mice. Furthermore, antagonistic monoclonal antibody (mAb) to human CLEC4A (hCLEC4A), which is the functional orthologue of mClec4A4, exerted protection against established tumors without any apparent signs of immune-related adverse events in hCLEC4A-transgenic mice. Thus, our findings highlight the critical role of mClec4A4 expressed on cDCs as a negative immune checkpoint molecule in the control of tumor progression and provide support for hCLEC4A as a potential target for immune checkpoint blockade in tumor immunotherapy.
  32. J Cancer Res Clin Oncol. 2023 Jul 09.
      Liver cancer is one of the most common malignancies. T-cell exhaustion is associated with immunosuppression of tumor and chronic infection. Although immunotherapies that enhance the immune response by targeting programmed cell death-1(PD-1)/programmed cell death ligand 1 (PD-L1) have been applied to malignancies, these treatments have shown limited response rates. This suggested that additional inhibitory receptors (IRs) also contributed to T-cell exhaustion and tumor prognosis. Exhausted T-cells (Tex) in the tumor immune microenvironment (TME) are usually in a dysfunctional state of exhaustion, such as impaired activity and proliferative ability, increased apoptosis rate, and reduced production of effector cytokines. Tex cells participate in the negative regulation of tumor immunity mainly through IRs on the cell surface, changes in cytokines and immunomodulatory cell types, causing tumor immune escape. However, T-cell exhaustion is not irreversible and targeted immune checkpoint inhibitors (ICIs) can effectively reverse the exhaustion of T-cells and restore the anti-tumor immune response. Therefore, the research on the mechanism of T-cell exhaustion in liver cancer, aimed at maintaining or restoring the effector function of Tex cells, might provide a new method for the treatment of liver cancer. In this review, we summarized the basic characteristics of Tex cells (such as IRs and cytokines), discussed the mechanisms associated with T-cell exhaustion, and specifically discussed how these exhaustion characteristics were acquired and shaped by key factors within TME. Then new insights into the molecular mechanism of T-cell exhaustion suggested a potential way to improve the efficacy of cancer immunotherapy, namely to restore the effector function of Tex cells. In addition, we also reviewed the research progress of T-cell exhaustion in recent years and provided suggestions for further research.
    Keywords:  Immune checkpoint inhibitors; Liver cancer; T-cell; T-cell exhaustion