Tumor-infiltrating γδ T cells as targets of immune checkpoint blockade in melanoma.

Melanoma is one of the most sensitive tumors to immune modulation, and the major challenge for melanoma patients' survival is immune checkpoint inhibitor (ICI) therapy. γδ T lymphocytes play an antitumoral role in a broad variety of tumors including melanoma and they are optimal candidates for cellular immunotherapy. Thus, a comprehensive analysis of the correlation between γδ T cells and immune checkpoint receptors in the context of melanoma was conducted, with the aim of devising an innovative combined immunotherapeutic strategy. In this study, using the GEPIA2.0 database, a significant positive correlation was observed between the expression of γδ T cell-related genes (TRGC1, TRGC2, TCRD) and immune checkpoint genes (PDCD1, HAVCR2, LAG3), highlighting the potential role of γδ T cells in the immune response within melanoma. Moreover, flow cytometry analysis unveiled a significant augmentation in the population of γδ T cells within melanoma lesions, which exhibited the expression of immune checkpoint receptors including LAG3, TIM3, and PD1. Analysis of single-cell RNA sequencing data revealed a significant enrichment and functional reprogramming of γδ T cell clusters in response to ICIs. Interestingly, the effects of ICI therapy varied between Vδ1 and Vδ2 γδ T cell subsets, with distinct changes in gene expression patterns. Last, a correlation analysis between γδ T cell abundance, immune checkpoint gene expression, and clinical outcomes in melanoma patients showed that low expression of immune checkpoint genes, including LAG3, HAVCR2, and PDCD1, was associated with improved 1-year overall survival, emphasizing the significance of these genes in predicting patient outcomes, potentially outweighing the impact of γδ T cell abundance. This study offers critical insights into the dynamic interaction between γδ T cells, immune checkpoint receptors, and melanoma, providing valuable perspectives for potential therapeutic avenues and predictive markers in this intricate interplay.

Emerging Role of Alarmins in Food Allergy: An Update on Pathophysiological Insights, Potential Use as Disease Biomarkers, and Therapeutic Implications.

Food allergies are immuno-mediated adverse reactions to ingestion or contact with foods, representing a widespread health problem. The immune response can be IgE-mediated, non-IgE-mediated, or with a mixed mechanism. The role of innate immunity and alarmins in the pathogenesis of diseases such as asthma and atopic dermatitis is well known. Some authors have investigated the correlation between alarmins and food allergies, often obtaining interesting results. We analyzed articles published in English from the last 22 years present on PubMed concerning the role of alarmins in the pathogenesis of food allergies and their potential use as disease biomarkers, response biomarkers to therapy, or potential therapeutic targets. Nuclear alarmins (TSLP, IL-33, IL-25) appear to have a critical role in IgE-mediated allergies but are also implicated in entities such as eosinophilic esophagitis. Calprotectin and defensins may play a role as disease biomarkers and could help predict response to therapy, although results in the literature are often conflicting. Despite the promising results, more studies on humans still need to be conducted. Deepening our knowledge regarding alarmins and their involvement in food allergies could lead to the development of new biological therapies, significantly impacting patients' quality of life.

An analysis of the immunomodulatory properties of human spheroids from adipose-derived stem cells.

AIMS: Current methods to induce tolerance following allotransplantation or in autoimmunity carry significant morbidity, and research is very active in investigating alternative methods which could minimize toxicity. Spheroids from adipose stem cells (SASCs) are increasingly gaining interest, they hold a great proliferative and differentiating potential. An immunomodulatory effect has not been investigated on SASCs yet. In this study, we analysed the immunomodulatory properties of SASCs and compared them to ADSCs. MAIN METHODS: Adipose stem cells (SASCs and ADSCs) and peripheral blood mononuclear cells (PBMCs) were collected from healthy individuals. We analysed the cytokine production and proliferation of T cells co-cultured with adipose samples or conditioned medium. KEY FINDINGS: SASCs modulated cytokines production and proliferation of heterologous and autologous T cells. In the heterologous assays, we observed a reduction of IFNγ and IL-17 production and an increase of IL-9 in γδ T cells. The soluble factors present in SASCs sovranatants were also able to induce a slight reduction of IFNγ and an increase of IL-9, IL-10 and IL-17 while they could not modulate the proliferative ability of γδ T cells. In the autologous assays, we observed a reduction of the proliferative ability of T cells in co-culture at different ratios with SASCs. Analysis of the SASCs secretome showed an increased IL-5, IL-10, IL-4 and IL-13 production compared to the ADSCs one, demonstrating greater anti-inflammatory properties. SIGNIFICANCE: Our preliminary results support the idea that SASCs exert more pronounced biological immune modulation compared to the classical adherent ADSCs, especially in heterologous experimental settings.

γδ T cells and their clinical application in colon cancer.

In recent years, research has focused on colorectal cancer to implement modern treatment approaches to improve patient survival. In this new era, γδ T cells constitute a new and promising candidate to treat many types of cancer because of their potent killing activity and their ability to recognize tumor antigens independently of HLA molecules. Here, we focus on the roles that γδ T cells play in antitumor immunity, especially in colorectal cancer. Furthermore, we provide an overview of small-scale clinical trials in patients with colorectal cancer employing either in vivo activation or adoptive transfer of ex vivo expanded γδ T cells and suggest possible combinatorial approaches to treat colon cancer.

Interleukin 9 neutralisation reduces collagen-induced arthritis severity in mouse models.

OBJECTIVES: Interleukin 9 (IL-9) is a mediator of tissue damage in several inflammatory diseases. In this study we aimed to evaluate the effects of in vivo IL-9 neutralisation in mice developing collagen induced arthritis (CIA). METHODS: DBA/1 were immunised with collagen in Freund's complete adjuvant (CFA) to induce arthritis. Anti-IL-9 mAb was injected in mice after the onset of arthritis (Group A) or on the same day as sensitisation and again on the day of the challenge (Group B). Histological analysis was performed in joints of mice and spleen cells were also analysed by flow cytometry. A geneset analysis was carried out on whole tarsal joint tissue transcriptomes. RESULTS: IL-9 was over-expressed in swollen joints of mice developing arthritis. Treatment with anti-IL-9 mAb after arthritis onset efficiently down-modulated the severity of joint inflammation. Similarly, anti-IL-9 mAb administered on the same day as sensitisation and on the day of challenge also delayed the onset of arthritis. Anti-IL-9 mAb injection after the onset of arthritis was associated with a decrease of CD4+ TNF-α+ cells and an increase of CD4+ FoxP3+ IL-10+ cells. Geneset analysis in CIA showed an up-regulation of GATA3 with no significant direct interactions between IL-9 and GATA3, which instead was mediated by IL-5 through STAT6. CONCLUSIONS: Our results suggest that IL-9 is involved in the immunopathogenesis of CIA. Further implications for the clinical translation of our findings are discussed.

Phenotypical and Functional Alteration of γδ T Lymphocytes in COVID-19 Patients: Reversal by Statins.

(1) Background: statins have been considered an attractive class of drugs in the pharmacological setting of COVID-19 due to their pleiotropic properties and their use correlates with decreased mortality in hospitalized COVID-19 patients. Furthermore, it is well known that statins, which block the mevalonate pathway, affect γδ T lymphocyte activation. As γδ T cells participate in the inflammatory process of COVID-19, we have investigated the therapeutical potential of statins as a tool to inhibit γδ T cell pro-inflammatory activities; (2) Methods: we harvested peripheral blood mononuclear cells (PBMCs) from COVID-19 patients with mild clinical manifestations, COVID-19 recovered patients, and healthy controls. We performed ex vivo flow cytometry analysis to study γδ T cell frequency, phenotype, and exhaustion status. PBMCs were treated with Atorvastatin followed by non-specific and specific stimulation, to evaluate the expression of pro-inflammatory cytokines; (3) Results: COVID-19 patients had a lower frequency of circulating Vδ2+ T lymphocytes but showed a pronounced pro-inflammatory profile, which was inhibited by in vitro treatment with statins; (4) Conclusions: the in vitro capacity of statins to inhibit Vδ2+ T lymphocytes in COVID-19 patients highlights a new potential biological function of these drugs and supports their therapeutical use in these patients.

Molecular and pro-inflammatory aspects of COVID-19: The impact on cardiometabolic health.

Obesity, type 2 diabetes (T2DM), hypertension (HTN), and Cardiovascular Disease (CVD) often cluster together as "Cardiometabolic Disease" (CMD). Just under 50% of patients with CMD increased the risk of morbidity and mortality right from the beginning of the COVID-19 pandemic as it has been reported in most countries affected by the SARS-CoV2 virus. One of the pathophysiological hallmarks of COVID-19 is the overactivation of the immune system with a prominent IL-6 response, resulting in severe and systemic damage involving also cytokines such as IL2, IL4, IL8, IL10, and interferon-gamma were considered strong predictors of COVID-19 severity. Thus, in this mini-review, we try to describe the inflammatory state, the alteration of the adipokine profile, and cytokine production in the obese state of infected and not infected patients by SARS-CoV2 with the final aim to find possible influences of COVID-19 on CMD and CVD. The immunological-based discussion of the molecular processes could inspire the study of promising targets for managing CMD patients and its complications during COVID-19.

Anti-inflammatory properties of lemon-derived extracellular vesicles are achieved through the inhibition of ERK/NF-κB signalling pathways.

Chronic inflammation is associated with the occurrence of several diseases. However, the side effects of anti-inflammatory drugs prompt the identification of new therapeutic strategies. Plant-derived extracellular vesicles (PDEVs) are gaining increasing interest in the scientific community for their biological properties. We isolated PDEVs from the juice of Citrus limon L. (LEVs) and characterized their flavonoid, limonoid and lipid contents through reversed-phase high-performance liquid chromatography coupled to electrospray ionization quadrupole time-of-flight mass spectrometry (RP-HPLC-ESI-Q-TOF-MS). To investigate whether LEVs have a protective role on the inflammatory process, murine and primary human macrophages were pre-treated with LEVs for 24 h and then were stimulated with lipopolysaccharide (LPS). We found that pre-treatment with LEVs decreased gene and protein expression of pro-inflammatory cytokines, such as IL-6, IL1-ß and TNF-α, and reduced the nuclear translocation and phosphorylation of NF-κB in LPS-stimulated murine macrophages. The inhibition of NF-κB activation was associated with the reduction in ERK1-2 phosphorylation. Furthermore, the ability of LEVs to decrease pro-inflammatory cytokines and increase anti-inflammatory molecules was confirmed ex vivo in human primary T lymphocytes. In conclusion, we demonstrated that LEVs exert anti-inflammatory effects both in vitro and ex vivo by inhibiting the ERK1-2/NF-κB signalling pathway.

A Mathematical Model of In Vitro Cellular Uptake of Zoledronic Acid and Isopentenyl Pyrophosphate Accumulation.

The mevalonate pathway is an attractive target for many areas of research, such as autoimmune disorders, atherosclerosis, Alzheimer's disease and cancer. Indeed, manipulating this pathway results in the alteration of malignant cell growth with promising therapeutic potential. There are several pharmacological options to block the mevalonate pathway in cancer cells, one of which is zoledronic acid (ZA) (an N-bisphosphonate (N-BP)), which inhibits the farnesyl pyrophosphate (FPP) synthase enzyme, inducing cell cycle arrest, apoptosis, inhibition of protein prenylation, and cholesterol reduction, as well as leading to the accumulation of isopentenyl pyrophosphate (IPP). We extrapolated the data based on two independently published papers that provide numerical data on the uptake of zoledronic acid (ZA) and the accumulation of IPP (Ag) and its isomer over time by using in vitro human cell line models. Two different mathematical models for IPP kinetics are proposed. The first model (Model 1) is a simpler ordinary differential equation (ODE) compartmental system composed of 3 equations with 10 parameters; the second model (Model 2) is a differential algebraic equation (DAE) system with 4 differential equations, 1 algebraic equation and 13 parameters incorporating the formation of the ZA+enzyme+Ag complex. Each of the two models aims to describe two different experimental situations (continuous and pulse experiments) with the same ZA kinetics. Both models fit the collected data very well. With Model 1, we obtained a prevision accumulation of IPP after 24 h of 169.6 pmol/mgprot/h with an IPP decreasing rate per (pmol/mgprot) of ZA (kXGZ) equal to 13.24/h. With Model 2, we have comprehensive kinetics of IPP upon ZA treatment. We calculate that the IPP concentration was equal to 141.6 pmol/mgprot/h with a decreasing rate/percentage of 0.051 (kXGU). The present study is the first to quantify the influence of ZA on the pharmacodynamics of IPP. While still incorporating a small number of parameters, Model 2 better represents the complexity of the biological behaviour for calculating the IPP produced in different situations, such as studies on γδ T cell-based immunotherapy. In the future, additional clinical studies are warranted to further evaluate and fine-tune dosing approaches.

Harnessing Unconventional T Cells and Innate Lymphoid Cells to Prevent and Treat Hematological Malignancies: Prospects for New Immunotherapy.

Unconventional T cells and innate lymphoid cells (ILCs) make up a heterogeneous set of cells that characteristically show prompt responses toward specific antigens. Unconventional T cells recognize non-peptide antigens, which are bound and presented by diverse non-polymorphic antigen-presenting molecules and comprise γδ T cells, MR1-restricted mucosal-associated invariant T cells (MAITs), and natural killer T cells (NKTs). On the other hand, ILCs lack antigen-specific receptors and act as the innate counterpart to the T lymphocytes found in the adaptive immune response. The alteration of unconventional T cells and ILCs in frequency and functionality is correlated with the onset of several autoimmune diseases, allergy, inflammation, and tumor. However, depending on the physio-pathological framework, unconventional T cells may exhibit either protective or pathogenic activity in a range of neoplastic diseases. Nonetheless, experimental models and clinical studies have displayed that some unconventional T cells are potential therapeutic targets, as well as prognostic and diagnostic markers. In fact, cell-mediated immune response in tumors has become the focus in immunotherapy against neoplastic disease. This review concentrates on the present knowledge concerning the function of unconventional T cell sets in the antitumor immune response in hematological malignancies, such as acute and chronic leukemia, multiple myeloma, and lymphoproliferative disorders. Moreover, we discuss the possibility that modulating the activity of unconventional T cells could be useful in the treatment of hematological neoplasms, in the prevention of specific conditions (such as graft versus host disease), and in the formulation of an effective anticancer vaccine therapy. The exact knowledge of the role of these cells could represent the prerequisite for the creation of a new form of immunotherapy for hematological neoplasms.

Platelets accumulate in lung lesions of tuberculosis patients and inhibit T-cell responses and Mycobacterium tuberculosis replication in macrophages.

Platelets regulate human inflammatory responses that lead to disease. However, the role of platelets in tuberculosis (TB) pathogenesis is still unclear. Here, we show that patients with active TB have a high number of platelets in peripheral blood and a low number of lymphocytes leading to a high platelets to lymphocytes ratio (PL ratio). Moreover, the serum concentration of different mediators promoting platelet differentiation or associated with platelet activation is increased in active TB. Immunohistochemistry analysis shows that platelets localise around the lung granuloma lesions in close contact with T lymphocytes and macrophages. Transcriptomic analysis of caseous tissue of human pulmonary TB granulomas, followed by Gene Ontology analysis, shows that 53 platelet activation-associated genes are highly expressed compared to the normal lung tissue. In vitro activated platelets (or their supernatants) inhibit BCG-induced T- lymphocyte proliferation and IFN-γ production. Likewise, platelets inhibit the growth of intracellular macrophages of Mycobacterium (M.) tuberculosis. Soluble factors released by activated platelets mediate both immunological and M. tuberculosis replication activities. Furthermore, proteomic and neutralisation studies (by mAbs) identify TGF-ß and PF4 as the factors responsible for inhibiting T-cell response and enhancing the mycobactericidal activity of macrophages, respectively. Altogether these results highlight the importance of platelets in TB pathogenesis.

Comprehensive Analysis of the ILCs and Unconventional T Cells in Virus Infection: Profiling and Dynamics Associated with COVID-19 Disease for a Future Monitoring System and Therapeutic Opportunities.

This review is a comprehensive analysis of the effects of SARS-CoV-2 infection on Unconventional T cells and innate lymphoid cells (ILCs). COVID-19 affected patients show dysregulation of their adaptive immune systems, but many questions remain unsolved on the behavior of Unconventional cells and ILCs during infection, considering their role in maintaining homeostasis in tissue. Therefore, we highlight the differences that exist among the studies in cohorts of patients who in general were categorized considering symptoms and hospitalization. Moreover, we make a critical analysis of the presence of particular clusters of cells that express activation and exhausted markers for each group in order to bring out potential diagnostic factors unconsidered before now. We also focus our attention on studies that take into consideration recovered patients. Indeed, it could be useful to determine Unconventional T cells' and ILCs' frequencies and functions in longitudinal studies because it could represent a way to monitor the immune status of SARS-CoV-2-infected subjects. Possible changes in cell frequencies or activation profiles could be potentially useful as prognostic biomarkers and for future therapy. Currently, there are no efficacious therapies for SARS-CoV-2 infection, but deep studies on involvement of Unconventional T cells and ILCs in the pathogenesis of COVID-19 could be promising for targeted therapies.

Impact of the flame retardant 2,2'4,4'-tetrabromodiphenyl ether (PBDE-47) in THP-1 macrophage-like cell function via small extracellular vesicles.

2,2'4,4'-tetrabromodiphenyl ether (PBDE-47) is one of the most widespread environmental brominated flame-retardant congeners which has also been detected in animal and human tissues. Several studies have reported the effects of PBDEs on different health issues, including neurobehavioral and developmental disorders, reproductive health, and alterations of thyroid function. Much less is known about its immunotoxicity. The aim of our study was to investigate the effects that treatment of THP-1 macrophage-like cells with PBDE-47 could have on the content of small extracellular vesicles' (sEVs) microRNA (miRNA) cargo and their downstream effects on bystander macrophages. To achieve this, we purified sEVs from PBDE-47 treated M(LPS) THP-1 macrophage-like cells (sEVsPBDE+LPS) by means of ultra-centrifugation and characterized their miRNA cargo by microarray analysis detecting the modulation of 18 miRNAs. Furthermore, resting THP-1 derived M(0) macrophage-like cells were cultured with sEVsPBDE+LPS, showing that the treatment reshaped the miRNA profiles of 12 intracellular miRNAs. This dataset was studied in silico, identifying the biological pathways affected by these target genes. This analysis identified 12 pathways all involved in the maturation and polarization of macrophages. Therefore, to evaluate whether sEVsPBDE+LPS can have some immunomodulatory activity, naïve M(0) THP-1 macrophage-like cells cultured with purified sEVsPBDE+LPS were studied for IL-6, TNF-α and TGF-ß mRNAs expression and immune stained with the HLA-DR, CD80, CCR7, CD38 and CD209 antigens and analyzed by flow cytometry. This analysis showed that the PBDE-47 treatment does not induce the expression of specific M1 and M2 cytokine markers of differentiation and may have impaired the ability to make immunological synapses and present antigens, down-regulating the expression of HLA-DR and CD209 antigens. Overall, our study supports the model that perturbation of miRNA cargo by PBDE-47 treatment contributes to the rewiring of cellular regulatory pathways capable of inducing perturbation of differentiation markers on naïve resting M(0) THP-1 macrophage-like cells.

Metabolic Changes in Tumor Microenvironment: How Could They Affect γδ T Cells Functions?

The metabolic changes that occur in tumor microenvironment (TME) can influence not only the biological activity of tumor cells, which become more aggressive and auto sustained, but also the immune response against tumor cells, either producing ineffective responses or polarizing the response toward protumor activity. γδ T cells are a subset of T cells characterized by a plasticity that confers them the ability to differentiate towards different cell subsets according to the microenvironment conditions. On this basis, we here review the more recent studies focused on altered tumor metabolism and γδ T cells, considering their already known antitumor role and the possibility of manipulating their effector functions by in vitro and in vivo approaches. γδ T cells, thanks to their unique features, are themselves a valid alternative to overcome the limits associated with the use of conventional T cells, such as major histocompatibility complex (MHC) restriction, costimulatory signal and specific tumor-associated antigen recognition. Lipids, amino acids, hypoxia, prostaglandins and other metabolic changes inside the tumor microenvironment could reduce the efficacy of this important immune population and polarize γδ T cells toward IL17 producing cells that play a pro tumoral role. A deeper knowledge of this phenomenon could be helpful to formulate new immunotherapeutic approaches that target tumor metabolisms.

Lymphopenia in COVID-19: γδ T Cells-Based Therapeutic Opportunities.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection dysregulates the immune system by lymphopenia of B cells, monocytes, eosinophils, basophils, and cytotoxic cells such as CD8, γδ T cells, and natural killer (NK) cells. Despite many studies being conducted to better understand the effects of SARS-CoV-2 on the immune system, many mechanisms still remain unclear, hindering the development of novel therapeutic approaches and strategies to improve the host's immune defense. This mini-review summarizes the findings on the role of γδ T cells in coronavirus disease 2019 (COVID-19), providing an overview of the excellent anti-viral therapeutic potential of γδ T cells, that had not yet been exploited in depth.

Deciphering human γδ T cell response in cancer: Lessons from tumor-infiltrating γδ T cells.

The finding that γδ T cells are present among tumor-infiltrating lymphocytes in humans suggests they participate in tumor immune surveillance, but their relevance is unclear because the relative abundance of tumor-infiltrating γδ T cells correlates with positive or negative, or even do not correlate with prognosis. This likely depends on the fact that tumor-infiltrating γδ T cells may play substantially different effector or regulatory functions, and correlation with patient's prognosis relies on distinct γδ T cell subsets in the context of the tumor. There is interest to exploit γδ T cells in tumor immunotherapy, but to make this approach successful there is urgent need to fully understand the biological functions of γδ T cells and of how they can be manipulated in vivo and ex vivo to safely provide benefit to the host. This review focuses on our previous and ongoing studies of tumor-infiltrating γδ T lymphocytes in different types of human cancer. Moreover, we discuss the interaction of tumor-infiltrating γδ T cells with other cells and molecules present in the tumor microenvironment, and their clinical relevance on the ground, that deep knowledge in this field can be used further for better immunotherapeutic intervention in cancer.

Analysis of colon-infiltrating γδ T cells in chronic inflammatory bowel disease and in colitis-associated cancer.

Inflammatory bowel disease (IBD) remains a global health problem with a significant percentage of patients progressing to chronic inflammation and colitis-associated cancer (CAC). Whether or not γδ T cells contribute to initiation and maintenance of inflammation in IBD and in the development of CAC is not known. We have evaluated the frequency, phenotype, and functions of γδ T cells among tissue-infiltrating lymphocytes in healthy donors and IBD and CAC patients. Results show that Vδ1 T cells are the dominant γδ T-cell population in healthy tissue, whereas Vδ2 T significantly abound in chronic IBD. Vδ2 T cells produce more IFN-γ, TNF-α, and IL-17 than Vδ1 T cells in chronic inflamed IBD. In CAC patients no significant cytokine production was detected in tissue-resident Vδ1 T cells, but Vδ2 T cells produced remarkable amounts of IFN-γ and TNF-α; these data were confirmed by the analysis of an independent cohort of IBD transcriptomes. Moreover, transcriptomes of IBD patients revealed a clear-cut clusterization of genes related with the maintenance of the inflammatory status. In conclusion, our results demonstrating that Vδ2 T cells have a proinflammatory profile in chronic IBD are suggestive of their participation in IBD and CAC pathogenesis.

NKp46-expressing human gut-resident intraepithelial Vδ1 T cell subpopulation exhibits high antitumor activity against colorectal cancer.

γδ T cells account for a large fraction of human intestinal intraepithelial lymphocytes (IELs) endowed with potent antitumor activities. However, little is known about their origin, phenotype, and clinical relevance in colorectal cancer (CRC). To determine γδ IEL gut specificity, homing, and functions, γδ T cells were purified from human healthy blood, lymph nodes, liver, skin, and intestine, either disease-free, affected by CRC, or generated from thymic precursors. The constitutive expression of NKp46 specifically identifies a subset of cytotoxic Vδ1 T cells representing the largest fraction of gut-resident IELs. The ontogeny and gut-tropism of NKp46+/Vδ1 IELs depends both on distinctive features of Vδ1 thymic precursors and gut-environmental factors. Either the constitutive presence of NKp46 on tissue-resident Vδ1 intestinal IELs or its induced expression on IL-2/IL-15-activated Vδ1 thymocytes are associated with antitumor functions. Higher frequencies of NKp46+/Vδ1 IELs in tumor-free specimens from CRC patients correlate with a lower risk of developing metastatic III/IV disease stages. Additionally, our in vitro settings reproducing CRC tumor microenvironment inhibited the expansion of NKp46+/Vδ1 cells from activated thymic precursors. These results parallel the very low frequencies of NKp46+/Vδ1 IELs able to infiltrate CRC, thus providing insights to either follow-up cancer progression or to develop adoptive cellular therapies.

γδ cell-based immunotherapy for cancer.

Introduction: Cancer immunotherapy relies on the development of an efficient and long-lasting anti-tumor response, generally mediated by cytotoxic T cells. γδ T cells possess distinctive features that justify their use in cancer immunotherapy. Areas covered: Here we will review our current knowledge on the functions of human γδ T cells that may be relevant in tumor immunity and the most recent advances in our understanding of how these functions are regulated in the tumor microenvironment. We will also discuss the major achievements and limitations of γδ T cell-based immunotherapy of cancer. Expert opinion: Several small-scale clinical trials have been conducted in cancer patients using either in vivo activation of γδ T cells or adoptive transfer of ex vivo-expanded γδ T cells. Both strategies are safe and give some clinical benefit to patients, thus providing a proof of principle for their utilization in addition to conventional therapies. However, low objective response rates have been obtained in both settings and therefore larger and well-controlled trials are needed. Discovering the factors which influence the success of γδ T cell-based immunotherapy will lead to a better understanding of their mechanism of action and to harness these cells for effective and durable anti-tumor responses.