Anti-tumour Functions Research Articles

Transgelin 2 guards T cell lipid metabolism and antitumour function.

Mounting effective immunity against pathogens and tumours relies on the successful metabolic programming of T cells by extracellular fatty acids1-3. Fatty-acid-binding protein 5 (FABP5) has a key role in this process by coordinating the efficient import and trafficking of lipids that fuel mitochondrial respiration to sustain the bioenergetic requirements of protective CD8+ T cells4,5. However, the mechanisms that govern this immunometabolic axis remain unexplored. Here we report that the cytoskeletal organizer transgelin 2 (TAGLN2) is necessary for optimal fatty acid uptake, mitochondrial respiration and anticancer function in CD8+ T cells. TAGLN2 interacts with FABP5 to facilitate its cell surface localization and function in activated CD8+ T cells. Analyses of ovarian cancer specimens revealed that endoplasmic reticulum (ER) stress responses induced by the tumour microenvironment repress TAGLN2 in infiltrating CD8+ T cells, thereby enforcing their dysfunctional state. Restoring TAGLN2 expression in ER-stressed CD8+ T cells increased their lipid uptake, mitochondrial respiration and cytotoxic capacity. Accordingly, chimeric antigen receptor T cells overexpressing TAGLN2 bypassed the detrimental effects of tumour-induced ER stress and demonstrated therapeutic efficacy in mice with metastatic ovarian cancer. Our study establishes the role of cytoskeletal TAGLN2 in T cell lipid metabolism and highlights the potential to enhance cellular immunotherapy in solid malignancies by preserving the TAGLN2-FABP5 axis.

Immune Checkpoint Inhibitor Therapy for Metastatic Melanoma: What Should We Focus on to Improve the Clinical Outcomes?

Immune checkpoint inhibitors (ICIs) have transformed cancer treatment by enhancing anti-tumour immune responses, demonstrating significant efficacy in various malignancies, including melanoma. However, over 50% of patients experience limited or no response to ICI therapy. Resistance to ICIs is influenced by a complex interplay of tumour intrinsic and extrinsic factors. This review summarizes current ICIs for melanoma and the factors involved in resistance to the treatment. We also discuss emerging evidence that the microbiota can impact ICI treatment outcomes by modulating tumour biology and anti-tumour immune function. Furthermore, microbiota profiles may offer a non-invasive method for predicting ICI response. Therefore, future research into microbiota manipulation could provide cost-effective strategies to enhance ICI efficacy and improve outcomes for melanoma patients.

Immune escape between endoplasmic reticulum stress-related cancer cells and exhausted CD8+T cells leads to neoadjuvant chemotherapy resistance in ovarian cancer

Our study aims to explore the effects of neoadjuvant chemotherapy (NACT) on tumour cells and immune cells in the immune microenvironment of patients with high-grade serous ovarian cancer (HGSOC).Single-cell RNA sequencing data of paired ovarian cancer tissues were analysed before and after NACT in 11 patients with HGSOC. The effect of NACT on two major cell components of the tumour microenvironment, epithelial cells and CD8+T cells, was investigated. The mechanisms of epithelial cell evasion by NACT and immune killing were explored from the perspectives of gene expression, functional characteristics, transcriptional regulation, and cell communication. Key targets for reversing NACT resistance were identified and possible therapeutic strategies proposed.While NACT improved the de novo differentiation of anti-tumour CD8+T cells, enhancing their anti-tumour function, it increased the proportion of cancer cells with high HSP90B1 expression. Thus, the potential reasons for NACT resistance were identified as: 1) high levels of endoplasmic reticulum stress (ERS) characteristics, 2) high expression of the MDK-NCL ligand-receptor pair between them and exhausted CD8+T cells before NACT, and 3) high expression of the NECTIN2-TIGIT immune ligand-receptor pair between them and exhausted CD8+T cells after NACT.Thus, our study reveals the mechanisms underlying NACT resistance in patients with HGSOC from the perspective of the independent and interactive roles of cancer cells and CD8+T cells. We propose therapeutic strategies targeting the ERS marker HSP90B1 and the immune escape marker MDK before or during NACT, while targeting NECTIN2 blockade after NACT. This approach may offer new insights into combination treatments for patients with HGSOC displaying NACT resistance.

HVEM in acute lymphocytic leukemia facilitates tumour immune escape by inhibiting CD8+ T cell function.

Leukaemia remains a major contributor to global mortality, representing a significant health risk for a substantial number of cancer patients. Despite notable advancements in the field, existing treatments frequently exhibit limited efficacy or recurrence. Here, we explored the potential of abolishing HVEM (herpes virus entry mediator, TNFRSF14) expression in tumours as an effective approach to treat acute lymphoblastic leukaemia (ALL) and prevent its recurrence. The clinical correlations between HVEM and leukaemia were revealed by public data analysis. HVEM knockout (KO) murine T cell lymphoblastic leukaemia cell line EL4 were generated using CRISPR-Cas9 technology, and syngeneic subcutaneous tumour models were established to investigate the in vivo function of HVEM. Immunohistochemistry (IHC), RNA-seq and flow cytometry were used to analyse the tumour immune microenvironment (TIME) and tumour draining lymph nodes (dLNs). Immune functions were investigated by depletion of immune subsets in vivo and T cell functional assays in vitro. The HVEM mutant EL4 cell lines were constructed to investigate the functional domain responsible for immune escape. According to public databases, HVEM is highly expressed in patients with ALL and acute myeloid leukemia (AML) and is negatively correlated with patient prognosis. Genetic deletion of HVEM in EL4 cells markedly inhibited tumour progression and prolonged the survival of tumour-bearing mice. Our experiments proved that HVEM exerted its immunosuppressive effect by inhibiting antitumour function of CD8+ T cell through CRD1 domain both in vivo and in vitro. Additionally, we identified a combination therapy capable of completely eradicating ALL tumours, which induces immune memory toward tumour protection. Our study reveals the potential mechanisms by which HVEM facilitates ALL progression, and highlights HVEM as a promising target for clinical applications in relapsed ALL therapy.

Formyl peptide enhances cancer immunotherapy by activating antitumoral neutrophils, and T cells

Neutrophils are heterogeneous and plastic, with the ability to polarize from antitumour to protumour phenotype and modulate tumour microenvironment components. While some advances have been made, the neutrophil-targeting therapy remains underexplored. Activation of formyl peptide receptors (FPRs) by formylated peptides is needed for local control of infection through the recruitment of activated neutrophils while the potential contribution of antitumour activity remains underexplored. Here, we demonstrate that neutrophils can be harnessed to suppress tumour growth through the action of the formyl peptide (FP) on the formyl peptide receptor (FPR). Mechanistically, FP efficiently recruits neutrophils to produce reactive oxygen species production (ROS), resulting in the direct killing of tumours. Antitumour functions disappeared when neutrophils were depleted by anti-Ly6G antibodies. Interestingly, extensive T-cell activation was observed in mouse tumours treated with FP, showing the potential to alter the immune suppressed tumour microenvironment (TME) and further sensitize mice to anti-PD1 therapy. Transcriptomic and flow cytometry analyses revealed the mechanisms of FP-sensitized anti-PD1 therapy, mainly including stimulated neutrophils and an altered immune-suppressed tumour microenvironment. Collectively, these data establish FP as an effective combination partner for sensitizing anti-PD1 therapy by stimulating tumour-infiltrated neutrophils.

CD5 blockade, a novel immune checkpoint inhibitor, enhances T cell anti-tumour immunity and delays tumour growth in mice harbouring poorly immunogenic 4T1 breast tumour homografts.

CD5 is a member of the scavenger receptor cysteine-rich superfamily that is expressed on T cells and a subset of B cells (B1a) cell and can regulate the T cell receptor signaling pathway. Blocking CD5 function may have therapeutic potential in treatment of cancer by enhancing cytotoxic T lymphocyte recognition and ablation of tumour cells. The effect of administering an anti-CD5 antibody to block or reduce CD5 function as an immune checkpoint blockade to enhance T cell anti-tumour activation and function in vivo has not been explored. Here we challenged mice with poorly immunogenic 4T1 breast tumour cells and tested whether treatment with anti-CD5 monoclonal antibodies (MAb) in vivo could enhance non-malignant T cell anti-tumour immunity and reduce tumour growth. Treatment with anti-CD5 MAb resulted in an increased fraction of CD8+ T cells compared to CD4+ T cell in draining lymph nodes and the tumour microenvironment. In addition, it increased activation and effector function of T cells isolated from spleens, draining lymph nodes, and 4T1 tumours. Furthermore, tumour growth was delayed in mice treated with anti-CD5 MAb. These data suggest that use of anti-CD5 MAb as an immune checkpoint blockade can both enhance activation of T cells in response to poorly immunogenic antigens and reduce tumour growth in vivo. Exploration of anti-CD5 therapies in treatment of cancer, alone and in combination with other immune therapeutic drugs, is warranted.

Dendritic cells as orchestrators of anticancer immunity and immunotherapy.

Dendritic cells (DCs) are a heterogeneous group of antigen-presenting innate immune cells that regulate adaptive immunity, including against cancer. Therefore, understanding the precise activities of DCs in tumours and patients with cancer is important. The classification of DC subsets has historically been based on ontogeny; however, single-cell analyses are now additionally revealing a diversity of functional states of DCs in cancer. DCs can promote the activation of potent antitumour T cells and immune responses via numerous mechanisms, although they can also be hijacked by tumour-mediated factors to contribute to immune tolerance and cancer progression. Consequently, DC activities are often key determinants of the efficacy of immunotherapies, including immune-checkpoint inhibitors. Potentiating the antitumour functions of DCs or using them as tools to orchestrate short-term and long-term anticancer immunity has immense but as-yet underexploited therapeutic potential. In this Review, we outline the nature and emerging complexity of DC states as well as their functions in regulating adaptive immunity across different cancer types. We also describe how DCs are required for the success of current immunotherapies and explore the inherent potential of targeting DCs for cancer therapy. We focus on novel insights on DCs derived from patients with different cancers, single-cell studies of DCs and their relevance to therapeutic strategies.

Microbiota and beneficial metabolites in colorectal cancer.

Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related death worldwide. In recent years, the impact of the gut microbiota on the development of CRC has become clear. The gut microbiota is the community of microorganisms living in the gut symbiotic relationship with the host. These microorganisms contribute to the development of CRC through various mechanisms that are not yet fully understood. Increasing scientific evidence suggests that metabolites produced by the gut microbiota may influence CRC development by exerting protective and deleterious effects. This article reviews the metabolites produced by the gut microbiota, which are derived from the intake of complex carbohydrates, proteins, dairy products, and phytochemicals from plant foods and are associated with a reduced risk of CRC. These metabolites include short-chain fatty acids (SCFAs), indole and its derivatives, conjugated linoleic acid (CLA) and polyphenols. Each metabolite, its association with CRC risk, the possible mechanisms by which they exert anti-tumour functions and their relationship with the gut microbiota are described. In addition, other gut microbiota-derived metabolites that are gaining importance for their role as CRC suppressors are included.

Effective γδ T-cell clinical therapies: current limitations and future perspectives for cancer immunotherapy.

γδ T cells are a unique subset of T lymphocytes, exhibiting features of both innate and adaptive immune cells and are involved with cancer immunosurveillance. They present an attractive alternative to conventional T cell-based immunotherapy due, in large part, to their lack of major histocompatibility (MHC) restriction and ability to secrete high levels of cytokines with well-known anti-tumour functions. To date, clinical trials using γδ T cell-based immunotherapy for a range of haematological and solid cancers have yielded limited success compared with in vitro studies. This inability to translate the efficacy of γδ T-cell therapies from preclinical to clinical trials is attributed to a combination of several factors, e.g. γδ T-cell agonists that are commonly used to stimulate populations of these cells have limited cellular uptake yet rely on intracellular mechanisms; administered γδ T cells display low levels of tumour-infiltration; and there is a gap in the understanding of γδ T-cell inhibitory receptors. This review explores the discrepancy between γδ T-cell clinical and preclinical performance and offers viable avenues to overcome these obstacles. Using more direct γδ T-cell agonists, encapsulating these agonists into lipid nanocarriers to improve their pharmacokinetic and pharmacodynamic profiles and the use of combination therapies to overcome checkpoint inhibition and T-cell exhaustion are ways to bridge the gap between preclinical and clinical success. Given the ability to overcome these limitations, the development of a more targeted γδ T-cell agonist-checkpoint blockade combination therapy has the potential for success in clinical trials which has to date remained elusive.

How chemokines organize the tumour microenvironment.

For our immune system to contain or eliminate malignant solid tumours, both myeloid and lymphoid haematopoietic cells must not only extravasate from the bloodstream into the tumour tissue but also further migrate to various specialized niches of the tumour microenvironment to functionally interact with each other, with non-haematopoietic stromal cells and, ultimately, with cancer cells. These interactions regulate local immune cell survival, proliferative expansion, differentiation and their execution of pro-tumour or antitumour effector functions, which collectively determine the outcome of spontaneous or therapeutically induced antitumour immune responses. None of these interactions occur randomly but are orchestrated and critically depend on migratory guidance cues provided by chemokines, a large family of chemotactic cytokines, and their receptors. Understanding the functional organization of the tumour immune microenvironment inevitably requires knowledge of the multifaceted roles of chemokines in the recruitment and positioning of its cellular constituents. Gaining such knowledge will not only generate new insights into the mechanisms underlying antitumour immunity or immune tolerance but also inform the development of biomarkers (or 'biopatterns') based on spatial tumour tissue analyses, as well as novel strategies to therapeutically engineer immune responses in patients with cancer. Here we will discuss recent observations on the role of chemokines in the tumour microenvironment in the context of our knowledge of their physiological functions in development, homeostasis and antimicrobial responses.

The β1-adrenergic receptor links sympathetic nerves to T cell exhaustion.

CD8+ T cells are essential components of the immune response against viral infections and tumours, and are capable of eliminating infected and cancerous cells. However, when the antigen cannot be cleared, T cells enter a state known as exhaustion1. Although it is clear that chronic antigen contributes to CD8+ T cell exhaustion, less is known about how stress responses in tissues regulate T cell function. Here we show a new link between the stress-associated catecholamines and the progression of T cell exhaustion through the β1-adrenergic receptor ADRB1. We identify that exhausted CD8+ T cells increase ADRB1 expression and that exposure of ADRB1+ T cells to catecholamines suppresses their cytokine production and proliferation. Exhausted CD8+ T cells cluster around sympathetic nerves in an ADRB1-dependent manner. Ablation of β1-adrenergic signalling limits the progression of T cells towards the exhausted state in chronic infection and improves effector functions when combined with immune checkpoint blockade (ICB) in melanoma. In a pancreatic cancer model resistant to ICB, β-blockers and ICB synergize to boost CD8+ T cell responses and induce the development of tissue-resident memory-like T cells. Malignant disease is associated with increased catecholamine levels in patients2,3, and our results establish a connection between the sympathetic stress response, tissue innervation and T cell exhaustion. Here,we uncover a new mechanism by which blocking β-adrenergic signalling in CD8+ T cells rejuvenates anti-tumour functions.

A multifunctional nano-hydroxyapatite/MXene scaffold for the photothermal/dynamic treatment of bone tumours and simultaneous tissue regeneration

After resection of bone tumour, the risk of cancer recurrence and numerous bone defects continues to threaten the health of patients. To overcome the challenge, we developed a novel multifunctional scaffold material consisting mainly of nano-hydroxyapatite particles (n-HA), MXene nanosheets and g-C3N4 to prevent tumour recurrence and promote bone formation. N-HA has the potential to restrict the growth of osteosarcoma cells, and the combination of MXene and g-C3N4 enables the scaffolds to produce photodynamic and photothermal effects simultaneously under near infrared (NIR) irradiation. Surprisingly, n-HA can further enhance the synergistic anti-tumour function of photodynamic and photothermal, and the scaffolds can eradicate osteosarcoma cells in only 10 min at a mild temperature of 45 ℃. Moreover, the scaffold exhibit exceptional cytocompatibility and possesses the capacity to induce osteogenic differentiation of bone marrow mesenchymal stem cells. Therefore, this multifunctional scaffold can not only inhibits the proliferation of bone tumour cells and rapidly eradicate bone tumour through NIR irradiation, but also enhances osteogenic activity. This promising measure can be used to treat tissue damage after bone tumour resection.

Plasma lipid levels are associated with the CD8+ T-cell infiltration and prognosis of patients with pancreatic cancer.

Recently, researchers have found that the tumour microenvironment plays an important role in tumours. We aimed to investigate the effects of plasma lipids on the prognosis of patients with pancreatic cancer and the infiltration of CD8+ T lymphocytes in tumour tissue. We enrolled patients with pancreatic ductal adenocarcinoma (PDAC) who underwent pancreatic surgery between 2012 and 2021. Clinical pathological data were recorded; total cholesterol (TC) and triglyceride (TG) levels were measured; and tissue samples were collected. A tissue microarray was generated using collected tissue samples, and CD8 staining was performed to determine immunoreactive scores (IRSs). The correlations of TC and TG levels with clinicopathological characteristics and prognosis were analysed. Finally, the correlations of TC and TG levels with CD8+ T-cell infiltration were analysed. A total of 90 eligible PDAC patients were included. TC levels were significantly correlated with tumour grade and lymph node metastasis, and TG levels were significantly correlated with perineural invasion. The Kaplan-Meier survival analysis results indicated that the prognosis in the high TC group was significantly worse than that in the low TC group, and the prognosis in the high TG group was significantly worse than that in the low TG group. Cox multivariate analysis indicated that TC was an independent indicator of poor prognosis of pancreatic cancer patients after surgery. Spearman correlation analysis indicated that there were significant negative correlations between CD8 IRS and TC and between CD8 IRS and TG. TC and TG levels are significantly related to the prognosis of pancreatic cancer patients. They may be associated with tumour progression to higher grades, lymph node metastasis and/or nerve invasion. More importantly, TC and TG may reduce CD8+ T lymphocyte infiltration into pancreatic cancer tissue, affecting antitumour immune functions and immunotherapy efficacy.

BMP9-induced vascular normalisation improves the efficacy of immunotherapy against hepatitis B virus-associated hepatocellular carcinoma.

In the past decade, the field of tumour immunotherapy has made a great progress. However, the efficacy of immune checkpoint blocking (ICB) in the treatment of hepatocellular carcinoma (HCC) remains limited. Cytotoxic lymphocyte trafficking into tumours is critical for the success of ICB. Therefore, additional strategies that increase cytotoxic lymphocyte trafficking into tumours are urgently needed to improve patient immune responses. Paired adjacent tissue and cancerous lesions with HBV-associated HCC were subjected to RNA-seq analysis. Bone morphogenetic protein (BMP9), which reflects vessel normalisation, was identified through Cytoscape software, clinical specimens and Gene Expression Omnibus (GEO) datasets for HCC. The functional effects and mechanism of BMP9 on the tumour vasculature were evaluated in cells and animals. An ultrasound-targeted microbubble destruction (UTMD)-mediated BMP9 delivery strategy was used to normalise the vasculature and evaluate therapeutic efficacy mediated by cytotoxic lymphocytes (NK cells) in combination with a PD-L1 antibody in human cancer xenografts of immune-deficient mice. We discovered that hepatitis B virus (HBV) infection-induced downregulation of BMP9 expression correlated with a poor prognosis and pathological vascular abnormalities in patients with HCC. BMP9 overexpression in HBV-infected HCC cells promoted intra-tumoural cytotoxic lymphocyte infiltration via vascular normalisation by inhibiting the Rho-ROCK-myosin light chain (MLC) signalling cascade, resulting in enhanced efficacy of immunotherapy. Furthermore, UTMD-mediated BMP9 delivery restored the anti-tumour function of cytotoxic lymphocytes (NK cells) and showed therapeutic efficacy in combination with a PD-L1 antibody in human cancer xenografts of immune-deficient mice. HBV-induced BMP9 downregulation causes vascular abnormalities that inhibit intra-tumoural cytotoxic lymphocyte infiltration, providing a rationale for developing and combining immunotherapy with BMP9-based therapy to treat HBV-associated HCC.

Exploring the effect of polyamines on NK cell function in colorectal cancer process based on glycolysis

Natural killer (NK) cells are lymphocytes with important anti-tumour functions. Cellular metabolism is dynamically regulated in NK cells and strongly influences their responses. Myc is a key regulator of immune cell activity and function, but little is known about how Myc controls NK cell activation and function. In this study, we found that c-Myc is involved in the regulation of NK cell immune activity. In the development of colon cancer, the energy generation disorder of tumor cells promotes the plunder of polyamines of NK cells by tumor cells, resulting in the inhibition of NK cell c-Myc. After inhibition of c-Myc, glycolysis of NK cells was impaired, resulting in decreased killing activity. There are three main types of polyamines: putrescine (Put), spermidine (Spd) and spermine (Spm). We found that the NK cells could reverse the inhibition state of c-Myc and glycolysis energy supply disorder and recover the killing activity of NK cells after giving certain spermidine. These results suggest that polyamine content and glycolysis supply under the regulation of c-Myc play a crucial role in the immune activity of NK cells.

Cytokine concentration in peripheral blood of patients with colorectal cancer.

The role of tumour secretory cytokines and peripheral circulatory cytokines in tumour progression has received increasing attention; however, the role of tumour-related inflammatory cytokines in colorectal cancer (CRC) remains unclear. In this study, the concentrations of various cytokines in the peripheral blood of healthy controls and patients with CRC at different stages were compared. Peripheral blood samples from 4 healthy participants and 22 colorectal cancer patients were examined. Luminex beads were used to evaluate concentration levels of 40 inflammatory cytokines in peripheral blood samples. In peripheral blood, compared with healthy controls and early stage (I + II) CRC patients, advanced CRC (III + IV) patients had increased concentrations of mononuclear/macrophage chemotactic-related proteins (CCL7, CCL8, CCL15, CCL2, and MIF), M2 polarization-related factors (IL-1β, IL-4), neutrophil chemotactic and N2 polarization-related cytokines (CXCL2, CXCL5, CXCL6, IL-8), dendritic cells (DCs) chemotactic-related proteins (CCL19, CCL20, and CCL21), Natural killer (NK) cell related cytokines (CXCL9, CXCL10), Th2 cell-related cytokines (CCL1, CCL11, CCL26), CXCL12, IL-2, CCL25, and CCL27, and decreased IFN-γ and CX3CL1 concentrations. The differential upregulation of cytokines in peripheral blood was mainly concentrated in CRC patients with distant metastasis and was related to the size of the primary tumour; however, there was no significant correlation between cytokine levels in peripheral blood and the propensity and mechanism of lymph node metastasis. Different types of immune cells may share the same chemokine receptors and can co-localise in response to the same chemokines and exert synergistic pro-tumour or anti-tumour functions in the tumour microenvironment. Chemokines and cytokines affect tumour metastasis and prognosis and may be potential targets for treatment.

Prevalence of tumour-infiltrating CD103+ cells identifies therapeutic-sensitive prostate cancer with poor clinical outcome.

The clinical significance and immune correlation of CD103+ cells in prostate cancer (PCa) remain explored. In total, 1080 patients with PCa underwent radical prostatectomy from three cohorts were enrolled for retrospective analysis. Tumour microarrays were constructed and fresh tumour samples were analysed by flow cytometry. High CD103+ cell infiltration correlated with reduced biochemical recurrence (BCR)-free survival in PCa. Adjuvant hormone therapy (HT) prolonged the BCR-free survival for high-risk node-negative diseases with CD103+ cell abundance. CD103+ cell infiltration correlated with less cytotoxic expression and increased infiltration of CD8+ and CD4+ T cells, M1 macrophages and mast cells in PCa. Intratumoral CD8+ T cell was the predominant source of CD103, and the CD103+ subset of CD8+ T cells was featured with high IL-10, PD-1 and CTLA-4 expression. Tumour-infiltrating CD103+ CD8+ T cells exerted anti-tumour function when treated with HT ex vivo. CD103+ cell infiltration predicted BCR-free survival and response to adjuvant HT in PCa. CD103+ cell infiltration correlated with an enriched but immune-evasive immune landscape. The study supported a model that CD103 expression conferred negative prognostic impact and immunosuppressive function to tumour-infiltrating CD8+ T cells, while the CD103+ CD8+ T cells exhibited a powerful anti-tumour immunity with response to HT.

Single-cell sequencing of PIT1-positive pituitary adenoma highlights the pro-tumour microenvironment mediated by IFN-γ-induced tumour-associated fibroblasts remodelling.

PIT1-positive pituitary adenoma (PIT1-PA) is one of the most important lineages of pituitary adenoma (PA), which causes systematic endocrine disorders and a worse prognosis. Tumour-associated fibroblast (TAF) is a crucial stroma cell type in the tumour microenvironment (TME). However, cellular and functional heterogeneity of TAF and immune cells in PIT1-PA have not been fully investigated. By single-cell RNA sequencing of four PIT1-PAs and further analyses, we characterised the molecular and functional profiles of 28 different cell subtypes. PA stem cells in PIT1/SF1-positve PA were in a hybrid epithelial/mesenchymal state, and differentiated along the PIT1- and SF- dependent branches. C1Q was overwhelmingly expressed in tumour-associated macrophages, indicating its pro-tumoral functionality. PIT1-PA progression was characterised by lower cell-cell communication strength and higher cell adhesion-associated signals, indicating the immunosuppressive but pro-invasive microenvironment. IFN-γ signal repressed functional remodelling of myofibroblastic TAF (mTAF) towards inflammatory TAF/antigen-presenting TAF. IFN-γ inhibited mTAF phenotypes and N-cadherin expression through STAT3 signal axis. CDH2 knockdown in TAFs abrogated their pro-tumour function in PAs. Our study builds up a cellular landscape of PIT1-PA TME and highlights anti-tumour function of IFN-γ mediated TAF remodelling, which benefits clinical treatments and drug development.

Dendritic cells direct circadian anti-tumour immune responses

The process of cancer immunosurveillance is a mechanism of tumour suppression that can protect the host from cancer development throughout its lifetime1,2. However, it is unknown whether the effectiveness of cancer immunosurveillance fluctuates over a single day. Here we demonstrate that the initial time of day of tumour engraftment dictates the ensuing tumour size across mouse cancer models. Using immunodeficient mice as well as mice lacking lineage-specific circadian functions, we show that dendritic cells (DCs) and CD8+ T cells exert circadian anti-tumour functions that control melanoma volume. Specifically, we find that rhythmic trafficking of DCs to the tumour draining lymph node governs a circadian response of tumour-antigen-specific CD8+ T cells that is dependent on the circadian expression of the co-stimulatory molecule CD80. As a consequence, cancer immunotherapy is more effective when synchronized with DC functions, shows circadian outcomes in mice and suggests similar effects in humans. These data demonstrate that the circadian rhythms of anti-tumour immune components are not only critical for controlling tumour size but can also be of therapeutic relevance.

The Interface of Tumour-Associated Macrophages with Dying Cancer Cells in Immuno-Oncology.

Tumour-associated macrophages (TAMs) are essential players in the tumour microenvironment (TME) and modulate various pro-tumorigenic functions such as immunosuppression, angiogenesis, cancer cell proliferation, invasion and metastasis, along with resistance to anti-cancer therapies. TAMs also mediate important anti-tumour functions and can clear dying cancer cells via efferocytosis. Thus, not surprisingly, TAMs exhibit heterogeneous activities and functional plasticity depending on the type and context of cancer cell death that they are faced with. This ultimately governs both the pro-tumorigenic and anti-tumorigenic activity of TAMs, making the interface between TAMs and dying cancer cells very important for modulating cancer growth and the efficacy of chemo-radiotherapy or immunotherapy. In this review, we discuss the interface of TAMs with cancer cell death from the perspectives of cell death pathways, TME-driven variations, TAM heterogeneity and cell-death-inducing anti-cancer therapies. We believe that a better understanding of how dying cancer cells influence TAMs can lead to improved combinatorial anti-cancer therapies, especially in combination with TAM-targeting immunotherapies.