bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2023‒12‒03
forty-four papers selected by
Peio Azcoaga, Biodonostia HRI

  1. Front Immunol. 2023 ;14 1295257
      Cancer progression is primarily caused by interactions between transformed cells and the components of the tumor microenvironment (TME). TAMs (tumor-associated macrophages) make up the majority of the invading immune components, which are further categorized as anti-tumor M1 and pro-tumor M2 subtypes. While M1 is known to have anti-cancer properties, M2 is recognized to extend a protective role to the tumor. As a result, the tumor manipulates the TME in such a way that it induces macrophage infiltration and M1 to M2 switching bias to secure its survival. This M2-TAM bias in the TME promotes cancer cell proliferation, neoangiogenesis, lymphangiogenesis, epithelial-to-mesenchymal transition, matrix remodeling for metastatic support, and TME manipulation to an immunosuppressive state. TAMs additionally promote the emergence of cancer stem cells (CSCs), which are known for their ability to originate, metastasize, and relapse into tumors. CSCs also help M2-TAM by revealing immune escape and survival strategies during the initiation and relapse phases. This review describes the reasons for immunotherapy failure and, thereby, devises better strategies to impair the tumor-TAM crosstalk. This study will shed light on the understudied TAM-mediated tumor progression and address the much-needed holistic approach to anti-cancer therapy, which encompasses targeting cancer cells, CSCs, and TAMs all at the same time.
    Keywords:  anticancer therapy; cancer stem cells; immunosuppression; immunotherapy; macrophage reprogramming; pro-tumor immunity; tumor microenvironment; tumor-associated macrophages
  2. Front Immunol. 2023 ;14 1303605
      Natural killer (NK) cells kill mutant cells through death receptors and cytotoxic granules, playing an essential role in controlling cancer progression. However, in the tumor microenvironment (TME), NK cells frequently exhibit an exhausted status, which impairs their immunosurveillance function and contributes to tumor immune evasion. Emerging studies are ongoing to reveal the properties and mechanisms of NK cell exhaustion in the TME. In this review, we will briefly introduce the maturation, localization, homeostasis, and cytotoxicity of NK cells. We will then summarize the current understanding of the main mechanisms underlying NK cell exhaustion in the TME in four aspects: dysregulation of inhibitory and activating signaling, tumor cell-derived factors, immunosuppressive cells, and metabolism and exhaustion. We will also discuss the therapeutic approaches currently being developed to reverse NK cell exhaustion and enhance NK cell cytotoxicity in the TME.
    Keywords:  NK cell; cancer; exhaustion; immunotherapy; tumor microenvironment
  3. Front Immunol. 2023 ;14 1315490
    Keywords:  calcium signaling; cancer; cancer immunity; ion channel; lymphocytes; myeloid-derived suppressor cells; tumor microenvironment
  4. Front Immunol. 2023 ;14 1295684
      Tumor-associated macrophages (TAMs) are integral to the tumor microenvironment (TME), influencing cancer progression significantly. Attracted by cancer cell signals, TAMs exhibit unparalleled adaptability, aligning with the dynamic tumor milieu. Their roles span from promoting tumor growth and angiogenesis to modulating metastasis. While substantial research has explored the fundamentals of TAMs, comprehending their adaptive behavior, and leveraging it for novel treatments remains challenging. This review delves into TAM polarization, metabolic shifts, and the complex orchestration of cytokines and chemokines determining their functions. We highlight the complexities of TAM-targeted research focusing on their adaptability and potential variability in therapeutic outcomes. Moreover, we discuss the synergy of integrating TAM-focused strategies with established cancer treatments, such as chemotherapy, and immunotherapy. Emphasis is laid on pioneering methods like TAM reprogramming for cancer immunotherapy and the adoption of single-cell technologies for precision intervention. This synthesis seeks to shed light on TAMs' multifaceted roles in cancer, pinpointing prospective pathways for transformative research and enhancing therapeutic modalities in oncology.
    Keywords:  cancer immunotherapy; clinical trials; phenotypic diversity; regulatory signaling pathways; tumor microenvironment (TME); tumor-associated macrophages (TAM)
  5. Front Immunol. 2023 ;14 1274547
      The emergence of immunotherapy has revolutionized the treatment landscape for various types of cancer. Nevertheless, lung cancer remains one of the leading causes of cancer-related mortality worldwide due to the development of resistance in most patients. As one of the most abundant groups of immune cells in the tumor microenvironment (TME), tumor-associated macrophages (TAMs) play crucial and complex roles in the development of lung cancer, including the regulation of immunosuppressive TME remodeling, metabolic reprogramming, neoangiogenesis, metastasis, and promotion of tumoral neurogenesis. Hence, relevant strategies for lung cancer therapy, such as inhibition of macrophage recruitment, TAM reprograming, depletion of TAMs, and engineering of TAMs for drug delivery, have been developed. Based on the satisfactory treatment effect of TAM-targeted therapy, recent studies also investigated its synergistic effect with current therapies for lung cancer, including immunotherapy, radiotherapy, chemotherapy, anti-epidermal growth factor receptor (anti-EGFR) treatment, or photodynamic therapy. Thus, in this article, we summarized the key mechanisms of TAMs contributing to lung cancer progression and elaborated on the novel therapeutic strategies against TAMs. We also discussed the therapeutic potential of TAM targeting as adjuvant therapy in the current treatment of lung cancer, particularly highlighting the TAM-centered strategies for improving the efficacy of anti-programmed cell death-1/programmed cell death-ligand 1 (anti-PD-1/PD-L1) treatment.
    Keywords:  PD-1/PD-L1; combined therapy; immunotherapy; lung cancer; tumor-associated macrophages
  6. Mol Cancer. 2023 Nov 27. 22(1): 187
      Immunotherapies have revolutionized the treatment paradigms of various types of cancers. However, most of these immunomodulatory strategies focus on harnessing adaptive immunity, mainly by inhibiting immunosuppressive signaling with immune checkpoint blockade, or enhancing immunostimulatory signaling with bispecific T cell engager and chimeric antigen receptor (CAR)-T cell. Although these agents have already achieved great success, only a tiny percentage of patients could benefit from immunotherapies. Actually, immunotherapy efficacy is determined by multiple components in the tumor microenvironment beyond adaptive immunity. Cells from the innate arm of the immune system, such as macrophages, dendritic cells, myeloid-derived suppressor cells, neutrophils, natural killer cells, and unconventional T cells, also participate in cancer immune evasion and surveillance. Considering that the innate arm is the cornerstone of the antitumor immune response, utilizing innate immunity provides potential therapeutic options for cancer control. Up to now, strategies exploiting innate immunity, such as agonists of stimulator of interferon genes, CAR-macrophage or -natural killer cell therapies, metabolic regulators, and novel immune checkpoint blockade, have exhibited potent antitumor activities in preclinical and clinical studies. Here, we summarize the latest insights into the potential roles of innate cells in antitumor immunity and discuss the advances in innate arm-targeted therapeutic strategies.
    Keywords:  Cancer immunotherapy; Chimeric antigen receptor; Dendritic cell; Innate immunity; Macrophage; Myeloid-derived suppressor cell; Natural killer cell; Neutrophil
  7. Nat Immunol. 2023 Dec;24(12): 1982-1993
      Visualization of the cellular heterogeneity and spatial architecture of the tumor microenvironment (TME) is becoming increasingly important to understand mechanisms of disease progression and therapeutic response. This is particularly relevant in the era of cancer immunotherapy, in which the contexture of immune cell positioning within the tumor landscape has been proven to affect efficacy. Although single-cell technologies have mostly replaced conventional approaches to analyze specific cellular subsets within tumors, those that integrate a spatial dimension are now on the rise. In this Review, we assess the strengths and limitations of emerging spatial technologies with a focus on their applications in tumor immunology, as well as forthcoming opportunities for artificial intelligence (AI) and the value of integrating multiomics datasets to achieve a holistic picture of the TME.
  8. Front Immunol. 2023 ;14 1280601
      Malignancies contain a relatively small number of Mesenchymal stem/stromal cells (MSCs), constituting a crucial tumor microenvironment (TME) component. These cells comprise approximately 0.01-5% of the total TME cell population. MSC differentiation potential and their interaction with the tumor environment enable these cells to affect tumor cells' growth, immune evasion, metastasis, drug resistance, and angiogenesis. This type of MSC, known as cancer-associated mesenchymal stem/stromal cells (CA-MSCs (interacts with tumor/non-tumor cells in the TME and affects their function by producing cytokines, chemokines, and various growth factors to facilitate tumor cell migration, survival, proliferation, and tumor progression. Considering that the effect of different cells on each other in the TME is a multi-faceted relationship, it is essential to discover the role of these relationships for targeting in tumor therapy. Due to the immunomodulatory role and the tissue repair characteristic of MSCs, these cells can help tumor growth from different aspects. CA-MSCs indirectly suppress antitumor immune response through several mechanisms, including decreasing dendritic cells (DCs) antigen presentation potential, disrupting natural killer (NK) cell differentiation, inducing immunoinhibitory subsets like tumor-associated macrophages (TAMs) and Treg cells, and immune checkpoint expression to reduce effector T cell antitumor responses. Therefore, if these cells can be targeted for treatment so that their population decreases, we can hope for the treatment and improvement of the tumor conditions. Also, various studies show that CA-MSCs in the TME can affect other vital aspects of a tumor, including cell proliferation, drug resistance, angiogenesis, and tumor cell invasion and metastasis. In this review article, we will discuss in detail some of the mechanisms by which CA-MSCs suppress the innate and adaptive immune systems and other mechanisms related to tumor progression.
    Keywords:  MSCs; angiogenesis; cancer; immunosuppression; metastasis; tumor growth
  9. Trends Mol Med. 2023 Nov 30. pii: S1471-4914(23)00265-4. [Epub ahead of print]
      Cancer immunity is subject to spatiotemporal regulation by leukocyte interaction with the tumor microenvironment. Growing evidence suggests an emerging role for the vasculature in tumor immune evasion and immunotherapy resistance. Beyond the conventional functions of the tumor vasculature, such as providing oxygen and nutrients to support tumor progression, we propose multiplex mechanisms for vascular regulation of tumor immunity: The immunosuppressive vascular niche locoregionally educates circulation-derived immune cells by angiocrines, aberrant endothelial metabolism induces T cell exclusion and inactivation, and topologically and biochemically abnormal vascularity forms a pathophysiological barrier that hampers lymphocyte infiltration. We postulate that genetic and metabolic reprogramming of endothelial cells may rewire the immunosuppressive vascular microenvironment to overcome immunotherapy resistance, serving as a next-generation vascular targeting strategy for cancer treatment.
    Keywords:  CAR T cells; angiogenesis; cancer immunotherapy; endothelial cell metabolism; tumor microenvironment; vascular reprogramming
  10. Front Med (Lausanne). 2023 ;10 1328045
    Keywords:  cancer cell; immune cell; immunotherapy; prognostic marker; tumor microenvironment
  11. Gan To Kagaku Ryoho. 2023 Oct;50(10): 1099-1101
      It has been reported that tumor cell-intrinsic cyclic GMP-AMP synthase(cGAS)-stimulator of interferon genes(STING) pathway is essential for radiotherapy(RT)-induced activation of anti-tumor immune responses. However, its role in the RT- induced remodeling of the tumor microenvironment(TME)in esophageal squamous cell carcinoma(ESCC), is largely unknown. In this study, we found that the tumor cell-intrinsic cGAS-STING pathway is a critical component for RT-induced activation of immune cells in the TME through the induction of type Ⅰ interferon and C-X-C motif chemokine ligand 10 in tumor cells in ESCC. However, at the same time, the tumor cell-intrinsic cGAS-STING pathway is also involved in RT-triggered infiltration and polarization of immunosuppressive CD163+ tumor-associated macrophages (TAM) through the induction of interleukin 34 (IL-34) in tumor cells in ESCC. Our findings suggest that targeting IL-34 to impede the infiltration and polarization of CD163+ TAM could potentially enhance the efficacy of RT-induced immune cell activation in ESCC TME.
  12. ACS Omega. 2023 Nov 14. 8(45): 42072-42085
      Cancer cells exhibit aberrant extracellular matrix mechanosensing due to the altered expression of mechanosensory cytoskeletal proteins. Such aberrant mechanosensing of the tumor microenvironment (TME) by cancer cells is associated with disease development and progression. In addition, recent studies show that such mechanosensing changes the mechanobiological properties of cells, and in turn cells become susceptible to mechanical perturbations. Due to an increasing understanding of cell biomechanics and cellular machinery, several approaches have emerged to target the mechanobiological properties of cancer cells and cancer-associated cells to inhibit cancer growth and progression. In this Perspective, we summarize the progress in developing mechano-based approaches to target cancer by interfering with the cellular mechanosensing machinery and overall TME.
  13. Front Immunol. 2023 ;14 1275028
      Natural killer (NK) cells, as fundamental components of innate immunity, can quickly react to abnormalities within the body. In-depth research has revealed that NK cells possess regulatory functions not only in innate immunity but also in adaptive immunity under various conditions. Multiple aspects of the adaptive immune process are regulated through NK cells. In our review, we have integrated multiple studies to illuminate the regulatory function of NK cells in regulating B cell and T cell responses during adaptive immune processes, focusing on aspects including viral infections and the tumor microenvironment (TME). These insights provide us with many new understandings on how NK cells regulate different phases of the adaptive immune response.
    Keywords:  B cell; NK cell; T cell; adaptive immunity; regulation; tumor; virus infection
  14. Gan To Kagaku Ryoho. 2023 Oct;50(10): 1027-1031
      CAR-T cell therapy has demonstrated efficacy in hematopoietic tumors such as leukemia, myeloma, and non-Hodgkin's B-cell lymphoma in patients refractory to chemotherapy. However, in solid tumors, they are still limited by several barriers, including limited migration and invasion to tumor cells, the presence of an immunosuppressive tumor microenvironment, and adverse events associated with such therapies. In recent years, next-generation CAR immune cell technology has expanded and made progress in augmenting immune cells, activating endogenous immunity, and arming cells to resist suppression by the tumor microenvironment.
  15. Mol Cancer. 2023 Nov 29. 22(1): 191
      Despite major improvements in immunotherapeutic strategies, the immunosuppressive tumor microenvironment remains a major obstacle for the induction of efficient antitumor responses. In this study, we show that local delivery of a bispecific Clec9A-PD-L1 targeted type I interferon (AcTaferon, AFN) overcomes this hurdle by reshaping the tumor immune landscape.Treatment with the bispecific AFN resulted in the presence of pro-immunogenic tumor-associated macrophages and neutrophils, increased motility and maturation profile of cDC1 and presence of inflammatory cDC2. Moreover, we report empowered diversity in the CD8+ T cell repertoire and induction of a shift from naive, dysfunctional CD8+ T cells towards effector, plastic cytotoxic T lymphocytes together with increased presence of NK and NKT cells as well as decreased regulatory T cell levels. These dynamic changes were associated with potent antitumor activity. Tumor clearance and immunological memory, therapeutic immunity on large established tumors and blunted tumor growth at distant sites were obtained upon co-administration of a non-curative dose of chemotherapy.Overall, this study illuminates further application of type I interferon as a safe and efficient way to reshape the suppressive tumor microenvironment and induce potent antitumor immunity; features which are of major importance in overcoming the development of metastases and tumor cell resistance to immune attack. The strategy described here has potential for application across to a broad range of cancer types.
    Keywords:  AcTakine; Cancer immunotherapy; Immune checkpoint; Tumor microenvironment; Type I Interferon
  16. Curr Pharm Des. 2023 Nov 30.
      Triple-negative breast cancers are highly aggressive, a heterogeneous form of breast cancer with a high re-occurrence rate that further lacks an efficient treatment strategy and prognostic marker. The tumor microenvironment of the disease comprises cancer-associated fibroblasts, cancer stem cells, immunological molecules, epithelial-mesenchymal transition, and a metastatic microenvironment that contributes to disease progression and metastasis to distant sites. Emerging evidence indicated that miRNA clusters would be of clinical utility as they exert an oncogenic or tumor suppressor role in TNBC. The present review article aims to highlight the therapeutic significance of miRNA in targeting the above-mentioned signaling cascades and modulating the intracellular crosstalk in the tumor microenvironment of TNBC. Prognostic implications of miRNAs to depict disease-free survival, distant metastasis-free survival, relapse-free survival, and overall survival outcome were also unveiled.
    Keywords:  CAFs; CSCs; EMT; TME; TNBC; miRNAs; prognosis; therapeutic
  17. Cancer Cell Int. 2023 Nov 25. 23(1): 294
      Triple-negative breast Cancer (TNBC) is a highly malignant cancer with unclear pathogenesis. Within the tumor microenvironment (TME), cancer-associated fibroblasts (CAFs) vitally influence tumor onset and progression. Thus, this research aimed to identify distinct subgroups of CAF using single-cell and TNBC-related information from the GEO and TCGA databases, respectively. The primary aim was to establish a novel predictive model based on the CAF features and their clinical relevance. Moreover, the CAFs were analyzed for their immune characteristics, response to immunotherapy, and sensitivity to different drugs. The developed predictive model demonstrated significant effectiveness in determining the prognosis of patients with TNBC, TME, and the immune landscape of the tumor. Of note, the expression of GPR34 was significantly higher in TNBC tissues compared to that in other breast cancer (non-TNBC) tissues, indicating that GPR34 plays a crucial role in the onset and progression of TNBC. In summary, this research has yielded a novel predictive model for TNBC that holds promise for the accurate prediction of prognosis and response to immunotherapy in patients with TNBC.
    Keywords:  Cancer-associated fibroblast; GPR34; Prognosis; Triple-negative breast cancer; Tumor microenvironment
  18. Semin Cancer Biol. 2023 Nov 28. pii: S1044-579X(23)00147-5. [Epub ahead of print]97 104-123
      In cancer patients, immune cells are often functionally compromised due to the immunosuppressive features of the tumor microenvironment (TME) which contribute to the failures in cancer therapies. Clinical and experimental evidence indicates that developing tumors adapt to the immunological environment and create a local microenvironment that impairs immune function by inducing immune tolerance and invasion. In this context, microenvironmental hypoxia, which is an established hallmark of solid tumors, significantly contributes to tumor aggressiveness and therapy resistance through the induction of tumor plasticity/heterogeneity and, more importantly, through the differentiation and expansion of immune-suppressive stromal cells. We and others have provided evidence indicating that hypoxia also drives genomic instability in cancer cells and interferes with DNA damage response and repair suggesting that hypoxia could be a potential driver of tumor mutational burden. Here, we reviewed the current knowledge on how hypoxic stress in the TME impacts tumor angiogenesis, heterogeneity, plasticity, and immune resistance, with a special interest in tumor immunogenicity and hypoxia targeting. An integrated understanding of the complexity of the effect of hypoxia on the immune and microenvironmental components could lead to the identification of better adapted and more effective combinational strategies in cancer immunotherapy. Clearly, the discovery and validation of therapeutic targets derived from the hypoxic tumor microenvironment is of major importance and the identification of critical hypoxia-associated pathways could generate targets that are undeniably attractive for combined cancer immunotherapy approaches.
    Keywords:  Hypoxia; Immune tolerance; Immunotherapy; Plasticity; Tumor microenvironment
  19. Zhonghua Yu Fang Yi Xue Za Zhi. 2023 Nov 06. 57(11): 1895-1900
      Eosinophils are important immune cells that contain eosinophilic particles and play a key role in allergic diseases such as asthma and helminth infections. An increasing number of studies have confirmed that eosinophils infiltrate a variety of tumor tissues, which can synthesize and secrete a large number of bioactive substances under certain circumstances, such as cytotoxic cationic proteins, cytokines, growth factors, chemokines, enzymes and so on, which may affect angiogenesis and matrix remodeling or change the tumor microenvironment, thereby affecting tumor progression. This review focused on the role of eosinophils in lung cancer and provided an outlook on the issues in clinical and basic research.
  20. Bioact Mater. 2024 Feb;32 530-542
      Immune checkpoint blockade (ICB) therapy is a revolutionary approach to treat cancers, but still have limited clinical applications. Accumulating evidence pinpoints the immunosuppressive characteristics of the tumor microenvironment (TME) as one major obstacle. The TME, characterized by acidity, hypoxia and elevated ROS levels, exerts its detrimental effects on infiltrating anti-tumor immune cells. Here, we developed a TME-responsive and immunotherapeutic catalase-loaded calcium carbonate nanoparticles (termed as CAT@CaCO3 NPs) as the simple yet versatile multi-modulator for TME remodeling. CaCO3 NPs can consume protons in the acidic TME to normalize the TME pH. CAT catalyzed the decomposition of ROS and thus generated O2. The released Ca2+ led to Ca2+ overload in the tumor cells which then triggered the release of damage-associated molecular patterns (DAMP) signals to initiate anti-tumor immune responses, including tumor antigen presentation by dendritic cells. Meanwhile, CAT@CaCO3 NPs-induced immunosupportive TME also promoted the polarization of the M2 tumor-associated macrophages to the M1 phenotype, further enhancing tumor antigen presentation. Consequently, T cell-mediated anti-tumor responses were activated, the efficacy of which was further boosted by aPD-1 immune checkpoint blockade. Our study demonstrated that local treatment of CAT@CaCO3 NPs and aPD-1 combination can effectively evoke local and systemic anti-tumor immune responses, inhibiting the growth of treated tumors and distant diseases.
    Keywords:  Calcium carbonate nanoparticles; Cancer immunotherapy; Drug delivery; Immune checkpoint inhibitor; Immune modulation; Tumor microenvironment
  21. Innate Immun. 2023 Nov 28. 17534259231215581
      Myeloid-derived suppressor cells (MDSCs) are notable innate immune cells, which are further divided into two subpopulations, i.e., monocytic and granulocytic. These cells are traditionally considered to mainly suppress the T-cell responses. However, more updated data indicate that their properties are rather immunomodulatory than solely immunosuppressive. Indeed, MDSCs display extensive crosstalk with other either innate or adaptive immune cells, and, according to the situation under which they are triggered, they may enhance or attenuate the immune response. However, their positive role in host's defense mechanisms under specific conditions is rarely discussed in the literature. In this mini-review, the authors briefly summarise the mechanisms of action of MDSCs under distinct conditions, such as infections and malignancies, with a particular emphasis on their role as components of the innate immunity system.
    Keywords:  infection; innate immune cells; innate immune response; innate immunity; myeloid-derived suppressor cells
  22. J Immunol Res. 2023 ;2023 5599660
      The clinical efficacy of surgery, radiotherapy, and chemotherapy for cancer is usually limited by the deterioration of tumor microenvironment (TME). Neutrophil extracellular traps (NETs) are decondensed chromatin extruded by neutrophils and are widely distributed among various cancers, such as pancreatic cancer, breast cancer, and hepatocellular carcinoma. In the TME, NETs interact with stromal components, immune cells and cancer cells, which allows for the reshaping of the matrix and the extracellular environment that favors the initiation, progression, and metastasis of cancer. In addition, NETs impair the proliferation and activation of T cells and NK cells, thus producing a suppressive TME that restricts the effect of immunotherapy. A better understanding of the function of NETs in the TME will provide new opportunities for the prevention of cancer metastasis and the discovery of novel therapy strategies.
  23. Front Cell Dev Biol. 2023 ;11 1275543
      The occurrence and progression of tumors are inseparable from glucose metabolism. With the development of tumors, the volume increases gradually and the nutritional supply of tumors cannot be fully guaranteed. The tumor microenvironment changes and glucose deficiency becomes the common stress environment of tumors. Here, we discuss the mutual influences between glucose deprivation and other features of the tumor microenvironment, such as hypoxia, immune escape, low pH, and oxidative stress. In the face of a series of stress responses brought by glucose deficiency, different types of tumors have different coping mechanisms. We summarize the tumor studies on glucose deficiency in the last decade and review the genes and pathways that determine the fate of tumors under harsh conditions. It turns out that most of these genes help tumor cells survive in glucose-deprivation conditions. The development of related inhibitors may bring new opportunities for the treatment of tumors.
    Keywords:  cancer; cell death; cell survival; glucose deprivation; tumor microenvironment
  24. Biomed Pharmacother. 2023 Nov 30. pii: S0753-3322(23)01752-3. [Epub ahead of print]170 115954
      The potential of Ferrimagnetic vortex iron oxide nanoring-mediated mild magnetic hyperthermia (FVIO-MHT) in solid tumor therapy has been demonstrated. However, the impact of FVIO-MHT on the tumor microenvironment (TME) remains unclear. This study utilized single-cell transcriptome sequencing to examine the alterations in the TME in response to FVIO-MHT in breast cancer. The results revealed the cellular composition within the tumor microenvironment (TME) was primarily modified due to a decrease in tumor cells and an increased infiltration of myeloid cells. Subsequently, an enhancement in active oxygen (ROS) metabolism was observed, indicating oxidative damage to tumor cells. Interestingly, FVIO-MHT reprogrammed the macrophages' phenotypes, as evidenced by alterations in the transcriptome characteristics associated with both classic and alternative activated phenotypes. And an elevated level of ROS generation and oxidative phosphorylation suggested that activated phagocytosis and inflammation occurred in macrophages. Additionally, cell-cell communication analysis revealed that FVIO-MHT attenuated the suppression between tumor cells and macrophages by inhibiting phagocytic checkpoint and macrophage migration inhibitory factor signaling pathways. Inhibition of B2m, an anti-phagocytosis checkpoint, could promote macrophage-mediated phagocytosis and significantly inhibit tumor growth. These data emphasize FVIO-MHT may promote the antitumor capabilities of macrophages by alleviating the suppression between tumor cells and macrophages.
    Keywords:  Ferrimagnetic vortex-domain iron oxide nanoring; Macrophages; Mild magnetic hyperthermia; Phagocytosis checkpoints; Single-cell RNA sequencing; Tumor microenvironment
  25. J Hepatocell Carcinoma. 2023 ;10 2083-2099
      Globally, primary liver cancer is the third leading cause of cancer death, and hepatocellular carcinoma (HCC) accounts for 75%-95%. The tumor microenvironment (TME), composed of the extracellular matrix, helper cells, immune cells, cytokines, chemokines, and growth factors, promotes the immune escape, invasion, and metastasis of HCC. Tumor metastasis and postoperative recurrence are the main threats to the long-term prognosis of HCC. TME-related therapies are increasingly recognized as effective treatments. Molecular-targeted therapy, immunotherapy, and their combined therapy are the main approaches. Immunotherapy, represented by immune checkpoint inhibitors (ICIs), and targeted therapy, highlighted by tyrosine kinase inhibitors (TKIs), have greatly improved the prognosis of HCC. This review focuses on the TME compositions and emerging therapeutic approaches to TME in HCC.
    Keywords:  hepatocellular carcinoma; immunotherapy; targeted therapy; tumor microenvironment
  26. Adv Mater. 2023 Nov 28. e2309094
      Inhibition of glutamine metabolism in tumor cells can cause metabolic compensation-mediated glycolysis enhancement and PD-L1 upregulation-induced immune evasion, significantly limiting the therapeutic efficacy of glutamine inhibitors. Here, inspired by the specific binding of receptor and ligand, a PD-L1-targeting metabolism and immune regulator (PMIR) was constructed by decorating the glutaminase inhibitor (BPTES)-loading zeolitic imidazolate framework (ZIF) with PD-L1-targeting peptides for regulating the metabolism within the tumor microenvironment (TME) to improve immunotherapy. At tumor sites, PMIR inhibited glutamine metabolism of tumor cells for elevating glutamine levels within the TME to improve the function of immune cells. Ingeniously, the accompanying PD-L1 upregulation on tumor cells caused self-amplifying accumulation of PMIR through PD-L1 targeting, while also blocking PD-L1, which had the effects of converting enemies into friends. Meanwhile, PMIR exactly offset the compensatory glycolysis, while disrupting the redox homeostasis in tumor cells via the cooperation of components of the ZIF and BPTES. These together caused immunogenic cell death of tumor cells and relieved PD-L1-mediated immune evasion, further reshaping the immunosuppressive TME and evoking robust immune responses to effectively suppress bilateral tumor progression and metastasis. This work proposed a rational strategy to surmount the obstacles in glutamine inhibition for boosting existing clinical treatments. This article is protected by copyright. All rights reserved.
    Keywords:  Drug delivering; Glutamine inhibition; Metabolic reprogramming; Self-amplifying PD-L1 targeting; Tumor immunotherapy
  27. bioRxiv. 2023 Nov 15. pii: 2023.11.13.566775. [Epub ahead of print]
      The efficacy of chimeric antigen receptor (CAR)-T therapy has been limited against brain tumors to date. CAR-T cells infiltrating syngeneic intracerebral SB28-EGFRvIII glioma revealed impaired mitochondrial ATP production and a markedly hypoxic status compared to ones migrating to subcutaneous tumors. Drug screenings to improve metabolic states of T cells under hypoxic conditions led us to evaluate the combination of AMPK activator Metformin and the mTOR inhibitor Rapamycin (Met+Rap). Met+Rap-pretreated mouse CAR-T cells showed activated PPAR-gamma coactivator 1α (PGC-1α) through mTOR inhibition and AMPK activation, and a higher level of mitochondrial spare respiratory capacity than those pretreated with individual drugs or without pretreatment. Moreover, Met+Rap-pretreated CAR-T cells demonstrated persistent and effective anti-glioma cytotoxic activities in the hypoxic condition. Furthermore, a single intravenous infusion of Met+Rap-pretreated CAR-T cells significantly extended the survival of mice bearing intracerebral SB28-EGFRvIII gliomas. Mass cytometric analyses highlighted increased glioma-infiltrating CAR-T cells in the Met+Rap group with fewer Ly6c+ CD11b+ monocytic myeloid-derived suppressor cells in the tumors. Finally, human CAR-T cells pretreated with Met+Rap recapitulated the observations with murine CAR-T cells, demonstrating improved functions in vitro hypoxic conditions. These findings advocate for translational and clinical exploration of Met+Rap-pretreated CAR-T cells in human trials.
  28. Sci Rep. 2023 Nov 27. 13(1): 20874
      Glioblastoma (GBM) is an aggressive primary CNS malignancy and clinical outcomes have remained stagnant despite introduction of new treatments. Understanding the tumor microenvironment (TME) in which tumor associated macrophages (TAMs) interact with T cells has been of great interest. Although previous studies examining TAMs in GBM have shown that certain TAMs are associated with specific clinical and/or pathologic features, these studies used an outdated M1/M2 paradigm of macrophage polarization and failed to include the continuum of TAM states in GBM. Perhaps most significantly, the interactions of TAMs with T cells have yet to be fully explored. Our study uses single-cell RNA sequencing data from adult IDH-wildtype GBM, with the primary aim of deciphering the cellular interactions of the 7 TAM subtypes with T cells in the GBM TME. Furthermore, the interactions discovered herein are compared to IDH-mutant astrocytoma, allowing for focus on the cellular ecosystem unique to GBM. The resulting ligand-receptor interactions, signaling sources, and global communication patterns discovered provide a framework for future studies to explore methods of leveraging the immune system for treating GBM.
  29. Nat Immunol. 2023 Dec;24(12): 2008-2020
      Our increased understanding of how key metabolic pathways are activated and regulated in malignant cells has identified metabolic vulnerabilities of cancers. Translating this insight to the clinics, however, has proved challenging. Roadblocks limiting efficacy of drugs targeting cancer metabolism may lie in the nature of the metabolic ecosystem of tumors. The exchange of metabolites and growth factors between cancer cells and nonmalignant tumor-resident cells is essential for tumor growth and evolution, as well as the development of an immunosuppressive microenvironment. In this Review, we will examine the metabolic interplay between tumor-resident cells and how targeted inhibition of specific metabolic enzymes in malignant cells could elicit pro-tumorigenic effects in non-transformed tumor-resident cells and inhibit the function of tumor-specific T cells. To improve the efficacy of metabolism-targeted anticancer strategies, a holistic approach that considers the effect of metabolic inhibitors on major tumor-resident cell populations is needed.
  30. Autoimmunity. 2023 Dec;56(1): 2281226
      Tumor-secreted exosomes are critical for the functional regulation of tumor-associated macrophages (TAMs). This study aimed to explore how exosomes secreted by ovarian carcinoma cells regulate the phenotype and function of macrophages. Hypoxic treatment of A2780 cells was postulated to mimic the tumor microenvironment, and exosomes were co-cultured with TAMs. miR-1225-5p was enriched in hypoxic exosomes and contributed to M2 macrophage polarizationby modulating Toll-like receptor 2 expression (TLR2). Furthermore, hypoxia-treated macrophages promote ovarian cancer cell viability, migration, and invasion via the wnt/β-catenin pathway. This study clarified that exosomal miR-1225-5p promotes macrophage M2-like polarization by targeting TLR2 to promote ovarian cancer, which may via the wnt/β-catenin pathway.
    Keywords:  Ovarian cancer; TLR2; exosome; hsa-miR-1225-5p; macrophages; wnt/β-catenin pathway
  31. Nat Immunol. 2023 Dec;24(12): 1994-2007
      The advent of chimeric antigen receptor (CAR) T cell therapy has resulted in unprecedented long-term clearance of relapse/refractory hematological malignancies in both pediatric and adult patients. However, severe toxicities, such as cytokine release syndrome and neurotoxicity, associated with CAR T cells affect therapeutic utility; and treatment efficacies for solid tumors are still not impressive. As a result, engineering strategies that modify other immune cell types, especially natural killer (NK) cells have arisen. Owing to both CAR-dependent and CAR-independent (innate immune-mediated) antitumor killing capacity, major histocompatibility complex-independent cytotoxicity, reduced risk of alloreactivity and lack of major CAR T cell toxicities, CAR NK cells constitute one of the promising next-generation CAR immune cells that are also amenable as 'off-the-shelf' therapeutics. In this Review, we compare CAR T and CAR NK cell therapies, with particular focus on immunological synapses, engineering strategies and challenges.
  32. Clin Breast Cancer. 2023 Nov 05. pii: S1526-8209(23)00271-9. [Epub ahead of print]
      Triple-negative breast cancer (TNBC) is a unique subtype of breast cancer characterized by the lack of expression of the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. TNBC exhibits a high degree of aggressiveness, metastatic potential, and a poor prognosis. Despite the limited success of conventional treatments, immune checkpoint inhibitors (ICIs) have emerged as promising therapeutics for TNBC. Therefore, understanding the mechanisms underlying innate and acquired resistance to ICIs in TNBC is essential. Numerous studies suggest that intrinsic and extrinsic factors significantly contribute to the development of ICI resistance in TNBC. Intrinsic resistance may result from alterations in tumor-intrinsic signaling pathways, such as dysregulation of interferon (IFN) signaling or other signaling pathways. In contrast, extratumoral mechanisms may develop due to alterations in the tumor microenvironment, changes in T cell-related factors or adaptations within the immune system itself. In this paper, we endeavor to elucidate the underlying mechanisms of immune resistance by systematically examining immune mechanisms, the present state of immunotherapy, and the processes of immune resistance. Nonetheless, enhancing our understanding of the mechanisms underlying intratumoral and extratumoral resistance to ICIs in TNBC is crucial for optimizing patient outcomes in this challenging disease. Persistent efforts to identify novel targets for combination therapies, biomarkers that can predict the response to immunotherapy, and resistance mechanisms will be instrumental in achieving this objective.
    Keywords:  Immunotherapy T cell ICIs; TNBC Immune-Resistance PD-1 CTLA-4 TME
  33. Medicine (Baltimore). 2023 Nov 24. 102(47): e36045
      As individuals age, cancer becomes increasingly common. This continually rising risk can be attributed to various interconnected factors that influence the body's susceptibility to cancer. Among these factors, the accumulation of senescent cells in tissues and the subsequent decline in immune cell function and proliferative potential are collectively referred to as immunosenescence. Reduced T-cell production, changes in secretory phenotypes, increased glycolysis, and the generation of reactive oxygen species are characteristics of immunosenescence that contribute to cancer susceptibility. In the tumor microenvironment, senescent immune cells may promote the growth and spread of tumors through multiple pathways, thereby affecting the effectiveness of immunotherapy. In recent years, immunosenescence has gained increasing attention due to its critical role in tumor development. However, our understanding of how immunosenescence specifically impacts cancer immunotherapy remains limited, primarily due to the underrepresentation of elderly patients in clinical trials. Furthermore, there are several age-related intervention methods, including metformin and rapamycin, which involve genetic and pharmaceutical approaches. This article aims to elucidate the defining characteristics of immunosenescence and its impact on malignant tumors and immunotherapy. We particularly focus on the future directions of cancer treatment, exploring the complex interplay between immunosenescence, cancer, and potential interventions.
  34. Methods Mol Biol. 2024 ;2729 143-158
      Antibodies that block immune checkpoints, also called immune checkpoint inhibitors (ICI), have demonstrated impressive anti-tumor efficacy. The success of ICIs results from a complex interplay between cancer cells and their immune microenvironment. One of the predictors for ICI efficacy is the expression of the targeted immune checkpoint, such as programmed death ligand 1 (PD-L1). Immune checkpoints can be expressed on tumor cells and/or subsets of immune cells. PET imaging offers unique possibilities to study the dynamics of immune checkpoint expression in tumor and normal tissues in a longitudinal manner. In this chapter, we describe the methodology to use zirconium-89-labeled antibodies to assess the expression of immune checkpoint molecules in syngeneic murine tumor models by PET imaging.
    Keywords:  Antibody; Cancer; Immune checkpoints; PET; Zirconium-89
  35. bioRxiv. 2023 Nov 16. pii: 2023.11.14.567108. [Epub ahead of print]
      The tumor microenvironment (TME) is a complex and dynamic ecosystem that involves interactions between different cell types, such as cancer cells, immune cells, and stromal cells. These interactions can promote or inhibit tumor growth and affect response to therapy. Multitype Gibbs point process (MGPP) models are statistical models used to study the spatial distribution and interaction of different types of objects, such as the distribution of cell types in a tissue sample. Such models are potentially useful for investigating the spatial relationships between different cell types in the tumor microenvironment, but so far studies of the TME using cell-resolution imaging have been largely limited to spatial descriptive statistics. However, MGPP models have many advantages over descriptive statistics, such as uncertainty quantification, incorporation of multiple covariates and the ability to make predictions. In this paper, we describe and apply a previously developed MGPP method, the saturated pairwise interaction Gibbs point process model , to a publicly available multiplexed imaging dataset obtained from colorectal cancer patients. Importantly, we show how these methods can be used as joint species distribution models (JSDMs) to precisely frame and answer many relevant questions related to the ecology of the tumor microenvironment.
  36. Front Immunol. 2023 ;14 1286750
      The ability to expand and activate natural Killer (NK) cells ex vivo has dramatically changed the landscape in the development of novel adoptive cell therapies for treating cancer over the last decade. NK cells have become a key player for cancer immunotherapy due to their innate ability to kill malignant cells while not harming healthy cells, allowing their potential use as an "off-the-shelf" product. Furthermore, recent advancements in NK cell genetic engineering methods have enabled the efficient generation of chimeric antigen receptor (CAR)-expressing NK cells that can exert both CAR-dependent and antigen-independent killing. Clinically, CAR-NK cells have shown promising efficacy and safety for treating CD19-expressing hematologic malignancies. While the number of pre-clinical studies using CAR-NK cells continues to expand, it is evident that solid tumors pose a unique challenge to NK cell-based adoptive cell therapies. Major barriers for efficacy include low NK cell trafficking and infiltration into solid tumor sites, low persistence, and immunosuppression by the harsh solid tumor microenvironment (TME). In this review we discuss the barriers posed by the solid tumor that prevent immune cell trafficking and NK cell effector functions. We then discuss promising strategies to enhance NK cell infiltration into solid tumor sites and activation within the TME. This includes NK cell-intrinsic and -extrinsic mechanisms such as NK cell engineering to resist TME-mediated inhibition and use of tumor-targeted agents such as oncolytic viruses expressing chemoattracting and activating payloads. We then discuss opportunities and challenges for using combination therapies to extend NK cell therapies for the treatment of solid tumors.
    Keywords:  cancer immunotherapy; nanomedicine; natural killer cells; oncolytic virus; solid tumors; tumor microenvironment
  37. Front Oncol. 2023 ;13 1259034
      Macrophages represent an important component of the innate immune system. Under physiological conditions, macrophages, which are essential phagocytes, maintain a proinflammatory response and repair damaged tissue. However, these processes are often impaired upon tumorigenesis, in which tumor-associated macrophages (TAMs) protect and support the growth, proliferation, and invasion of tumor cells and promote suppression of antitumor immunity. TAM abundance is closely associated with poor outcome of cancer, with impediment of chemotherapy effectiveness and ultimately a dismal therapy response and inferior overall survival. Thus, cross-talk between cancer cells and TAMs is an important target for immune checkpoint therapies and metabolic interventions, spurring interest in it as a therapeutic vulnerability for both hematological cancers and solid tumors. Furthermore, targeting of this cross-talk has emerged as a promising strategy for cancer treatment with the antibody against CD47 protein, a critical macrophage checkpoint recognized as the "don't eat me" signal, as well as other metabolism-focused strategies. Therapies targeting CD47 constitute an important milestone in the advancement of anticancer research and have had promising effects on not only phagocytosis activation but also innate and adaptive immune system activation, effectively counteracting tumor cells' evasion of therapy as shown in the context of myeloid cancers. Targeting of CD47 signaling is only one of several possibilities to reverse the immunosuppressive and tumor-protective tumor environment with the aim of enhancing the antitumor response. Several preclinical studies identified signaling pathways that regulate the recruitment, polarization, or metabolism of TAMs. In this review, we summarize the current understanding of the role of macrophages in cancer progression and the mechanisms by which they communicate with tumor cells. Additionally, we dissect various therapeutic strategies developed to target macrophage-tumor cell cross-talk, including modulation of macrophage polarization, blockade of signaling pathways, and disruption of physical interactions between leukemia cells and macrophages. Finally, we highlight the challenges associated with tumor hypoxia and acidosis as barriers to effective cancer therapy and discuss opportunities for future research in this field.
    Keywords:  TAMs; cancer progression; cross-talk; hematological malignancies; macrophages; tumor cells
  38. Mol Cancer. 2023 Dec 02. 22(1): 194
      The molecules of Major histocompatibility class I (MHC-I) load peptides and present them on the cell surface, which provided the immune system with the signal to detect and eliminate the infected or cancerous cells. In the context of cancer, owing to the crucial immune-regulatory roles played by MHC-I molecules, the abnormal modulation of MHC-I expression and function could be hijacked by tumor cells to escape the immune surveillance and attack, thereby promoting tumoral progression and impairing the efficacy of cancer immunotherapy. Here we reviewed and discussed the recent studies and discoveries related to the MHC-I molecules and their multidirectional functions in the development of cancer, mainly focusing on the interactions between MHC-I and the multiple participators in the tumor microenvironment and highlighting the significance of targeting MHC-I for optimizing the efficacy of cancer immunotherapy and a deeper understanding of the dynamic nature and functioning mechanism of MHC-I in cancer.
    Keywords:  Antigen presentation; B2M; Cancer immune evasion; Cancer immunotherapy; MHC-I; TME
  39. Front Oncol. 2023 ;13 1270991
      Colorectal cancer (CRC) ranks third in terms of incidence among all kinds of cancer. The main cause of death is metastasis. Recent studies have shown that the gut microbiota could facilitate cancer metastasis by promoting cancer cells proliferation, invasion, dissemination, and survival. Multiple mechanisms have been implicated, such as RNA-mediated targeting effects, activation of tumor signaling cascades, secretion of microbiota-derived functional substances, regulation of mRNA methylation, facilitated immune evasion, increased intravasation of cancer cells, and remodeling of tumor microenvironment (TME). The understanding of CRC metastasis was further deepened by the mechanisms mentioned above. In this review, the mechanisms by which the gut microbiota participates in the process of CRC metastasis were reviewed as followed based on recent studies.
    Keywords:  colorectal cancer; gut microbiota; immune evasion; metastasis; tumor progression
  40. Cell Signal. 2023 Nov 28. pii: S0898-6568(23)00409-6. [Epub ahead of print] 110994
      Primary liver cancer is known for its high incidence and fatality rate. Over the years, therapeutic strategies for primary liver cancer have advanced significantly. Nonetheless, a substantial number of patients have not benefited from these methods, underscoring the pressing need for new and effective treatments for primary liver cancer. Ubiquitination is a critical post-translational modification that enables proteins to fulfill their normal biological functions and maintain their expression stability within cells. Importantly, increasing evidence suggests that the progression of liver cancer cells is often accompanied by disruptions in protein ubiquitination and deubiquitination processes. In this comprehensive review, we have compiled pertinent research about dysregulated ubiquitination in hepatocellular carcinoma (HCC) to broaden our understanding in this field. We elucidate the connections between the ubiquitination proteasome system, deubiquitination, and HCC. Furthermore, we shed light on the role of ubiquitination in cells situated within the tumor microenvironment of HCC including its involvement in mediating the activation of oncogenic pathways, reprogramming metabolic processes, and perturbing normal cellular functions. In conclusion, targeting the dysregulation of ubiquitination in HCC holds promise as a prospective and complementary therapeutic approach to existing treatments.
    Keywords:  Hepatocellular carcinoma; Tumor microenvironment; Ubiquitin-ligating enzymes; Ubiquitination
  41. Front Immunol. 2023 ;14 1297175
      Following the success of cancer immunotherapy using large molecules against immune checkpoint inhibitors, the concept of using small molecules to interfere with intracellular negative regulators of anti-tumor immune responses has emerged in recent years. The main targets for small molecule drugs currently include enzymes of negative feedback loops in signaling pathways of immune cells and proteins that promote immunosuppressive signals within the tumor microenvironment. In the adaptive immune system, negative regulators of T cell receptor signaling (MAP4K1, DGKα/ζ, CBL-B, PTPN2, PTPN22, SHP1), co-receptor signaling (CBL-B) and cytokine signaling (PTPN2) have been preclinically validated as promising targets and initial clinical trials with small molecule inhibitors are underway. To enhance innate anti-tumor immune responses, inhibitory immunomodulation of cGAS/STING has been in the focus, and inhibitors of ENPP1 and TREX1 have reached the clinic. In addition, immunosuppressive signals via adenosine can be counteracted by CD39 and CD73 inhibition, while suppression via intratumoral immunosuppressive prostaglandin E can be targeted by EP2/EP4 antagonists. Here, we present the status of the most promising small molecule drug candidates for cancer immunotherapy, all residing relatively early in development, and the potential of relevant biomarkers.
    Keywords:  T-cell receptor signaling; adenosine; biomarker; cGAS/STING; cancer immunotherapy; immuno-oncology; small molecule inhibitors; tumor microenvironment
  42. Mol Ther Oncolytics. 2023 Dec 19. 31 100740
      Lactic acid is one of the most abundant products of cellular metabolism and has historically been considered a cell-damaging metabolic product. However, as research has deepened, the beneficial effects of lactic acid on tumor cells and the tumor microenvironment have received increasing attention from the oncology community. Lactic acid can not only provide tumor cells with energy but also act as a messenger molecule that promotes tumor growth and progression and protects tumor cells from immune cells and killing by radiation and chemotherapy. Thus, the inhibition of tumor cell lactic acid metabolism has emerged as a novel antitumor treatment strategy that can also effectively enhance the efficacy of conventional antitumor therapies. In this review, we classify the currently available therapies targeting lactic acid metabolism and examine their prospects for clinical application.
    Keywords:  acidic tumor microenvironment; cancer; drug delivery; lactic acid metabolism; targeted therapy
  43. Bioimpacts. 2023 ;13(6): 439-455
      Introduction: Immunotherapy has revolutionized how cancer is treated. Many of these immunotherapies rely on ex vivo expansion of immune cells, classically T cells. Still, several immunological obstacles remain, including tumor impermeability by immune cells and the immunosuppressive nature of the tumor microenvironment (TME). Logistically, high costs of treatment and variable clinical responses have also plagued traditional T cell-based immunotherapies.
    Methods: To review the existing literature on cellular immunotherapy, the PubMed database was searched for publications using variations of the phrases "cancer immunotherapy", "ex vivo expansion", and "adoptive cell therapy". The database was searched for clinical trials related to ex vivo cellular therapies using the same phrases. The National Comprehensive Cancer Network guidelines for cancer treatment were also referenced.
    Results: To circumvent the challenges of traditional T cell-based immunotherapies, researchers have developed newer therapies including tumor infiltrating lymphocyte (TIL), chimeric antigen receptor (CAR), T cell receptor (TCR) modified T cell, and antibody-armed T cell therapies. Additionally, newer immunotherapeutic strategies have used other immune cells, including natural killer (NK) and dendritic cells (DC), to modulate the T cell immune response to cancers. From a prognostic perspective, circulating tumor cells (CTC) have been used to predict cancer morbidity and mortality.
    Conclusion: This review highlights the mechanism and clinical utility of various types of ex vivo cellular therapies in the treatment of cancer. Comparing these therapies or using them in combination may lead to more individualized and less toxic chemotherapeutics.
    Keywords:  Adoptive cell therapy; Cancer immunotherapy; Circulating tumor cells; DC vaccination; Ex vivo expansion; T cell immunotherapy
  44. J Immunother Cancer. 2023 Dec 01. pii: e007447. [Epub ahead of print]11(12):
      BACKGROUND: One reason patients with cancer cannot benefit from immunotherapy is the lack of immune cell infiltration in tumor tissues. Cancer-associated fibroblasts (CAFs) are emerging as central players in immune regulation that shapes tumor microenvironment (TME). Earlier we reported that integrin α5 was enriched in CAFs in colorectal cancer (CRC), however, its role in TME and cancer immunotherapy remains unclear. Here, we aimed to investigate the role for integrin α5 in fibroblasts in modulating antitumor immunity and therapeutic efficacy combined with checkpoint blockade in CRC.METHODS: We analyzed the CRC single-cell RNA sequencing (scRNA-seq) database to define the expression of ITGA5 in CRC tumor stroma. Experimentally, we carried out in vivo mouse tumor xenograft models to confirm the targeting efficacy of combined α5β1 inhibition and anti-Programmed death ligand 1 (PD-L1) blockade and in vitro cell-co-culture assay to investigate the role of α5 in fibroblasts in affecting T-cell activity. Clinically, we analyzed the association between α5 expression and infiltrating T cells and evaluated their correlation with patient survival and immunotherapy prognosis in CRC.
    RESULTS: We revealed that ITGA5 was enriched in FAP-CAFs. Both ITGA5 knockout fibroblasts and therapeutic targeting of α5 improved response to anti-PD-L1 treatment in mouse subcutaneous tumor models. Mechanistically, these treatments led to increased tumor-infiltrating CD8+ T cells. Furthermore, we found that α5 in fibroblasts correlated with extracellular matrix (ECM)-related genes and affected ECM deposition in CRC tumor stroma. Both in vivo analysis and in vitro culture and cell killing experiment showed that ECM proteins and α5 expression in fibroblasts influence T-cell infiltration and activity. Clinically, we confirmed that high α5 expression was associated with fewer CD3+ T and CD8+ T cells, and tissues with low α5 and high CD3+ T levels correlated with better patient survival and immunotherapy response in a CRC cohort with 29 patients.
    CONCLUSIONS: Our study identified a role for integrin α5 in fibroblasts in modulating antitumor immunity by affecting ECM deposition and showed therapeutic efficacy for combined α5β1 inhibition and PD-L1 blockade in CRC.
    Keywords:  Biomarkers, Tumor; CD8-Positive T-Lymphocytes; Immunomodulation; Immunotherapy; Tumor Microenvironment