Cell Antitumour Immunity Research Articles

Transcriptional signature of CD56bright NK cells predicts favourable prognosis in bladder cancer

Human natural killer (NK) cells can be sub-divided into two functional subsets but the clinical significance of these CD56bright and CD56dim NK cells in anti-tumour immunity remains largely unexplored. We determined the relative abundances of gene signatures for CD56bright and CD56dim NK cells along with 3 stromal and 18 other immune cell types in the patient tumour transcriptomes from the cancer genome atlas bladder cancer dataset (TCGA-BLCA). Using this computational approach, CD56bright NK cells were predicted to be the more abundant tumour-infiltrating NK subset which was also associated with improved patient prognosis. A similar favorable survival trend was projected using gene signatures for mature myeloid dendritic cells (mDC) and CD8+ effector memory T cells (TEM) and unveiled a potential CD56bright NK-mDC-CD8+T cell crosstalk in the BLCA tumour microenvironment. Expression of transcripts encoding the activating NK cell receptors, NKG2D, NKp44, CD2, and CD160, showed positive survival trends in combination with CD56bright NK cell infiltration. Transcription factors including HOBIT, IRF3, and STAT2 were also correlated with CD56bright NK cell abundance. Additionally, a HOBIT-dependent tissue-residency program correlated with the CD56bright NK and CD8+ TEM cell signatures was found to be associated with favourable BLCA patient survival. Overall, our study highlights the significance of CD56bright NK cells in BLCA patient prognosis. Our findings facilitate a better understanding of the NK cell anti-tumour responses that may ultimately lead to the development of promising NK and T cell-based therapies for BLCA.

Modi-2 a vaccine stimulating CD4 responses to homocitrullinated self epitopes as therapy for solid cancers

Stresses within the tumour microenvironment can mediate post-translational modifications of self-proteins. Homocitrullination is the conversion of lysine to homocitrulline which generates neoepitopes and bypasses self-tolerance. In this study a vaccine targeting homocitrullinated antigens was assessed for stimulation of anti-tumour immunity. Peptides that bind HLA are often hydrophobic which can complicate large scale manufacture and solubility. Here we demonstrate the self-assembling nanoparticle technology (SNAPvaxTM) to co-deliver four homocitrullinated peptides and adjuvant in nanoparticles of a precise size and composition as a vaccine (“Modi-2”) that is optimized for manufacturing ease and T cell induction. Strong T cell responses and anti-tumour immunity in mouse tumour models was stimulated against against B16 melanoma (p = 0.0113), CT26 colorectal cancer (p < 0.0001) and 4T1 breast cancer (p = 0.0090). We demonstrate that human lung, colorectal, breast and prostate tumours express the Modi-2 target antigens and propose the Modi-2 vaccine has potential for translation into clinic in several cancer indications.

Fractionated photoimmunotherapy stimulates an anti-tumour immune response: an integrated mathematical and in vitro study

BackgroundAdvanced epithelial ovarian cancer (EOC) has high recurrence rates due to disseminated initial disease presentation. Cytotoxic phototherapies, such as photodynamic therapy (PDT) and photoimmunotherapy (PIT, cell-targeted PDT), have the potential to treat disseminated malignancies due to safe intraperitoneal delivery.MethodsWe use in vitro measurements of EOC tumour cell and T cell responses to chemotherapy, PDT, and epidermal growth factor receptor targeted PIT as inputs to a mathematical model of non-linear tumour and immune effector cell interaction. The model outputs were used to calculate how photoimmunotherapy could be utilised for tumour control.ResultsIn vitro measurements of PIT dose responses revealed that although low light doses (<10 J/cm2) lead to limited tumour cell killing they also increased proliferation of anti-tumour immune effector cells. Model simulations demonstrated that breaking up a larger light dose into multiple lower dose fractions (vis-à-vis fractionated radiotherapy) could be utilised to effect tumour control via stimulation of an anti-tumour immune response.ConclusionsThere is promise for applying fractionated PIT in the setting of EOC. However, recommending specific fractionated PIT dosimetry and timing will require appropriate model calibration on tumour-immune interaction data in human patients and subsequent validation of model predictions in prospective clinical trials.

The stress response regulator HSF1 modulates natural killer cell anti-tumour immunity.

Diverse cellular insults converge on activation of the heat shock factor 1 (HSF1), which regulates the proteotoxic stress response to maintain protein homoeostasis. HSF1 regulates numerous gene programmes beyond the proteotoxic stress response in a cell-type- and context-specific manner to promote malignancy. However, the role(s) of HSF1 in immune populations of the tumour microenvironment remain elusive. Here, we leverage an in vivo model of HSF1 activation and single-cell transcriptomic tumour profiling to show that augmented HSF1 activity in natural killer (NK) cells impairs cytotoxicity, cytokine production and subsequent anti-tumour immunity. Mechanistically, HSF1 directly binds and regulates the expression of key mediators of NK cell effector function. This work demonstrates that HSF1 regulates the immune response under the stress conditions of the tumour microenvironment. These findings have important implications for enhancing the efficacy of adoptive NK cell therapies and for designing combinatorial strategies including modulators of NK cell-mediated tumour killing.

Cancer cell metabolism and antitumour immunity.

Accumulating evidence suggests that metabolic rewiring in malignant cells supports tumour progression not only by providing cancer cells with increased proliferative potential and an improved ability to adapt to adverse microenvironmental conditions but also by favouring the evasion of natural and therapy-driven antitumour immune responses. Here, we review cancer cell-intrinsic and cancercell-extrinsic mechanisms through which alterations of metabolism in malignant cells interfere with innate and adaptive immune functions in support of accelerated disease progression. Further, we discuss the potential of targeting such alterations to enhance anticancer immunity for therapeutic purposes.

Estrogen receptor regulation of the Immune Microenvironment in Breast Cancer

Breast cancer (BCa) is the most common cancer in women and the estrogen receptor (ER)+ subtype is increasing in incidence. There are numerous therapy options available for patients that target the ER, however issues such as innate and acquired treatment resistance, and treatment related side effects justify research into alternative therapeutic options for these patients. Patients of many solid tumour types have benefitted from immunotherapy, however response rates have been generally low in ER+ BCa. We summarise the recent work assessing CDK4/6 inhibitors for ER+ BCa and how they have been shown to prime anti-tumour immune cells and achieve impressive results in preclinical models. A great example of how the immune system might be activated against ER+ BCa. We review the role of estrogen signalling in immune cells, and explore recent data highlighting the hormonal regulation of the immune microenvironment of normal breast, BCa and immune disorders. As recent data has indicated that macrophages are particularly susceptible to estrogen signalling, we highlight macrophage phagocytosis as a key potential target for priming the tumour immune microenvironment. We challenge the generally accepted paradigm that ER+ BCa are "immune-cold" - advocating instead for research into therapies that could be used in combination with targeted therapies and/or immune checkpoint blockade to achieve durable antitumour responses in ER+ BCa.

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.

Tumour-reactive plasma cells in antitumour immunity: current insights and future prospects.

Tumour-reactive plasma cells (TRPCs) have been reported to be positively associated with the long-term survival of patients with various cancers. However, unlike tumour-specific antigen (TSA)-induced T cells which have precise effects against tumours, plasma cells require TSA to obtain specific responses. Therefore, the search for a TSA suitable for B-cell recognition is urgent. In this review, we discuss the functions of tumour-reactive plasma cells. Further, this review also explores the concept of screening for neoantigen-reactive plasma cells, drawing inspiration from T-cell screening methods. While challenges exist, such as epitope prediction and efficient screening, the development of novel techniques may lead to the discovery of highly specific plasma cells for adoptive cell therapy. In conclusion, tumour-reactive plasma cells are emerging as powerful players in cancer immunotherapy. Their ability to produce antibodies against a variety of antigens, especially neoantigens, opens new avenues for personalised treatments. Overcoming challenges in epitope prediction and screening will be crucial in harnessing the full potential of these plasma cells for the benefit of cancer patients.

The oesophageal adenocarcinoma tumour immune microenvironment dictates outcomes with different modalities of neoadjuvant therapy - results from the AGITG DOCTOR trial and the cancer evolution biobank.

A plateau in treatment effect can be seen for the current 'one-size-fits-all' approach to oesophageal adenocarcinoma (OAC) management using neoadjuvant chemoradiotherapy (nCRT) or chemotherapy (nCT). In OAC, the tumour microenvironment (TME) is largely immunosuppressed, however a subgroup of patients with an immune-inflamed TME exist and show improved outcomes. We aimed to understand the overall immune-based mechanisms underlying treatment responses and patient outcomes in OAC, and in relation to neoadjuvant therapy modality. This study included 107 patients; 68 patients were enrolled in the Australian Gastro-Intestinal Trials Group sponsored DOCTOR Trial, and 38 patients were included from the Cancer Evolution Biobank. Matched pre-treatment and post-treatment tumour biopsies were used to perform multi-modality analysis of the OAC TME including NanoString mRNA expression analysis, multiplex and single colour immunohistochemistry (IHC), and peripheral blood mononuclear cell analysis of tumour-antigen specific T cell responses. Patients with the best clinicopathological outcomes and survival had an immune-inflamed TME enriched with anti-tumour immune cells and pathways. Those with the worst survival showed a myeloid T regulatory cell enriched TME, with decreased CD8+ cell infiltration and increased pro-tumour immune cells. Multiplex IHC analysis identified that high intra-tumoural infiltration of CD8+ cells, and low infiltration with CD163+ cells was associated with improved survival. High tumour core CD8+ T cell infiltration, and a low tumour margin infiltration of CD163+ cells was also associated with improved survival. nCRT showed improved survival compared with nCT for patients with low CD8+, or high CD163+ cell infiltration. Poly-functional T cell responses were seen with tumour-antigen specific T cells. Overall, our study supports the development of personalised therapeutic approaches based on the immune microenvironment in OAC. Patients with an immune-inflamed TME show favourable outcomes regardless of treatment modality. However, in those with an immunosuppressed TME with CD163+ cell infiltration, treatment with nCRT can improve outcomes. Our findings support previous studies into the TME of OAC and with more research, immune based biomarker selection of treatment modality may lead in improved outcomes in this deadly disease.

B-cell-specific checkpoint molecules that regulate anti-tumour immunity.

The role of B cells in anti-tumour immunity is still debated and, accordingly, immunotherapies have focused on targeting T and natural killer cells to inhibit tumour growth1,2. Here, using high-throughput flow cytometry as well as bulk and single-cell RNA-sequencing and B-cell-receptor-sequencing analysis of B cells temporally during B16F10 melanoma growth, we identified a subset of B cells that expands specifically in the draining lymph node over time in tumour-bearing mice. The expanding B cell subset expresses the cell surface molecule T cell immunoglobulin and mucin domain 1 (TIM-1, encoded by Havcr1) and a unique transcriptional signature, including multiple co-inhibitory molecules such as PD-1, TIM-3, TIGIT and LAG-3. Although conditional deletion of these co-inhibitory molecules on B cells had little or no effect on tumour burden, selective deletion of Havcr1 in B cells both substantially inhibited tumour growth and enhanced effector T cell responses. Loss of TIM-1 enhanced the type 1 interferon response in B cells, which augmented B cell activation and increased antigen presentation and co-stimulation, resulting in increased expansion of tumour-specific effector T cells. Our results demonstrate that manipulation of TIM-1-expressing B cells enables engagement of the second arm of adaptive immunity to promote anti-tumour immunity and inhibit tumour growth.

Towards a better understanding of human iNKT cell subpopulations for improved clinical outcomes.

Invariant natural killer T (iNKT) cells are a unique T lymphocyte population expressing semi-invariant T cell receptors (TCRs) that recognise lipid antigens presented by CD1d. iNKT cells exhibit potent anti-tumour activity through direct killing mechanisms and indirectly through triggering the activation of other anti-tumour immune cells. Because of their ability to induce potent anti-tumour responses, particularly when activated by the strong iNKT agonist αGalCer, they have been the subject of intense research to harness iNKT cell-targeted immunotherapies for cancer treatment. However, despite potent anti-tumour efficacy in pre-clinical models, the translation of iNKT cell immunotherapy into human cancer patients has been less successful. This review provides an overview of iNKT cell biology and why they are of interest within the context of cancer immunology. We focus on the iNKT anti-tumour response, the seminal studies that first reported iNKT cytotoxicity, their anti-tumour mechanisms, and the various described subsets within the iNKT cell repertoire. Finally, we discuss several barriers to the successful utilisation of iNKT cells in human cancer immunotherapy, what is required for a better understanding of human iNKT cells, and the future perspectives facilitating their exploitation for improved clinical outcomes.

Abstract 1315: NETs act as immunosuppressive agents within lymph nodes during cancer

Abstract Metastasis is responsible for 90% of all cancer-related deaths, making it the most significant challenge in cancer treatment for clinicians worldwide. Metastasis is thought to occur in a stepwise process, in which local lymph nodes (LNs) are first colonized by tumour cells before proceeding to distal organs. However, the mechanism by which LN metastasis facilitates distal metastasis is poorly understood. LNs undergo environmental changes to accommodate tumour cell growth within, notably by shifting the environment towards immunosuppression to shut down anti-tumour immune cells. This immunosuppressive environment is critical for the establishment of LN metastases, as cytotoxic CD8 T cells will otherwise neutralize incoming circulating tumour cells. Neutrophils are among the first cells recruited to tumour-draining LNs to mediate the environmental shift, and yet their method of action has not been fully elucidated. They have recently been found to secrete NETs within LNs during cancer, which are pro-inflammatory web-like formations of DNA decorated with antimicrobial peptides. While NETs have been shown to exert pro-tumour effects in the tumour microenvironment and to facilitate metastasis as a whole, their role in LNs has never been explored. Using a NETs deficient mouse model (PAD4-/-), we report that NETs deposition within the tumour-draining LNs of mice upregulates the Treg population while simultaneously downregulating anti-tumour CD8 T cell proliferation and activation. Following these findings, we performed an in vitro suppression assay and found that NETs-educated Tregs hinder the expansion of CD8 T cells more than non-NETs-educated Tregs. Finally, through an induced metastasis mouse model, we have observed that tumour-draining LN resection as well as the absence of NETs protects against the development of distal metastasis, and decreases body-wide inflammation as seen by a lowered Neutrophil-to-Lymphocyte ratio in the circulation. Taken together, these findings highlight the role of NETs deposition in LNs as a key player in disease progression and bring forward a potential target for anti-metastatic drug development. Citation Format: Ariane Brassard, Xin Su, Iqraa Dhoparee-Doomah, Sabrina Leo, Lixuan Feng, France Bourdeau, Betty Giannias, Corissa Larson, Qian Qiu, Jonathan Spicer, Lorenzo Ferri, Jonathan Cools-Lartigue. NETs act as immunosuppressive agents within lymph nodes during cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1315.

Immune checkpoint inhibition: a future guided by radiology.

The limitation of the function of antitumour immune cells is a common hallmark of cancers that enables their survival. As such, the potential of immune checkpoint inhibition (ICI) acts as a paradigm shift in the treatment of a range of cancers but has not yet been fully capitalised. Combining minimally and non-invasive locoregional therapies offered by radiologists with ICI is now an active field of research with the aim of furthering therapeutic capabilities in medical oncology. In parallel to this impending advancement, the "imaging toolbox" available to radiologists is also growing, enabling more refined tumour characterisation as well as greater accuracy in evaluating responses to therapy. Options range from metabolite labelling to cellular localisation to immune checkpoint screening. It is foreseeable that these novel imaging techniques will be integrated into personalised treatment algorithms. This growth in the field must include updating the current standardised imaging criteria to ensure they are fit for purpose. Such criteria is crucial to both appropriately guide clinical decision-making regarding next steps of treatment, but also provide reliable prognosis. Quantitative approaches to these novel imaging techniques are also already being investigated to further optimise personalised therapeutic decision-making. The therapeutic potential of specific ICIs and locoregional therapies could be determined before administration thus limiting unnecessary side-effects whilst maintaining efficacy. Several radiological aspects of oncological care are advancing simultaneously. Therefore, it is essential that each development is assessed for clinical use and optimised to ensure the best treatment decisions are being offered to the patient. In this review, we discuss state of the art advances in novel functional imaging techniques in the field of immuno-oncology both pre-clinically and clinically.

Exosomal microRNAs in cancer: Potential biomarkers and immunotherapeutic targets for immune checkpoint molecules.

Exosomes are small extracellular vesicles with a lipid bilayer structure secreted from different cell types which can be found in various body fluids including blood, pleural fluid, saliva and urine. They carry different biomolecules including proteins, metabolites, and amino acids such as microRNAs which are small non-coding RNAs that regulate gene expression and promote cell-to-cell communication. One main function of the exosomal miRNAs (exomiRs) is their role in cancer pathogenesis. Alternation in exomiRs expression could indicate disease progression and can regulate cancer growth and facilitate drug response/resistance. It can also influence the tumour microenvironment by controlling important signaling that regulating immune checkpoint molecules leading to activation of T cell anti-tumour immunity. Therefore, they can be used as potential novel cancer biomarkers and innovative immunotherapeutic agents. This review highlights the use of exomiRs as potential reliable biomarkers for cancer diagnosis, treatment response and metastasis. Finally, discuses their potential as immunotherapeutic agents to regulate immune checkpoint molecules and promote T cell anti-tumour immunity.

The emerging roles of γδ T cells in cancer immunotherapy.

Current cancer immunotherapies are primarily predicated on αβ T cells, with a stringent dependence on MHC-mediated presentation of tumour-enriched peptides or unique neoantigens that can limit their efficacy and applicability in various contexts. After two decades of preclinical research and preliminary clinical studies involving very small numbers of patients, γδ T cells are now being explored as a viable and promising approach for cancer immunotherapy. The unique features of γδ T cells, including their tissue tropisms, antitumour activity that is independent of neoantigen burden and conventional MHC-dependent antigen presentation, and combination of typicalproperties of T cells and natural killer cells, make them very appealing effectors in multiple cancer settings. Herein, we review the main functions of γδ T cells in antitumour immunity, focusing on human γδ T cell subsets, with a particular emphasis on the differences between Vδ1+ and Vδ2+ γδ T cells, to discuss their prognostic value in patients with cancer and the key therapeutic strategies that are being developed in an attempt to improve the outcomes of these patients.

SETDB1: A perspective into immune cell function and cancer immunotherapy.

Oncogene SET Domain Bifurcated 1 (SETDB1)/ESET, an H3K9 methyltransferase, was originally discovered over two decades ago; however, its function in the immune response was not first reported until 2011. SETDB1 immune functions include B cell maturation, T cell activity regulation, and immune escape in cancer cells. In B lymphocytes, SETDB1 mediates the transition from pro-B to pre-B cells and represses endogenous retroviruses (ERV) to encourage B cell lineage differentiation and maturation. SETDB1 alters T cell function by methylating IL-2 and IL-17 promoters and mediating T cell lineage commitment and development. In addition, SETDB1 plays a critical role in ERV silencing within a variety of immune cells, which can indirectly weaken the immune response. Although SETDB1 is critical for normal immune cell function, overexpression in cancer cells negatively impacts immune cell fights against cancer through decreased tumour immunogenicity. Within cancer cells, SETDB1 overexpression represses production and infiltration of antitumour immune cells, mediates immune escape through TE and ERV silencing, represses the type I interferon pathway, and interferes in immune checkpoint blockade (ICB) outcomes by regulation of PD-L1 expression and IFN signalling. In this review, we further discuss the immunological mechanisms of SETDB1 in normal and cancerous cells and its implications in cancer immunotherapy.

STAT1 is regulated by TRIM24 and promotes immunosuppression in head and neck squamous carcinoma cells, but enhances T cell antitumour immunity in the tumour microenvironment

BackgroundHead and neck squamous cell carcinoma (HNSCC) is a significant problem and is frequently resistant to current treatments. STAT1 is important in anti-tumour immune responses against HNSCC. However, the role of STAT1 expression by tumour cells and its regulation during HNSCC is unclear.MethodsWe determined the effects of STAT1 inhibition on tumour development and immunity in CAL27 and UMSCC22A HNSCC cell lines in vitro and in a HNSCC carcinogen-induced model in vivo.ResultsSTAT1 siRNA knockdown in human HNSCC cells impaired their proliferation and expression of the immunosuppressive marker PD-L1. Stat1-deficient mice displayed increased oral lesion incidence and multiplicity during tumour carcinogenesis in vivo. Immunosuppressive markers PD-1 in CD8+ T cells and PD-L1 in monocytic MDSCs and macrophages were reduced in oral tumours and draining lymph nodes of tumour-bearing Stat1-deficient mice. However, STAT1 was required for anti-tumour functions of T cells during HNSCC in vivo. Finally, we identified TRIM24 to be a negative regulator of STAT1 that plays a similar tumorigenic function to STAT1 in vitro and thus may be a potential target when treating HNSCC.ConclusionOur findings indicate that STAT1 activity plays an important role in tumorigenicity and immunosuppression during HNSCC development.

Investigating the susceptibility of treatment-resistant oesophageal tumours to natural killer cell-mediated responses

The majority of oesophageal adenocarcinoma (OAC) patients do not respond to multimodal treatment regimens and face dismal survival rates. Natural killer (NK) cells are crucial anti-tumour immune cells, and this study investigated the susceptibility of treatment-resistant OAC cells to these potent tumour killers. Natural killer receptor (NKR) ligand expression by OE33CisP (cisplatin-sensitive) and OE33CisR (cisplatin-resistant) cells was investigated. The immunomodulatory effects of OE33CisP and OE33CisR cells on NK cell phenotype and function were assessed. Finally, the impact of chemotherapy regimens on NKR ligand shedding was examined. Our data revealed significantly less surface expression of activating ligands B7-H6, MICA/B, ULBP-3 and activating/inhibitory ligands PVRL-1 and PVRL-4 by OE33CisR cells, compared to OE33CisP cells. Co-culture with OE33CisR cells reduced the frequencies of NKp30+ and NKp46+ NK cells and increased frequencies of TIGIT+, FasL+ and TRAIL+ NK cells. Frequencies of IFN-γ-producing NK cells increased while frequencies of TIM-3+ NK cells decreased after culture with OE33CisP and OE33CisR cells. Frequencies of circulating NKp30+ NK cells were significantly lower in OAC patients with the poorest treatment response and in patients who received FLOT chemotherapy, while B7-H6 shedding by OAC tumour cells was induced by FLOT. Overall, OE33CisR cells express less activating NKR ligands than OE33CisP cells and have differential effects on NKR expression by NK cells. However, neither cell line significantly dampened NK cell cytokine production, death receptor expression or degranulation. In addition, our data indicate that FLOT chemotherapy may promote B7-H6 shedding and immune evasion with detrimental consequences in OAC patients.

Chemokine-targeted therapies: An opportunity to remodel immune profiles in gastro-oesophageal tumours.

Immunotherapies are transforming outcomes for many cancer patients and are quickly becoming the fourth pillar of cancer therapy. However, their efficacy of only ∼25% in gastro-oesophageal cancer has been disappointing. This is attributed to factors such as insufficient patient stratification and the pro-tumourigenic immune landscape of gastro-oesophageal tumours. The chemokine profiles of solid tumours and the availability of effector immune cells greatly influence the immune infiltrate, producing 'cold' or 'immune-excluded' tumours in which immunotherapies are unable to reinvigorate the immune response. Other biological functions for chemokines have emerged, such as promoting cell survival, polarising T cell responses, and supporting several hallmarks of cancer. Therefore, chemokine networks may be exploited with therapeutic intent to mobilise and polarise anti-tumour immune cells, with further utility as combination treatments to augment the efficacy of current cancer immunotherapies. Few studies have demonstrated the clinical benefit of chemokine-targeted therapies as monotherapies, and this review proposes their consideration as combination treatments. Herein, we explore the anti-tumour and pro-tumour implications of chemokine signalling in gastro-oesophageal cancer and discuss their value as prognostic and predictive biomarkers in response to treatment.

Lenvatinib enhances T cell immunity and the efficacy of adoptive chimeric antigen receptor-modified T cells by decreasing myeloid-derived suppressor cells in cancer

BackgroundLenvatinib, a tyrosine kinase inhibitor, has been approved for the treatment of several cancers. However, its regulatory activity and related mechanisms on T cell antitumour immunity need to be further investigated. MethodsThe antitumour activity of lenvatinib in immunocompetent and immunodeficient mice was compared to determine the role of T cell immunity. The antitumour activity of T cells was analysed by cytokine production and adoptive T cell therapy. The immunosuppressive effects of MDSCs on T cells were determined by detecting cytokine production in T cells after being cocultured with MDSCs. The adjuvant immunotherapy effect of lenvatinib was determined by combination therapy with CAR-T cells targeted carbonic anhydrase IX (CAIX) in a murine renal cancer model. ResultsThe antitumour activity of lenvatinib was greater in immunocompetent mice than in immunodeficient mice and was attenuated by CD8+T cell depletion. Lenvatinib increased proliferation, tumour infiltration and antitumour activity of T cells. Importantly, adoptive transfer of lenvatinib-treated T cells showed a long-term antitumour response in vivo. Mechanistically, lenvatinib upregulated T cell-related chemokines (CXCL10 and CCL8) in tumours and decreased the frequency and immunosuppressive activity of MDSCs. Furthermore, lenvatinib enhanced the efficacy of CAR-T cells in a murine renal cancer model. ConclusionOur study revealed novel antitumour mechanisms of lenvatinib by enhancing T cell-mediated antitumour immunity. These findings are of great significance for guiding the clinical use of lenvatinib and provide a good candidate for future combination therapy with T-cell therapies or other immunotherapies.