Activation and Functional Alteration of Mucosal-Associated Invariant T Cells in Adult Patients With Community-Acquired Pneumonia

Community-acquired pneumonia (CAP) remains the significant infectious cause of morbidity and mortality worldwide. Although mucosal-associated invariant T cells (MAIT) play roles in the pathogenesis of children CAP and ICU-associated pneumonia, their roles in adult CAP are largely unexplored. In this study, we investigated the frequency, phenotype, and function of MAIT cells in peripheral blood and bronchoalveolar lavage fluid (BALF) of adult CAP patients. Our data indicate that MAIT-cell frequency is profoundly lower in the peripheral blood of CAP patients compared to that in healthy individuals. Furthermore, the circulatory MAIT cells express higher levels of CD69 and PD-1 compared to those in healthy individuals. In BALF of CAP patients, MAIT-cell frequency is higher and MAIT cells express higher levels of CD69 and PD-1 compared to their matched blood counterparts. Levels of IL-17A and IFN-γ are increased in BALF of CAP patients compared to those in BALF of patients with pulmonary small nodules. The IL-17A/IFN-γ ratio is significantly positively correlated with MAIT frequency in BALF of CAP patients, suggesting a pathogenic role of MAIT-17 cells in CAP. Of note, blood MAIT-cell frequency in CAP patients is strongly negatively correlated with high-sensitivity C-reactive protein (hsCRP) and neutrophil count percentage in blood. The ability of circulating MAIT cells in CAP patients to produce IFN-γ is significantly impaired compared to those in healthy individuals. In summary, our findings suggest the possible involvement of MAIT cells in the immunopathogenesis of adult CAP.

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CXCL12-CXCR4-Mediated Chemotaxis Supports Accumulation of Mucosal-Associated Invariant T Cells Into the Liver of Patients With PBC

Frontiers in Immunology ◽

10.3389/fimmu.2021.578548 ◽

2021 ◽

Vol 12 ◽

Author(s):

Zhilei Chen ◽

Suying Liu ◽

Chengmei He ◽

Jinlei Sun ◽

Li Wang ◽

...

Keyword(s):

Flow Cytometry ◽

T Cells ◽

Cytokine Production ◽

Immunofluorescence Staining ◽

Primary Biliary Cholangitis ◽

Hepatic Hemangioma ◽

Cxcr4 Antagonist ◽

Mait Cells ◽

Ifn Γ ◽

Invariant T Cells

Objectives: To explore the potential role of CD3+CD8+CD161high TCRVα7.2+ mucosal-associated invariant T (MAIT) cells in the pathogenesis of primary biliary cholangitis (PBC).Methods: We enrolled 55 patients with PBC, 69 healthy controls (HCs), and 8 patients with hepatic hemangioma. Circulating MAIT cells and their chemokine receptor profiles and cytokine production were quantified using flow cytometry. Liver-resident MAIT cells were examined by immunofluorescence staining. CXCL12-mediated chemotaxis of MAIT cells was measured using a transwell migration assay. Plasma interleukin (IL)-18 was measured using ELISA, and cytokine production in IL-18-stimulated MAIT cells was detected using flow cytometry.Result: Peripheral MAIT cells were found to be significantly lower in patients with PBC (3.0 ± 3.2% vs. 9.4 ± 8.0%, p < 0.01) and negatively correlated with alkaline phosphatase (ALP) levels (r = −0.3209, p < 0.05). Liver immunofluorescence staining suggested that MAIT cells might accumulate in PBC liver. MAIT cells from patients with PBC expressed higher levels of CXCR4 (84.8 ± 18.0% vs. 58.7 ± 11.4%, p < 0.01), and the expression of CXCL12 was higher in PBC liver. CXCL12 promoted MAIT cell chemotaxis (70.4 ± 6.8% vs. 52.2 ± 3.5%, p < 0.01), which was attenuated by CXCR4 antagonist. MAIT cells from PBC produced significantly more interferon-γ (IFN-γ) (88.3 ± 4.2% vs. 64.2 ± 10.1%, p < 0.01), tumor necrosis factor-α (TNF-α) (93.0 ± 1.1% vs. 80.1 ± 5.3%, p < 0.01), Granzyme B (89.3 ± 3.3% vs. 72.1 ± 7.0%, p < 0.01), and perforin (46.8 ± 6.6% vs. 34.8 ± 7.7%, p < 0.05). MAIT cells from PBC expressed higher levels of IL18-Rα (83.8 ± 10.2% vs. 58.3 ± 8.7%, p < 0.01). Plasma IL-18 was more abundant in patients with PBC (286.8 ± 75.7 pg/ml vs. 132.9 ± 78.1 pg/ml, p < 0.01). IL-18 promoted IFN-γ production in MAIT cells (74.9 ± 6.6% vs. 54.7 ± 6.7%, p < 0.01), which was partially attenuated by blocking IL-18R (68.6 ± 8.3% vs. 43.5 ± 4.2%, p < 0.01).Conclusion: Mucosal-associated invariant T cells from patients with PBC accumulated in the liver via CXCL12-CXCR4-mediated chemotaxis, produced pro-inflammatory cytokines, and contributed to portal inflammation, which was potentially mediated by elevated IL-18. Targeting MAIT cells might be a therapeutic approach for PBC.

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MR1-restricted MAIT cells from the human lung mucosal surface have distinct phenotypic, functional, and transcriptomic features that are preserved in HIV infection

10.1101/2020.11.19.389858 ◽

2020 ◽

Author(s):

Sharon Khuzwayo ◽

Maphe Mthembu ◽

Erin W. Meermeier ◽

Sanjay M. Prakadan ◽

Samuel W. Kazer ◽

...

Keyword(s):

Hiv Infection ◽

Peripheral Blood ◽

Cell Receptor ◽

Peripheral Circulation ◽

Mucosal Surface ◽

Respiratory Pathogens ◽

Healthy Individuals ◽

Mait Cells ◽

And Function ◽

Mait Cell

AbstractMucosal associated invariant T (MAIT) cells are a class of innate-like T cells that utilize a semi-invariant αβ T cell receptor to recognize small molecule ligands produced by bacteria and fungi. Despite growing evidence that immune cells at mucosal surfaces are often phenotypically and functionally distinct from those in the peripheral circulation, knowledge about the characteristics of MAIT cells at the lung mucosal surface, the site of exposure to respiratory pathogens, is limited. HIV infection has been shown to have a profound effect on the number and function of MAIT cells in the peripheral blood, but its effect on lung mucosal MAIT cells is unknown. We examined the phenotypic, functional, and transcriptomic features of MR1 restricted MAIT cells from the peripheral blood and bronchoalveolar compartments of otherwise healthy individuals with latent Mycobacterium tuberculosis (Mtb) infection who were either HIV uninfected or HIV infected. Peripheral blood MAIT cells consistently co-expressed typical MAIT cell surface markers CD161 and CD26 in healthy individuals, while paired bronchoalveolar MAIT cells displayed heterogenous expression of these markers. Bronchoalveolar MAIT cells produced lower levels of pro-inflammatory cytokine IFN-γ and expressed higher levels of co-inhibitory markers PD-1 and TIM-3 than peripheral MAIT cells. HIV infection resulted in decreased frequencies and pro-inflammatory function of peripheral blood MAIT cells, while in the bronchoalveolar compartment MAIT cell frequency was decreased but phenotype and function were not significantly altered. Single-cell transcriptomic analysis demonstrated greater heterogeneity among bronchoalveolar compared to peripheral blood MAIT cells and suggested a distinct subset in the bronchoalveolar compartment. The transcriptional features of this bronchoalveolar subset were associated with atypical MAIT cells and tissue repair functions. In summary, we found previously undescribed phenotypic and transcriptional heterogeneity of bronchoalveolar MAIT cells in healthy people. In HIV infection, we found numeric depletion of MAIT cells in both anatomical compartments but preservation of the novel phenotypic and transcriptional features of bronchoalveolar MAIT cells.

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Activated but impaired IFN-γ production of mucosal-associated invariant T cells in patients with hepatocellular carcinoma

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-003685 ◽

2021 ◽

Vol 9 (11) ◽

pp. e003685

Author(s):

Wenyong Huang ◽

Dongmei Ye ◽

Wenjing He ◽

Xiaoshun He ◽

Xiaomin Shi ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

T Cells ◽

Peripheral Blood ◽

Healthy Controls ◽

Activation Markers ◽

Mait Cells ◽

Hla Dr ◽

Ifn Γ ◽

And Function

ObjectiveMucosal-associated invariant T (MAIT) cells are innate T cells with immunoregulatory activity and were recently found to be associated with various tumor types. The role of intrasinusoidal MAIT cells in hepatocellular carcinoma (HCC) has not been fully characterized.DesignPeripheral blood samples were obtained from patients with HCC and healthy controls. Liver-associated mononuclear cells (LMCs) were collected from liver perfusions of donors and patients with HCC undergoing liver transplantation. Blood and liver perfusates from patients with HCC were analyzed by flow cytometry for CD3 +CD161+Vα7.2+MAIT cell frequency, phenotype, and function.ResultsThere were fewer MAIT cells in the peripheral blood and liver of patients with HCC than in the healthy controls. Interferon-γ (IFN-γ) production by these cells was also reduced. Peripheral MAIT cells showed upregulation of HLA-DR (Human Leukocyte Antigen DR） and the inhibitory molecule PD-1 (Programmed Cell Death Protein 1), but no significant differences in upregulation were found in intrasinusoidal MAIT cells. MAIT cells were significantly enriched in the liver relative to that in the peripheral blood of patients with HCC. High levels of activation markers and exhaustion markers including HLA-DR, CD69, and PD-1 were observed in LMCs of patients with HCC but not in the peripheral blood. Single-cell RNA sequencing revealed that intrasinusoidal MAIT cells exhibited distinct features in patients with HCC and the controls.ConclusionOur study showed that alterations in MAIT cells are associated with HCC. The distinct activity and function of MAIT cells in the peripheral blood and liver of patients with HCC might suggest a potential role of these cells in disease pathogenesis.

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Activation of mucosal-associated invariant T cells in the lungs of sarcoidosis patients

Scientific Reports ◽

10.1038/s41598-019-49903-6 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Hisayo Matsuyama ◽

Takuma Isshiki ◽

Asako Chiba ◽

Tetsuo Yamaguchi ◽

Goh Murayama ◽

...

Keyword(s):

T Cells ◽

Peripheral Blood ◽

Lavage Fluid ◽

Interferon Γ ◽

Healthy Controls ◽

Expression Levels ◽

Mait Cells ◽

Clinical Biomarkers ◽

Cd69 Expression ◽

Factor Α

Abstract Although the pathogenesis of sarcoidosis is not fully understood, immunological characterization has elucidated highly polarized expression of the type 1 T helper cell response. Mucosal-associated invariant T (MAIT) cells are innate T cells that recognize bacterial riboflavin and rapidly produce cytokines such as interferon γ and tumor necrosis factor α. We prospectively evaluated the proportion of MAIT cells and the expression levels of cell surface markers in peripheral blood from 40 sarcoidosis patients and 28 healthy controls. MAIT cells in bronchoalveolar lavage fluid (BALF) were also examined in 12 sarcoidosis patients. In peripheral blood, the proportion of MAIT cells was lower (P = 0.0002), but the expression levels of CD69 and programmed death 1 on MAIT cells were higher in sarcoidosis patients than in healthy controls. Moreover, CD69 expression levels were significantly correlated with clinical biomarkers. Sarcoidosis patients with parenchymal infiltration in the lungs showed a significantly higher proportion and number of MAIT cells in BALF compared to patients without parenchymal infiltration. CD69 expression levels on MAIT cells in BALF were higher than levels in peripheral blood. The activation status of MAIT cells might reflect the disease activity of sarcoidosis. Therefore, it is a potential target for sarcoidosis treatment.

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Antigen-loaded MR1 tetramers define T cell receptor heterogeneity in mucosal-associated invariant T cells

Journal of Experimental Medicine ◽

10.1084/jem.20130958 ◽

2013 ◽

Vol 210 (11) ◽

pp. 2305-2320 ◽

Cited By ~ 317

Author(s):

Rangsima Reantragoon ◽

Alexandra J. Corbett ◽

Isaac G. Sakala ◽

Nicholas A. Gherardin ◽

John B. Furness ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Cell Biology ◽

Cell Receptor ◽

Phenotypic Characterization ◽

Mait Cells ◽

Invariant T Cells ◽

Human And Mouse ◽

Mait Cell

Mucosal-associated invariant T cells (MAIT cells) express a semi-invariant T cell receptor (TCR) α-chain, TRAV1-2–TRAJ33, and are activated by vitamin B metabolites bound by the major histocompatibility complex (MHC)–related class I–like molecule, MR1. Understanding MAIT cell biology has been restrained by the lack of reagents to specifically identify and characterize these cells. Furthermore, the use of surrogate markers may misrepresent the MAIT cell population. We show that modified human MR1 tetramers loaded with the potent MAIT cell ligand, reduced 6-hydroxymethyl-8-d-ribityllumazine (rRL-6-CH2OH), specifically detect all human MAIT cells. Tetramer+ MAIT subsets were predominantly CD8+ or CD4−CD8−, although a small subset of CD4+ MAIT cells was also detected. Notably, most human CD8+ MAIT cells were CD8α+CD8β−/lo, implying predominant expression of CD8αα homodimers. Tetramer-sorted MAIT cells displayed a TH1 cytokine phenotype upon antigen-specific activation. Similarly, mouse MR1–rRL-6-CH2OH tetramers detected CD4+, CD4−CD8− and CD8+ MAIT cells in Vα19 transgenic mice. Both human and mouse MAIT cells expressed a broad TCR-β repertoire, and although the majority of human MAIT cells expressed TRAV1-2–TRAJ33, some expressed TRAJ12 or TRAJ20 genes in conjunction with TRAV1-2. Accordingly, MR1 tetramers allow precise phenotypic characterization of human and mouse MAIT cells and revealed unanticipated TCR heterogeneity in this population.

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Mucosa-associated invariant T cells link intestinal immunity with antibacterial immune defects in alcoholic liver disease

Gut ◽

10.1136/gutjnl-2017-314458 ◽

2017 ◽

Vol 67 (5) ◽

pp. 918-930 ◽

Cited By ~ 39

Author(s):

Antonio Riva ◽

Vishal Patel ◽

Ayako Kurioka ◽

Hannah C Jeffery ◽

Gavin Wright ◽

...

Keyword(s):

T Cells ◽

Liver Disease ◽

Alcoholic Liver Disease ◽

Ethanol Exposure ◽

Intestinal Immunity ◽

Functional Impairments ◽

Mait Cells ◽

Invariant T Cells ◽

Mait Cell ◽

Bacterial Products

Background/aimsIntestinal permeability with systemic distribution of bacterial products are central in the immunopathogenesis of alcoholic liver disease (ALD), yet links with intestinal immunity remain elusive. Mucosa-associated invariant T cells (MAIT) are found in liver, blood and intestinal mucosa and are a key component of antibacterial host defences. Their role in ALD is unknown.Methods/designWe analysed frequency, phenotype, transcriptional regulation and function of blood MAIT cells in severe alcoholic hepatitis (SAH), alcohol-related cirrhosis (ARC) and healthy controls (HC). We also examined direct impact of ethanol, bacterial products from faecal extracts and antigenic hyperstimulation on MAIT cell functionality. Presence of MAIT cells in colon and liver was assessed by quantitative PCR and immunohistochemistry/gene expression respectively.ResultsIn ARC and SAH, blood MAIT cells were dramatically depleted, hyperactivated and displayed defective antibacterial cytokine/cytotoxic responses. These correlated with suppression of lineage-specific transcription factors and hyperexpression of homing receptors in the liver with intrahepatic preservation of MAIT cells in ALD. These alterations were stronger in SAH, where surrogate markers of bacterial infection and microbial translocation were higher than ARC. Ethanol exposure in vitro, in vivo alcohol withdrawal and treatment with Escherichia coli had no effect on MAIT cell frequencies, whereas exposure to faecal bacteria/antigens induced functional impairments comparable with blood MAIT cells from ALD and significant MAIT cell depletion, which was not observed in other T cell compartments.ConclusionsIn ALD, the antibacterial potency of MAIT cells is compromised as a consequence of contact with microbial products and microbiota, suggesting that the ‘leaky’ gut observed in ALD drives MAIT cell dysfunction and susceptibility to infection in these patients.

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Expansion of IL-17A–secreting CD8+ mucosa-associated invariant T cells in peripheral blood following stem cell mobilization

Blood Advances ◽

10.1182/bloodadvances.2018025601 ◽

2019 ◽

Vol 3 (5) ◽

pp. 718-723 ◽

Cited By ~ 2

Author(s):

Antiopi Varelias ◽

Kate H. Gartlan ◽

Andrew N. Wilkinson ◽

Stuart D. Olver ◽

Luke D. Samson ◽

...

Keyword(s):

T Cells ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Allogeneic Stem Cell Transplantation ◽

Peripheral Blood ◽

Stem Cell Mobilization ◽

Mait Cells ◽

Key Points ◽

Invariant T Cells ◽

Cell Mobilization

Key Points Stem cell mobilization with G-CSF promotes IL-17A secretion by donor CD8+ MAIT cells. Tbet and RORγt coexpression identifies potential IL-17A–secreting proinflammatory populations after allogeneic stem cell transplantation.

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Mucosal-Associated Invariant T Cells in Chronic Inflammatory Liver Disease

Seminars in Liver Disease ◽

10.1055/s-0037-1621709 ◽

2018 ◽

Vol 38 (01) ◽

pp. 060-065 ◽

Cited By ~ 13

Author(s):

Fabian Bolte ◽

Barbara Rehermann

Keyword(s):

T Cells ◽

Liver Disease ◽

Gastrointestinal Tract ◽

Inflammatory Cytokines ◽

Human Liver ◽

Bacterial Infections ◽

Mait Cells ◽

Microbiome Research ◽

Invariant T Cells ◽

Mait Cell

AbstractThe broadening field of microbiome research has led to a substantial reappraisal of the gut–liver axis and its role in chronic liver disease. The liver is a central immunologic organ that is continuously exposed to food and microbial-derived antigens from the gastrointestinal tract. Mucosal-associated invariant T (MAIT) cells are enriched in the human liver and can be activated by inflammatory cytokines and microbial antigens. In chronic inflammatory liver disease, MAIT cells are depleted suggesting an impaired MAIT cell-dependent protection against bacterial infections.

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Role of Innate-like Lymphocytes in the Pathogenesis of Community Acquired Pneumonia

10.1101/495556 ◽

2018 ◽

Cited By ~ 1

Author(s):

RF Hannaway ◽

X Wang ◽

M Schneider ◽

S Slow ◽

MR Schofield ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Bacterial Load ◽

Γδ T Cells ◽

Community Acquired Pneumonia ◽

Cell Abundance ◽

Mait Cells ◽

Bacterial Aetiology ◽

Mait Cell

AbstractBackgroundMucosal-associated invariant T (MAIT) cells and Vδ2+ γδ T cells are anti-bacterial innate-like lymphocytes (ILLs) that are enriched in blood and mucosa. ILLs have been implicated in control of bacterial infection. However, the role of ILLs in community-acquired pneumonia (CAP) is unknown.MethodsUsing sputum samples from a well-characterised CAP cohort, MAIT cell (Vα7.2-Jα12/20/33) and Vδ2+ T cell (Vδ2-Jδ1/2/3/4) abundance was determined by quantitative PCR. Cytokine and chemokine concentrations in sputum were measured. The capacity of bacteria in sputum to produce activating ligands for MAIT cells and Vδ2+ T cells was inferred by 16S rRNA sequencing.ResultsMAIT cell abundance in sputum was higher in patients with less severe pneumonia; duration of hospital admission was inversely correlated with both MAIT and Vδ2+ T cell abundance. The abundance of both ILLs was higher in patients with a confirmed bacterial aetiology, however there was no correlation with total bacterial load or the predicted capacity of bacteria to produce activating ligands. Sputum MAIT cell abundance was associated with interferon- α, and interferon-γ, and sputum neutrophil abundance, while Vδ2+ T cell abundance was associated with CXCL11 and interferon-γ.ConclusionsPulmonary MAIT and Vδ2+ T cells can be detected in sputum in CAP, where they may contribute to improved clinical outcome.

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166 Mucosal-associated invariant T-cells (MAIT) in pancreatic cancer

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0166 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A179-A179

Author(s):

Jéssica Kamiki ◽

Patrícia António ◽

Pedro Noronha ◽

Carolina Condeço ◽

Georgia Paraschoudi ◽

...

Keyword(s):

Pancreatic Cancer ◽

T Cells ◽

Cytokine Production ◽

Bacterial Species ◽

Mait Cells ◽

Ifn Γ ◽

Invariant T Cells ◽

Microbial Products

BackgroundImmunotherapy has changed the standard of care for multiple cancers; however, its efficacy is limited. Chemotherapy and radiation had little effect in pancreatic ductal adenocarcinoma (PDAC) outcome1 in patients with metastatic disease, hence the urgency for new effective courses of treatment. Increasing evidence suggests mucosal-associated invariant T-cells (MAIT) play a role in anti-cancer T-cell responses, by recognizing transformed cells or bacterial products. MAIT respond towards microbial antigens and vitamin derivatives, produce pro-inflammatory cytokines2 3 and have been found present in primary and metastatic cancer lesions.3 4 Long-term survival PDAC patients present a unique microbiome pattern. In contrast, some microbial species may promote oncogenesis.5 6The focus of this project is the characterization of MAIT as immune effector cells in PDAC specimens.MethodsWe performed a retrospective analysis of long-term survivors (LTS) and short-term survivors (STS) patients with pancreatic cancer associating clinical endpoints with the presence of MAIT infiltration in the tumor tissue using immunofluorescence staining for MR1 (MHC class I-related gene, a MAIT ligand receptor), CD3 and TCR Vα7.2 (frequently reported chain in MAIT). Tumor infiltrating lymphocytes (TILs) were expanded and tested for recognition of microbial products presented to TILs or to PBMCs defined by cytokine production (ELISA), cytotoxicity (CD107a induction assay), CD69 or 4-1BB upregulation (flow cytometry). Reactive MAIT will be molecularly defined by deep TCR (T-cell receptor) sequencing which allows to ‘back-trace’ MR1 reactive TIL in the tumor specimen. The complex interaction of microbial antigen presentation from freshly harvested tumor specimens to TILs is being optimized for Nanolive technology that allows to follow live cell interactions for several days.ResultsTIL reactivity directed against microbial products from different bacterial species was detected by IFN-γ production and CD69 upregulation in responder TILs. A broader panel of TILs is currently being tested against bacterial species. TCRs will undergo laser microdissection for subsequent TCR repertoire sequencing. A more pronounced MAIT infiltration in close vicinity to tumor cells in LTS compared to STS is being studied, further supporting the anti-tumor role of MAIT.ConclusionsMAIT cells may exhibit anti-tumor properties, based on cytokine production and cellular marker activation. TCRs directed against cancer cells can serve as viable blueprints to engage with MR1 on PDAC recognizing tumor-associated targets or microbial products that elicit IFN-γ production. This allows to explore MAIT TCRs for adoptive therapies or distinct microbial species that drive clinically relevant responses.AcknowledgementsThe authors would like to thank to Champalimaud Foundation Biobank and Vivarium Facility at Champalimaud Foundation.Ethics ApprovalThis study was approved by the Champalimaud Foundation Ethics Committee and by Ethics Research Committee of NOVA Medical School of NOVA University of Lisbon.ConsentFor each patient, written informed consent and approval by the Ethical Committee of the Champalimaud Foundation will be obtained. The study will be in compliance with the Declaration of Helsinki.ReferencesSideras, K. et al. Role of the immune system in pancreatic cancer progression and immune modulating treatment strategies. Cancer Treat. Rev 2014;40: 513–522.Toubal A, Nel I, Lotersztajn S & Lehuen A. Mucosal-associated invariant T cells and disease. Nat Rev. Immunol 2019;19:643–657.Lukasik Z, Elewaut D & Venken K. Mait cells come to the rescue in cancer immunotherapy?Cancers (Basel). 12, 1–19 ( 2020).Vacchini A, Chancellor A., Spagnuolo J., Mori L. & De Libero G. MR1-restricted t cells are unprecedented cancer fighters. Front Immunol 2020;11:1–8.Aykut B, et al. The fungal mycobiome promotes pancreatic oncogenesis via activation of MBL. Nature 2019:574;264–267.Pushalkar S, et al. The pancreatic cancer microbiome promotes oncogenesis by induction of innate and adaptive immune suppression. Cancer Discov 2018;8:403–416.

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