Immune surveillance of the liver by T cells

2020 ◽  
Vol 5 (51) ◽  
pp. eaba2351
Author(s):  
Xenia Ficht ◽  
Matteo Iannacone
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cross Talk ◽  
Immune Cell ◽  
Current Knowledge ◽  
Immune Surveillance ◽  
Neoplastic Diseases ◽  
Cell Responses ◽  
Immune Cell Subsets ◽  
Invariant T Cells

The liver is the target of several infectious, inflammatory, and neoplastic diseases, which affect hundreds of millions of people worldwide and cause an estimated death toll of more than 2 million people each year. Dysregulation of T cell responses has been implicated in the pathogenesis of these diseases; hence, it is critically important to understand the function and fate of T cells in the liver. Here, we provide an overview of the current knowledge on liver immune surveillance by conventional and invariant T cells and explore the complex cross-talk between immune cell subsets that determines the balance between hepatic immunity and tolerance.

scholarly journals Global immune characterization of HBV/HCV-related hepatocellular carcinoma identifies macrophage and T-cell subsets associated with disease progression

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Guohe Song ◽  
Yang Shi ◽  
Meiying Zhang ◽  
Shyamal Goswami ◽  
Saifullah Afridi ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
T Cell ◽  
Single Cell ◽  
Immune Cells ◽  
Immune Cell ◽  
T Cell Subsets ◽  
M2 Macrophage ◽  
Advanced Hcc ◽  
Immune Cell Subsets

AbstractDiverse immune cells in the tumor microenvironment form a complex ecosystem, but our knowledge of their heterogeneity and dynamics within hepatocellular carcinoma (HCC) still remains limited. To assess the plasticity and phenotypes of immune cells within HBV/HCV-related HCC microenvironment at single-cell level, we performed single-cell RNA sequencing on 41,698 immune cells from seven pairs of HBV/HCV-related HCC tumors and non-tumor liver tissues. We combined bio-informatic analyses, flow cytometry, and multiplex immunohistochemistry to assess the heterogeneity of different immune cell subsets in functional characteristics, transcriptional regulation, phenotypic switching, and interactions. We identified 29 immune cell subsets of myeloid cells, NK cells, and lymphocytes with unique transcriptomic profiles in HCC. A highly complex immunological network was shaped by diverse immune cell subsets that can transit among different states and mutually interact. Notably, we identified a subset of M2 macrophage with high expression of CCL18 and transcription factor CREM that was enriched in advanced HCC patients, and potentially participated in tumor progression. We also detected a new subset of activated CD8+ T cells highly expressing XCL1 that correlated with better patient survival rates. Meanwhile, distinct transcriptomic signatures, cytotoxic phenotypes, and evolution trajectory of effector CD8+ T cells from early-stage to advanced HCC were also identified. Our study provides insight into the immune microenvironment in HBV/HCV-related HCC and highlights novel macrophage and T-cell subsets that could be further exploited in future immunotherapy.

scholarly journals Emerging Roles of T Cells in the Pathogenesis of Nonalcoholic Steatohepatitis and Hepatocellular Carcinoma

2021 ◽  
Vol 12 ◽  
Author(s):  
Petra Hirsova ◽  
Adebowale O. Bamidele ◽  
Haiguang Wang ◽  
Davide Povero ◽  
Xavier S. Revelo
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
Liver Disease ◽  
T Cell ◽  
Nonalcoholic Steatohepatitis ◽  
Immune Cell ◽  
Current Knowledge ◽  
Significant Proportion ◽  
Nonalcoholic Fatty Liver ◽  
Integral Role

Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide. A significant proportion of patients with NAFLD develop a progressive inflammatory condition termed nonalcoholic steatohepatitis (NASH), which may eventually advance to cirrhosis and hepatocellular carcinoma (HCC). NASH is characterized by steatosis, hepatocyte ballooning, and lobular inflammation. Heightened immune cell infiltration is a hallmark of NASH, yet the mechanisms whereby hepatic inflammation occurs in NASH and how it contributes to disease initiation and progression remain incompletely understood. Emerging evidence indicates that intrahepatic T cell immune mechanisms play an integral role in the pathogenesis of NASH and its transition to HCC. In this review, we summarize the current knowledge regarding the T cell-mediated mechanisms of inflammation in NASH. We highlight recent preclinical and human studies implicating various subsets of conventional and innate-like T cells in the onset and progression of NASH and HCC. Finally, we discuss the potential therapeutic strategies targeting T cell-mediated responses for the treatment of NASH.

scholarly journals Potent Anti-Tumor Activity of Bcma CAR-T Therapy Against Heavily Treated Multiple Myeloma and Dynamics of Immune Cell Subsets Using Single-Cell Mass Cytometry

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1859-1859 ◽  
Author(s):  
Yongxian Hu ◽  
Zhang Yanlei ◽  
Guoqing Wei ◽  
Chang alex Hong ◽  
He Huang
Keyword(s):  
T Cells ◽  
T Cell ◽  
Single Cell ◽  
Immune Cell ◽  
Cell Mass ◽  
Mass Cytometry ◽  
Car T Cells ◽  
Car T Cell ◽  
Immune Cell Subsets ◽  
Car T

Background BCMA CAR-T cells have demonstrated substantial clinical activity against relapsed/refractory multiple myeloma (RRMM). In different clinical trials, the overall response rate (ORR) varied from 50% to 100%. Complete remission (CR) rate varied from 20% to 80%. Here we developed a BCMA CAR-T cell product manufactured via lentiviral vector-mediated transduction of activated T cells to express a second-generation CAR with 4-1BB costimulatory domain and evaluated the efficacy and safety, moreover, dynamics of immune cell subsets using single-cell mass cytometry during treatment were analyzed. Methods Our trial (ChiCTR1800017404) is a phase 1, single-arm, open-label single center study to evaluate the safety and efficacy of autologous BCMA CAR-T treatment for RRMM. Patients were subjected to a lymphodepleting regimen with Flu and Cy prior to CAR-T infusion. BCMA CAR-T cells were administered as a single infusion at a median dose of 3.5 (1 to 6) ×106/kg. MM response assessment was conducted according to the International Uniform Response Criteria. Cytokine-release syndrome (CRS) was graded as Lee DW et al described (Blood.2014;124(2):188-195). Phenotypic analysis of peripheral blood mononuclear cells (PBMCs), frozen BCMA CAR-T aliquots, phenotype and in vivo kinetics of immune cell subsets after CAR-T infusion were performed by single-cell mass cytometry. Results As of the data cut-off date (August 1st, 2019), 33 patients, median age 62.5 (49 to 75) years old were infused with BCMA CAR-T cells. The median observation period is 8.0 (0.7 to 18) months. ORR was 100% (The patient who died of infection at 20 days after CAR-T infusion were excluded). All the 32 patients achieved MRD negative in bone marrow by flow cytometry in 2 weeks after CAR-T infusion. Partial response (4 PR, 12.1%), VGPR (7 VGPR, 21.2%), and complete response (21 CR, 63.6%) within 12 weeks post CAR-T infusion were achieved. Durable responses from 4 weeks towards the data cut-off date were found in 28/33 patients (84.8%) (Figure 1a). All patients had detectable CAR-T expansion by flow cytometry from Day 3 post CAR-T cell infusion. The peak CAR-T cell expansion in CD3+ lymphocytes of peripheral blood (PB) varied from 35% to 95% with a median percentage of 82.9%. CRS was reported in all the 33 patients, including 4 with Grade 1, 13 with Grade 2 and 16 with Grade 3. During follow-up, 1-year progression-free survival (PFS) was 70.7% (Figure 1b) and overall survival (OS) was 71.7% (Figure 1c). Multivariate analysis of patients with PR and patients with CR+VGPR revealed that factors including extramedullary infiltration, age>60 years old, high-risk cytogenetics, late stage and CAR-T cell dose were not associated with clinical response (P>0.05). Single-cell mass cytometry revealed that the frequency of total T cells, CD8+ T cells, NK cells and CD3+CD56+ NKT cells in PB was not associated with BCM CAR-T expansion or clinical response. CD8+ Granzyme B+ Ki-67+ CAR-T cells expanded prominently in CRS period. As serum cytokines increased during CRS, non-CAR-T immune cell subsets including PD1+ NK cells, CD8+ Ki-67+ ICOS+ T cells expanded dominantly implying that non-CAR-T cells were also activated after CAR-T treatment. After CRS, stem cell like memory CAR-T cells (CD45RO+ CCR7- CD28- CD95+) remain the main subtype of CAR-T cells (Figure 1d). Conclusions Our data showed BCMA CAR-T treatment is safe with prominent efficacy which can overcome the traditional high-risk factors. We also observed high expansion level and long-term persistence of BCMA CAR-T cells contribute to potent anti-myeloma activity. Stem cell like memory CAR-T cells might be associated with long-term persistence of BCMA CAR-T cells. These initial data provide strong evidence to support the further development of this anti-myeloma cellular immunotherapy. Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals The role of synovial T-cell infiltration following knee joint injury in symptoms and progression to osteoarthritis

2019 ◽  
Author(s):  
Babak Moradi ◽  
Miriam T Jackson ◽  
Cindy C. Shu ◽  
Susan M Smith ◽  
Margaret M Smith ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Cell ◽  
Post Injury ◽  
Joint Injury ◽  
Cell Responses ◽  
Cellular Events ◽  
Bona Fide

AbstractObjectivesIdentification of osteoarthritis(OA)-specific synovial inflammatory pathways, and when in the clinical course they are active, is critical for their utility as therapeutic targets. We directly compared the mononuclear inflammatory/immune-cell responses following joint injury that does and does-not lead to OA, to define bona-fide OA-associated cellular events.MethodsWe undertook detailed temporal flow-cytometric and mRNA expression analysis in mice after sham or medial-meniscal-destiblization (DMM) surgery. We compared this with patients with meniscal injury and OA, and evaluated the role of synovial monocytes/macrophages versus lymphocytes in catabolic metalloproteinase secrection in vitro. We determined the effect of transient acute or delayed systemic T-cell depletion on DMM-induced OA pathology.ResultsOA-inducing/DMM and non-OA-inducing/Sham surgery had identical synovial monocyte/macrophage number, activation and polarization. The number and activation of synovial (not splenic or peripheral-blood) CD4 and CD8 lymphocytes was increased from 1-day after DMM versus Sham, and showed a persistent cyclical elevation throughout OA onset and progression. There was a temporal imbalance in synovial Th17/Treg and Th1/Th2 lymphocytes during DMM-induced OA initiation and progression. We confirmed early post-injury and late-OA CD3/CD8 T-cell responses in synovial tissues from patients, identified an association between CD8 and early post-injury symptoms, and defined a significant role for CD3+T-cells in synovial metalloproteinase secretion. Anti-CD3 cell-depletion studies in mice confirmed a key role for the earliest post-injury T-cell response in long-term OA pathology.ConclusionsWe identify a hitherto unappreciated pathophysiological role of acute T-cell activation after joint injury in long-term post-traumatic OA risk, providing a novel diagnostic and therapeutic target.Key MessagesWhat is already known about this subject?The presence of synovitis/joint-inflammation increases the risk not only of osteoarthritis (OA) progression but incident disease. While numerous inflammatory effectors including macrophages and lymphocytes have been identified in OA, their disease-specificity, temporal regulation, and association with risk of pathology onset and progression is lacking.How does this study add?By directly comparing the mononuclear inflammatory/immune-cell responses following significant joint injury that does (medial-meniscal-destabilization; DMM) and does-not (Sham-surgery) lead to OA in mice, we have defined bona-fide OA-associated cellular events. There was no difference in synovial or systemic monocyte/macrophage cell number, activation or polarization between DMM and Sham, both showing a successful wound-healing response. In contrast, increases in number and activation of synovial Th1- and Th17-CD4, and CD8 T-cells in DMM compared with Sham occurred within the first 3 days, and while recurring cyclically through subsequent disease onset, depletion studies indicated this initial influx was key to long-term ptOA risk.How might this impact on clinical practice of future developments?Acute increases in synovial T-cells following jont injury may be both a novel marker of OA risk, and a target to reduce long term structural damage.

scholarly journals Selective B cell depletion upon intravenous infusion of replication-incompetent anti-CD19 CAR lentivirus

2020 ◽  
Author(s):  
Craig M. Rive ◽  
Eric Yung ◽  
Lisa Dreolini ◽  
Daniel J. Woodsworth ◽  
Robert A. Holt
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Peripheral Blood ◽  
Immune Cell ◽  
Wild Type ◽  
Immune Cell Subsets ◽  
Car T

AbstractAnti-CD19 CAR-T therapy for B cell malignancies has shown clinical success, but a major limitation is the logistical complexity and high cost of manufacturing autologous cell products. Direct infusion of viral gene transfer vectors to initiate in vivo CAR-T transduction, expansion and anti-tumor activity could provide an alternative, universal approach for CAR-T and related immune effector cell therapies that circumvents ex vivo cell manufacturing. To explore the potential of this approach we first evaluated human and murine CD8+ T cells transduced with VSV-G pseudotyped lentivectors carrying an anti-CD19CAR-2A-GFP transgene comprising either an FMC63 (human) or 1D3 (murine) anti-CD19 binding domain. To evaluate CD19 antigen-driven CAR-T proliferation in vitro we co-cultured transduced murine T cells with an excess of irradiated splenocytes and observed robust expansion over a 9 week period relative to control T cells transduced with a GFP transgene (mean fold expansion +/- SD: ID3-CD19CAR-GFP modified T cells, 12.2 +/- 0.09 (p < 0.001); FMC63-CD19CAR-GFP modified T cells 8.8 +/- 0.03 (p < 0.001). CAR-T cells isolated at the end of the expansion period showed potent B cell directed cytolytic activity in vitro. Next, we administered approximately 20 million replication-incompetent lentiviral particles carrying either ID3-CD19CAR-GFP, FMC63-CD19CAR-GFP, or GFP-only transgene to to wild-type C57BL/6 mice by tail vein infusion and monitored the dynamics of immune cell subsets isolated from peripheral blood at weekly intervals. We saw emergence of a persistent CAR-transduced CD3+ T cell population beginning week 3-4 that reaching a maximum of 13.5 +/- 0.58 % (mean +/- SD) and 7.8 +/- 0.76% of the peripheral blood CD3+ T cell population in mice infused with ID3-CD19CAR-GFP lentivector or FMC63-CD19CAR-GFP lentivector, respectively, followed by a rapid decline, in each case of, the B cell content of peripheral blood. Complete B cell aplasia was apparent by week 5 and was sustained until the end of the protocol (week 8). None of these changes were observed in mice infused with GFP-only control lentivector, and significant CAR positive populations were not observed within other immune cell subsets, including macrophage, natural killer, or B cells. Within the T cell compartment, CD8+ effector memory cells were the predominant CAR-positive subset. Modest weight loss of 5.5 +/- 2.97 % (mean +/- SD) observed in some animals receiving an anti-CD19CAR-GFP transgene during the protocol. These results indicate that direct IV infusion of lentiviral particles carrying an anti-CD19 CAR transgene can transduce T cells that then fully ablate endogenous B cells in wild type mice. Based on these results it may be useful to further explore, using currently available vectors, the feasibility of systemic gene therapy as a modality for CAR-T intervention.

scholarly journals Mucosal Immunity andCandida albicansInfection

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
David L. Moyes ◽  
Julian R. Naglik
Keyword(s):  
T Cells ◽  
Candida Albicans ◽  
Host Defense ◽  
Mucosal Immunity ◽  
Immune Cell ◽  
Current Knowledge ◽  
Mucosal Surfaces ◽  
Immune Cell Subsets ◽  
Health And Disease ◽  
Review Current

Interactions between mucosal surfaces and microbial microbiota are key to host defense, health, and disease. These surfaces are exposed to high numbers of microbes and must be capable of distinguishing between those that are beneficial or avirulent and those that will invade and cause disease. Our understanding of the mechanisms involved in these discriminatory processes has recently begun to expand as new studies bring to light the importance of epithelial cells and novel immune cell subsets such as Th17 T cells in these processes. Elucidating how these mechanisms function will improve our understanding of many diverse diseases and improve our ability to treat patients suffering from these conditions. In our voyage to discover these mechanisms, mucosal interactions with opportunistic commensal organisms such as the fungusCandida albicansprovide insights that are invaluable. Here, we review current knowledge of the interactions betweenC. albicansand epithelial surfaces and how this may shape our understanding of microbial-mucosal interactions.

Immune Surveillance By Autoreactive Helper But Not Cytolytic T Cells Is a Common Phenomenon In Patients With Acute Myeloid Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1044-1044
Author(s):  
Tin Sing Lam ◽  
Marian van de Meent ◽  
J.H. Frederik Falkenburg ◽  
Inge Jedema
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Surveillance ◽  
Cell Populations ◽  
Target Cells ◽  
Common Phenomenon ◽  
Autoreactive T Cells ◽  
Cell Responses ◽  
Autoreactive T Cell ◽  
Cell Clones

Abstract The presence of immune surveillance as a mechanism to prevent the development of malignancies and/or to eradicate small numbers of developing tumor cells has been described by many researchers in the past. The development of an overt malignancy may therefore be seen as failure of immune surveillance. In previous studies we demonstrated the existence of autoreactive CD4 T cells showing HLA-restricted reactivity against myeloid cells as a common phenomenon in healthy individuals. These autoreactive T cells show a profound cytokine response, but do not exert significant cytotoxic effects. To investigate whether such autoreactive T cell responses could play a role in immune surveillance against myeloid malignancies, we investigated the functional reactivity and cell lineage specificity of autologous T cell responses mounted against mature acute myeloid leukemia (AML) blasts. T cells were isolated using the pan T isolation kit and magnetic bead separation (MACS) from peripheral blood of patients with AML in remission after induction chemotherapy and labeled with the fluorescent dye PKH26. These T cells were stimulated with autologous AML blasts at a 1/2 responder to stimulator ratio and cultured for 14 days in medium containing heat-inactivated human serum and 1 ng/mL IL7 and 0.01 ng/mL IL-15 (Miltenyi). At day 14, proliferating CD4 and CD8 T cells comprising 7.3% +/- 2.5% and 0.8 +/- 0.5% of the total T cell populations, respectively, were isolated single cell/well using flowcytometric cell sorting based on PKH dilution. T cell clones were expanded and tested against a panel of autologous and HLA-matched or HLA-mismatched allogeneic target cells, comprising AML blasts, EBV-LCL, monocytes, monocyte-derived dendritic cells (DCs), B cells and primary skin fibroblasts. The isolated CD4 clones produced interferon-gamma (IFNg) and/or interleukin 4 (IL-4) in response to stimulation with autologous AML blasts. This cytokine production could be blocked using pan-HLA-class-II and allele-specific blocking antibodies. HLA-DR, -DP, as well as –DQ restricted clones were found and these clones displayed an oligoclonal T cell receptor V-beta (TCR-VB) usage. Interestingly, these clones exerted also reactivity against autologous EBV-LCL, monocytes, DCs, HLA-class II expressing (IFNg pretreated) fibroblasts and to a lesser extend against autologous B cells, as well as to the same target cell populations (including AML blasts) obtained from allogeneic third party individuals that were matched for the HLA-molecules presenting the T cell epitopes. These results indicate recognition of common antigens, not restricted to the malignant cell populations. No reactivity was observed against HLA-mismatched target cells. In addition, a limited number of CD8 clones was isolated that showed a similar HLA-restricted cytokine production profile. Similar experiments were performed in serumfree X-vivo15 medium to exclude recognition of serum components. In contrast to the profound cytokine response, none of the isolated clones exerted substantial cytotoxicity against one of the targets. Some CD8 clones exerted a maximum of 17% lysis at a 10/1 effector to target ratio against AML blasts. Since no direct cytotoxicity by the autoreactive T cells could be demonstrated, we investigated whether crosstalk between the autoreactive T cells and the AML blasts may render the AML cells more sensitive to subsequent immune attack. The expression of costimulatory markers (CD40, CD80 and CD86) and adhesion (ICAM-1 /CD54) on the AML blasts was significantly increased after co-incubation with the autoreactive T cells. Similar AML responsive autoreactive T cell clones were obtained using T cells from HLA-matched healthy donors as responder cells, illustrating that these autoreactive T cells are part of the normal T cell repertoire and were not induced by the high dose chemotherapy that the patients had been subjected to. In conclusion, we here demonstrate that the presence of autoreactive helper T cells is a common phenomenon in patients with AML. We hypothesize that the large burden of myeloid cells at presentation of AML may result in the amplification of an autoreactive AML directed CD4 T cell response. This response does not result in a direct effective anti-AML immune surveillance, but the immune-modulatory effect on the AML phenotype upon crosstalk may pave the way for other immunological interventions. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Mucosal immune responses to HIV-1 in elite controllers: a potential correlate of immune control

Blood ◽  
2009 ◽  
Vol 113 (17) ◽  
pp. 3978-3989 ◽  
Author(s):  
April L. Ferre ◽  
Peter W. Hunt ◽  
J. William Critchfield ◽  
Delandy H. Young ◽  
Megan M. Morris ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Surveillance ◽  
Interleukin 2 ◽  
Rectal Mucosa ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Elite Controllers ◽  
Cell Responses ◽  
Hiv 1

AbstractThere exists a unique group of persons who are able to durably control HIV in the absence of therapy. The mechanisms of control in these persons remain poorly defined. In this study, we examined CD8+ T-cell responses in blood and rectal mucosa from 17 “elite controllers” (viral load < 75 copies/mL), 11 “viremic controllers” (75-2000 copies/mL), 14 noncontrollers (> 10 000 copies/mL), and 10 antiretroviral-treated persons (< 75 copies/mL). Production of interferon-γ, interleukin-2, tumor necrosis factor-α, macrophage inflammatory protein-1β, and CD107a by CD8+ T cells in response to HIV-1 Gag stimulation was measured using flow cytometry. Our hypothesis was that “polyfunctional” T cells producing multiple antiviral factors would be most abundant in mucosal tissues of HIV controllers. Mucosal CD8+ T-cell responses were significantly stronger and more complex in controllers than in antiretroviral-suppressed persons (P = .0004). The frequency of 4-function responses in rectal mucosa was higher in controllers than in noncontrollers and patients on therapy (P < .0001). Mucosal responses in controllers were frequently stronger and more complex than blood responses. These findings demonstrate that many controllers mount strong, complex HIV-specific T-cell responses in rectal mucosa. These responses may play an important role in mucosal immune surveillance, as suggested by their relative enrichment among persons who control HIV in the absence of therapy.

scholarly journals IRAK1-regulated IFN-γ signaling induces MDSC to facilitate immune evasion in FGFR1-driven hematological malignancies

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Baohuan Cai ◽  
Yun Liu ◽  
Yating Chong ◽  
Hualei Zhang ◽  
Atsuko Matsunaga ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Interferon Gamma ◽  
Immune Evasion ◽  
Immune Cell ◽  
Immune Surveillance ◽  
Leukemia Cell ◽  
Leukemia Cells ◽  
Rapid Progression ◽  
Ifn Γ

Abstract Background Stem Cell leukemia/lymphoma syndrome (SCLL) presents as a myeloproliferative disease which can progress to acute myeloid leukemia and is associated with the coincident development of B-cell and T-cell lymphomas. SCLL is driven by the constitutive activation of fibroblast growth factor receptor-1 (FGFR1) as a result of chromosome translocations with poor outcome. Mouse models have been developed which faithfully recapitulate the human disease and have been used to characterize the molecular genetic events that are associated with development and progression of the disease. Methods CRISPR/Cas9 approaches were used to generate SCLL cells null for Interleukin receptor associated kinase 1 (IRAK1) and interferon gamma (IFNG) which were introduced into syngeneic hosts through tail vein injection. Development of the disease and changes in immune cell composition and activity were monitored using flow cytometry. Bead-based immunoassays were used to compare the cytokine and chemokine profiles of control and knock out (KO) cells. Antibody mediated, targeted depletion of T cell and MDSCs were performed to evaluate their role in antitumor immune responses. Results In SCLL, FGFR1 activation silences miR-146b-5p through DNMT1-mediated promoter methylation, which derepresses the downstream target IRAK1. IRAK1 KO SCLL cells were xenografted into immunocompetent syngeneic mice where the typical rapid progression of disease was lost and the mice remained disease free. IRAK1 in this system has no effect on cell cycle progression or apoptosis and robust growth of the KO cells in immunodeficient mice suggested an effect on immune surveillance. Depletion of T-cells in immunocompetent mice restored leukemogenesis of the KO cells, and tumor killing assays confirmed the role of T cells in tumor clearance. Analysis of the immune cell profile in mice transplanted with the IRAK1 expressing mock control (MC) cells shows that there is an increase in levels of myeloid-derived suppressor cells (MDSCs) with a concomitant decrease in CD4+/CD8+ T-cell levels. MDSC suppression assays and depletion experiments showed that these MDSCs were responsible for suppression of the T cell mediated leukemia cell elimination. Immuno-profiling of a panel of secreted cytokines and chemokines showed that activation of IFN-γ is specifically impaired in the KO cells. In vitro and in vivo expression assays and engraftment with interferon gamma receptor-1 (IFNGR1) null mice and IFNG KO SCLL cells, showed the leukemia cells produced IFN-γ directly participating in the induction of MDSCs to establish immune evasion. Inhibition of IRAK1 using pacritinib suppresses leukemogenesis with impaired induction of MDSCs and attenuated suppression of CD4+/CD8+ T-cells. Conclusions IRAK1 orchestrates a previously unknown FGFR1-directed immune escape mechanism in SCLL, through induction of MDSCs via regulation of IFN-γ signaling from leukemia cells, and targeting IRAK1 may provide a means of suppressing tumor growth in this syndrome by restoring immune surveillance.

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