参考文献

IntroductionRecently,more and more research illustrated the importance of inducing CD4+ T helper type (Th)-1 dominant immunity for the success of tumor immunotherapy. Our prior studies revealed the crucial role of CD4+ Th1 cells in orchestrating systemic and durable antitumor immunity,which contributes to the satisfactory outcomes of the novel cryo-thermal therapy in the B16F10 tumor model. However,the mechanism for maintaining the cryo-thermal therapy-mediated durable CD4+ Th1-dominant response remains uncovered. Additionally,cryo-thermal-induced early-stage CD4+ Th1-dominant T cell response showed a correlation with the favorable prognosis in patients with colorectal cancer liver metastasis (CRCLM). We hypothesized that CD4+ Th1-dominant differentiation induced during the early stage post cryo-thermal therapy would affect the balance of CD4+ subsets at the late phase.MethodsTo understand the role of interferon (IFN)-γ,the major effector of Th1 subsets,in maintaining long-term CD4+ Th1-prone polarization,B16F10 melanoma model was established in this study and a monoclonal antibody was used at the early stage post cryo-thermal therapy for interferon (IFN)-γ signaling blockade,and the influence on the phenotypic and functional change of immune cells was evaluated.ResultsIFNγ at the early stage after cryo-thermal therapy maintained long-lasting CD4+ Th1-prone immunity by directly controlling Th17,Tfh,and Tregs polarization,leading to the hyperactivation of Myeloid-derived suppressor cells (MDSCs) represented by abundant interleukin (IL)-1β generation,and thereby further amplifying Th1 response.DiscussionOur finding emphasized the key role of early-phase IFNγ abundance post cryo-thermal therapy,which could be a biomarker for better prognosis after cryo-thermal therapy. View Publication

Stimulator of interferon genes (STING) is a central component of the cytosolic nucleic acids sensing pathway and as such master regulator of the type I interferon response. Due to its critical role in physiology and its’ involvement in a variety of diseases,STING has been a focus for drug discovery. Targeted protein degradation (TPD) has emerged as a promising pharmacology for targeting previously considered undruggable proteins by hijacking the cellular ubiquitin proteasome system (UPS) with small molecules. Here,we identify AK59 as a STING degrader leveraging HERC4,a HECT-domain E3 ligase. Additionally,our data reveals that AK59 is effective on the common pathological STING mutations,suggesting a potential clinical application of this mechanism. Thus,these findings introduce HERC4 to the fields of TPD and of compound-induced degradation of STING,suggesting potential therapeutic applications. In this paper,Mutlu et al. identifies a STING degrader,AK59,which inhibits downstream cGAS/STING activity through STING degradation employing a HECT-domain E3 ligase HERC4 and proteasomal ubiquitination pathway. View Publication

Although Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) have been approved in multiple diseases,including BRCA1/2 mutant breast cancer,responses are usually transient requiring the deployment of combination therapies for optimal efficacy. Here we thus explore mechanisms underlying sensitivity and resistance to PARPi using two intrinsically PARPi sensitive (T22) and resistant (T127) syngeneic murine breast cancer models in female mice. We demonstrate that tumor associated macrophages (TAM) potentially contribute to the differential sensitivity to PARPi. By single-cell RNA-sequencing,we identify a TAM_C3 cluster,expressing genes implicated in anti-inflammatory activity,that is enriched in PARPi resistant T127 tumors and markedly decreased by PARPi in T22 tumors. Rps19/C5aR1 signaling is selectively elevated in TAM_C3. C5aR1 inhibition or transferring C5aR1hi cells increases and decreases PARPi sensitivity,respectively. High C5aR1 levels in human breast cancers are associated with poor responses to immune checkpoint blockade. Thus,targeting C5aR1 may selectively deplete pro-tumoral macrophages and engender sensitivity to PARPi and potentially other therapies. PARP inhibitors (PARPi) have been approved for the treatment of metastatic triple-negative breast cancer (BC),however resistance and recurrence are often observed. Here,in preclinical models of BRCA1/2 wild type and homologous recombination competent BC,the authors show that C5aR1-positive tumor associated macrophages are associated with PARPi-resistance,suggesting targeting C5aR1 as a therapeutic option. View Publication

SummarySeptic patients with worst clinical prognosis have increased circulating immature granulocytes (IG),displaying limited phagocytosis and reactive oxygen species (ROS) production. Here,we developed an ex vivo model of incubation of human granulocytes,from septic patients or healthy donors,with Escherichia coli. We showed that the ROS production in Sepsis-IG is lower due to decreased activation and protein expression of the NADPH oxidase complex. We also demonstrated that the low level of ROS production and lower phagocytosis of IG in sepsis induce the bacterial SOS response,leading to the expression of the SOS-regulated quinolone resistance gene qnrB2. Without antimicrobial pressure,the sepsis immune response alone may promote antibiotic resistance expression. Graphical abstract Highlights•Immature granulocytes in sepsis have decreased phagocytosis and ROS production•SOS response is induced in granulocyte-phagocyted bacteria and is ROS dependent•The level of bacterial SOS induction depends on granulocyte maturation and priming•Phagocyted bacteria induce SOS-dependent quinolone resistance qnrB2 expression Immunology; Microbiology; Bacteriology View Publication

BackgroundNatural killer (NK) cells are key effector cells of antitumor immunity. However,tumors can acquire resistance programs to escape NK cell-mediated immunosurveillance. Identifying mechanisms that mediate this resistance enables us to define approaches to improve immune-mediate antitumor activity. In previous studies from our group,a genome-wide CRISPR-Cas9 screen identified Charged Multivesicular Body Protein 2A (CHMP2A) as a novel mechanism that mediates tumor intrinsic resistance to NK cell activity.MethodsHere,we use an immunocompetent mouse model to demonstrate that CHMP2A serves as a targetable regulator of not only NK cell-mediated immunity but also other immune cell populations. Using the recently characterized murine 4MOSC model system,a syngeneic,tobacco-signature murine head and neck squamous cell carcinoma model,we deleted mCHMP2A using CRISPR/Cas9-mediated knock-out (KO),following orthotopic transplantation into immunocompetent hosts.ResultsWe found that mCHMP2A KO in 4MOSC1 cells leads to more potent NK-mediated tumor cell killing in vitro in these tumor cells. Moreover,following orthotopic transplantation,KO of mCHMP2A in 4MOSC1 cells,but not the more immune-resistant 4MOSC2 cells enables both T cells and NK cells to better mediate antitumor activity compared with wild type (WT) tumors. However,there was no difference in tumor development between WT and mCHMP2A KO 4MOSC1 or 4MOSC2 tumors when implanted in immunodeficient mice. Mechanistically,we find that mCHMP2A KO 4MOSC1 tumors transplanted into the immunocompetent mice had significantly increased CD4+T cells,CD8+T cells. NK cell,as well as fewer myeloid-derived suppressor cells (MDSC).ConclusionsTogether,these studies demonstrate that CHMP2A is a targetable inhibitor of cellular antitumor immunity. View Publication

SummaryDrug resistance threatens the effective control of infections,including parasitic diseases such as leishmaniases. Neutrophils are essential players in antimicrobial control,but their role in drug-resistant infections is poorly understood. Here,we evaluated human neutrophil response to clinical parasite strains having distinct natural drug susceptibility. We found that Leishmania antimony drug resistance significantly altered the expression of neutrophil genes,some of them transcribed by specific neutrophil subsets. Infection with drug-resistant parasites increased the expression of detoxification pathways and reduced the production of cytokines. Among these,the chemokine CCL3 was predominantly impacted,which resulted in an impaired ability of neutrophils to attract myeloid cells. Moreover,decreased myeloid recruitment when CCL3 levels are reduced was confirmed by blocking CCL3 in a mouse model. Collectively,these findings reveal that the interplay between naturally drug-resistant parasites and neutrophils modulates the infected skin immune microenvironment,revealing a key role of neutrophils in drug resistance. Graphical abstract Highlights•Drug-resistant parasites induce distinct neutrophil transcriptional programs•Meglumine-antimoniate-resistant (MAR) Leishmania limits neutrophil chemokine release•Infection with MAR parasites impairs CCL3-driven early myeloid cell recruitment Immunology; Parasitology View Publication

SummaryThe viral vector-based COVID-19 vaccine Ad26.COV2.S has been recommended by the WHO since 2021 and has been administered to over 200 million people. Prior studies have shown that Ad26.COV2.S induces durable neutralizing antibodies (NAbs) that increase in coverage of variants over time,even in the absence of boosting or infection. Here,we studied humoral responses following Ad26.COV2.S vaccination in individuals enrolled in the initial Phase 1/2a trial of Ad26.COV2.S in 2020. Through 8 months post vaccination,serum NAb responses increased to variants,including B.1.351 (Beta) and B.1.617.2 (Delta),without additional boosting or infection. The level of somatic hypermutation,measured by nucleotide changes in the VDJ region of the heavy and light antibody chains,increased in Spike-specific B cells. Highly mutated mAbs from these sequences neutralized more SARS-CoV-2 variants than less mutated comparators. These findings suggest that the increase in NAb breadth over time following Ad26.COV2.S vaccination is mediated by affinity maturation. Graphical abstract Highlights•Ad26.COV2.S induced neutralizing antibodies increase in breadth over 8 months•Somatic hypermutation in spike specific B cells also increases over 8 months•Highly mutated monoclonal antibodies neutralize more variants than less mutated•Ad26.COV2.S induces long term affinity maturation Health sciences; Immunity; Immune response; Virology View Publication

SummaryHispanic/Latino children have the highest risk of acute lymphoblastic leukemia (ALL) in the US compared to other racial/ethnic groups,yet the basis of this remains incompletely understood. Through genetic fine-mapping analyses,we identified a new independent childhood ALL risk signal near IKZF1 in self-reported Hispanic/Latino individuals,but not in non-Hispanic White individuals,with an effect size of ∼1.44 (95% confidence interval = 1.33–1.55) and a risk allele frequency of ∼18% in Hispanic/Latino populations and <0.5% in European populations. This risk allele was positively associated with Indigenous American ancestry,showed evidence of selection in human history,and was associated with reduced IKZF1 expression. We identified a putative causal variant in a downstream enhancer that is most active in pro-B cells and interacts with the IKZF1 promoter. This variant disrupts IKZF1 autoregulation at this enhancer and results in reduced enhancer activity in B cell progenitors. Our study reveals a genetic basis for the increased ALL risk in Hispanic/Latino children. Graphical abstract Highlights•IKZF1 variants contribute to the increased risk of ALL in Hispanic/Latino children•Risk allele is associated with Indigenous American ancestry and underwent selection•Risk variant impacts IKZF1 enhancer that is selectively active in B cell development•Risk allele reduces enhancer activity,chromatin accessibility,and IKZF1 expression Genetic fine-mapping across the IKZF1 gene revealed a variant associated with childhood ALL that contributes to the increased risk of this disease in Hispanic/Latino individuals. The ALL risk allele reduces enhancer activity and IKZF1 expression specifically in B cell progenitors,likely resulting in stalled B cell development and an increased risk of ALL. View Publication

AbstractIntestinal chronic inflammation is associated with microbial dysbiosis and accumulation of various immune cells including myeloid-derived suppressor cells (MDSC),which profoundly impact the immune microenvironment,perturb homeostasis and increase the risk to develop colitis-associated colorectal cancer (CAC). However,the specific MDSCs–dysbiotic microbiota interactions and their collective impact on CAC development remain poorly understood. In this study,using a murine model of CAC,we demonstrate that CAC-bearing mice exhibit significantly elevated levels of highly immunosuppressive MDSCs,accompanied by microbiota alterations. Both MDSCs and bacteria that infiltrate the colon tissue and developing tumors can be found in close proximity,suggesting intricate MDSC-microbiota cross-talk within the tumor microenvironment. To investigate this phenomenon,we employed antibiotic treatment to disrupt MDSC–microbiota interactions. This intervention yielded a remarkable reduction in intestinal inflammation,decreased MDSC levels,and alleviated immunosuppression,all of which were associated with a significant reduction in tumor burden. Furthermore,we underscore the causative role of dysbiotic microbiota in the predisposition toward tumor development,highlighting their potential as biomarkers for predicting tumor load. We shed light on the intimate MDSCs-microbiota cross-talk,revealing how bacteria enhance MDSC suppressive features and activities,inhibit their differentiation into mature beneficial myeloid cells,and redirect some toward M2 macrophage phenotype. Collectively,this study uncovers the role of MDSC-bacteria cross-talk in impairing immune responses and promoting tumor growth,providing new insights into potential therapeutic strategies for CAC.Significance:MDSCs–dysbiotic bacteria interactions in the intestine play a crucial role in intensifying immunosuppression within the CAC microenvironment,ultimately facilitating tumor growth,highlighting potential therapeutic targets for improving the treatment outcomes of CAC. View Publication

α-Defensin 1-3 (DEFA1A3) are host antimicrobial peptides with potent innate immune functions during infectious diseases. Differential UTI risk has been linked to DEFA1A3 DNA polymorphisms. This study elucidates mechanisms of DEFA1A3 gene dose–dependent protection against UTI pathogenesis. Antimicrobial peptides (AMPs) are host defense effectors with potent neutralizing and immunomodulatory functions against invasive pathogens. The AMPs α-Defensin 1-3/DEFA1A3 participate in innate immune responses and influence patient outcomes in various diseases. DNA copy-number variations in DEFA1A3 have been associated with severity and outcomes in infectious diseases including urinary tract infections (UTIs). Specifically,children with lower DNA copy numbers were more susceptible to UTIs. The mechanism of action by which α-Defensin 1-3/DEFA1A3 copy-number variations lead to UTI susceptibility remains to be explored. In this study,we use a previously characterized transgenic knock-in of the human DEFA1A3 gene mouse to dissect α-Defensin 1-3 gene dose–dependent antimicrobial and immunomodulatory roles during uropathogenic Escherichia coli (UPEC) UTI. We elucidate the relationship between kidney neutrophil– and collecting duct intercalated cell–derived α-Defensin 1-3/DEFA1A3 expression and UTI. We further describe cooperative effects between α-Defensin 1-3 and other AMPs that potentiate the neutralizing activity against UPEC. Cumulatively,we demonstrate that DEFA1A3 directly protects against UPEC meanwhile impacting pro-inflammatory innate immune responses in a gene dosage–dependent manner. View Publication