T-cell Deficiency Research Articles

γδ T Cells Mediate Protection against Neutrophil-associated Lung Inflammation in Pulmonary Melioidosis.

Pulmonary melioidosis is a severe tropical infection caused by Burkholderia pseudomallei and is associated with high mortality, despite early antibiotic treatment. γδ T cells have been increasingly implicated as drivers of the host neutrophil response during bacterial pneumonia, but their role in pulmonary melioidosis is unknown. Here, we report that in patients with melioidosis, a lower peripheral blood γδ T-cell concentration is associated with higher mortality, even when adjusting for severity of illness. γδ T cells were also enriched in the lung and protected against mortality in a mouse model of pulmonary melioidosis. γδ T-cell deficiency in infected mice induced an early recruitment of neutrophils to the lung, independent of bacterial burden. Subsequently, γδ T-cell deficiency resulted in increased neutrophil-associated inflammation in the lung as well as impaired bacterial clearance. In addition, γδ T cells influenced neutrophil function and subset diversity in the lung after infection. Our results indicate that γδ T cells serve a novel protective role in the lung during severe bacterial pneumonia by regulating excessive neutrophil-associated inflammation.

Primary Cutaneous Acral-type CD8-positive T-cell Lymphoproliferations: Widely Divergent Clinical Outcomes Despite Nearly Identical Histomorphology

Abstract Introduction/Objective Non-epidermotropic and acral CD8(+) T-cell proliferations have recently been reclassified as lymphoproliferative disorders (LPDs) due to their indolent course clinical. Here, we describe two cases with similar histomorphology but disparate clinical outcomes, highlighting the diagnostic challenges. Methods/Case Report Case 1: An 89-year-old male developed a 2 cm erythematous papule on the forehead. Biopsy showed a non-epidermotropic pan-dermal lymphocytic infiltrate, a distinct grenz zone, and areas of necrosis. Case 2: A 53-year-old male presented with a rapidly growing, ulcerating 8.9 cm scalp lesion. Biopsy showed a deep dermal lymphoid infiltrate with complete epidermal sparing. In both cases neoplastic cells were positive by immunohistochemistry for CD2, CD3, CD5, CD7 (partial), CD8, granzyme B, TIA-1, and CD68 (perinuclear dot-like pattern). The Ki-67 proliferation index varied modestly between cases (50% in case 1 and 70% in case 2, respectively). Despite treatment, within the span of a few months, case 2 developed adjacent, widely distributed scalp nodules with extensive local tissue destruction. Pathology was consistent with recurrent disease (flow cytometry demonstrating T-cells, co-expressing CD8, CD2, CD3, CD5, CD7 and monotypic TRBC1). Results (if a Case Study enter NA) NA Conclusion CD8+ T-cell lymphoproliferative disorders, specifically primary cutaneous acral CD8+ T-cell lymphoproliferative disorder, is a rare cutaneous T-cell disorder that was re-classified, owing to its indolent clinical course, low risk of systemic dissemination, and favorable prognosis. We report two cases of nearly identical isolated cutaneous lesions that demonstrated a CD8(+)-cytotoxic phenotype with CD68-dot-like positivity. Although all morphologic findings were supportive of the diagnosis, the aggressive clinical progression in case 2 highlights the potential for the disease to defy the classically described indolent behavior. Given that few cases with aggressive clinical courses have been published, we present these cases to underscore their complexity and propose that the classification incorporate clinicopathological correlation to guide management.

Are immunosenescent T cells really senescent?

Loss of proper T-cell functioning is a feature of aging that increases the risk of developing chronic diseases. In aged individuals, highly differentiated T cells arise with a reduced expression of CD28 and CD27 and an increased expression of KLRG-1 or CD57. These cells are often referred to as immunosenescent T cells but may still be highly active and contribute to autoimmunity. Another population of T cells known as exhausted T cells arises after chronic antigen stimulation and loses its effector functions, leading to a failure to combat malignancies and viral infections. A process called cellular senescence also increases during aging, and targeting this process has proven to be fruitful against a range of age-related pathologies in animal models. Cellular senescence occurs in cells that are irreparably damaged, limiting their proliferation and typically leading to chronic secretion of pro-inflammatory factors. To develop therapies against pathologies caused by defective T-cell function, it is important to understand the differences and similarities between immunosenescence and cellular senescence. Here, we review the hallmarks of cellular senescence versus senescent and exhausted T cells and provide considerations for the development of specific therapies against age-related diseases.

Abnormal Immune Profile in Individuals with Kabuki Syndrome.

To analyze the lymphocyte subsets in individuals with Kabuki syndrome for better characterizing the immunological phenotype of this rare congenital disorder. We characterized the immunological profile including B-, T- and natural killer-cell subsets in a series (N = 18) of individuals with Kabuki syndrome. All 18 individuals underwent genetic analysis: 15 had a variant in KMT2D and 3 a variant in KDM6A. Eleven of the 18 individuals (61%) had recurrent infections and 9 (50%) respiratory infections. Three (17%) had autoimmune diseases. On immunological analysis, 6 (33%) had CD4 T-cell lymphopenia, which was preferentially associated with the KMT2D truncating variant (5/9 individuals). Eight of 18 individuals (44%) had a humoral deficiency and eight (44%) had B lymphopenia. We found abnormal distributions of T-cell subsets, especially a frequent decrease in recent thymic emigrant CD4 + naive T-cell count in 13/16 individuals (81%). The immunological features of Kabuki syndrome showed variable immune disorders with CD4 + T-cell deficiency in one third of cases, which had not been previously reported. In particular, we found a reduction in recent thymic emigrant naïve CD4 + T-cell count in 13 of 16 individuals, representing a novel finding that had not previously been reported.

Comprehensive exploration of FCHO1 mutations: Clinical manifestations and implications across disorders.

FCH domain only 1 (FCHO1) is a key player in clathrin-mediated endocytosis, vital for various cellular processes, including immune regulation and cancer progression. However, the clinical implications of FCHO1 mutations, particularly in combined immunodeficiency, remain unclear. This systematic review aims to provide an objective analysis of the molecular genetics, clinical manifestations, and potential therapeutic targets associated with FCHO1 mutations. A systematic search following Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines was conducted across electronic databases up to March 25, 2024, to identify studies investigating the relationship between FCHO1 and different clinical manifestations. Eligibility criteria were applied to screen studies, and data extraction included study characteristics, reported symptoms, genetic variants, and primary outcomes. In silico analyses were performed to assess protein-protein interactions and gene expression patterns. Five studies were included, offering insights into the molecular genetics, T-cell deficiency mechanisms, clinical manifestations, and potential therapeutic targets associated with FCHO1 mutations. Molecular analyses identified specific mutations disrupting FCHO1 function, leading to impaired T-cell proliferation, cytokine production, and susceptibility to infections. Clinically, patients exhibited recurrent infections, lymphopenia, and malignancies, with allogeneic hematopoietic stem cell transplantation emerging as a therapeutic option. In silico analyses revealed potential interactions and co-expression between FCHO1 and genes involved in cancer progression and immune signaling pathways. This systematic review objectively elucidates the multifaceted role of FCHO1 in immune regulation and disease pathogenesis. Understanding the molecular mechanisms underlying FCHO1 mutations and their impact on disease manifestations is crucial for guiding clinical management and developing targeted therapeutic strategies.

CD8+ T-cell deficiency protects mice from abdominal aortic aneurysm formation in response to calcium chloride2.

Abdominal aortic aneurysm (AAA) is an aneurysm-like dilated and highly fatal cardiovascular disease. CD8+ T cells have been shown to be critical for vascular pathological processes, but the contribution of these lymphocytes to vascular diseases remains elusive. Eight-week-old male wildtype (CD8+/+) and Cd8a knockout (CD8-/-) mice were used in a calcium chloride2 (CaCl2)-induced experimental AAA model. At 6 weeks after surgery, CD8+ T-cell deletion prevented the formation of AAA, accompanied by reductions of the levels of inflammatory (interferon-γ [IFN-γ], interleukin-1β, monocyte chemoattractant protein-1, intracellular adhesion molecule-1, vascular cell adhesion molecule-1, NOD-like receptor protein 3, caspase-1), oxidative stress [NADPH oxidase and gp91phox], and proteolysis (cathepsin S, cathepsin K, matrix metalloproteinase-2 [MMP-2] and MMP-9) proteins and/or genes in plasma and/or AAA tissues. Immunoreactivities of MMP-2 and MMP-9 were observed in macrophages. An injection of IFN-γ and adoptive transfer of CD8+ T cells of IFN-γ+/+ mice diminished CD8-/--mediated vasculoprotective actions in the AAA mice. In vitro, IFN-γ enhanced MMP-2 and MMP-9 gelatinolytic activities in macrophage and/or vascular smooth muscle cells. The vasculoprotective effects of CD8+ T-cell deletion in a mouse CaCl2-induced AAA model were likely attributable to, at least in part, the attenuation of IFN-γ-dependent inflammation action, oxidative stress production, and proteolysis, suggesting a novel therapeutic target for AAA formation by regulating CD8+ T-cell-derived IFN-γ secretion.

Targeting ROS-sensing Nrf2 potentiates anti-tumor immunity of intratumoral CD8+ T and CAR-T cells

Cytotoxic T lymphocytes (CTLs) play a crucial role in cancer rejection. However, CTLs encounter dysfunction and exhaustion in the immunosuppressive tumor microenvironment (TME). Although the reactive oxygen species (ROS)-rich TME attenuates CTL function, the underlying molecular mechanism remains poorly understood. The nuclear factor erythroid 2-related 2 (Nrf2) is the ROS-responsible factor implicated in increasing susceptibility to cancer progression. Therefore, we examined how Nrf2 is involved in anti-tumor responses of CD8+ T and chimeric antigen receptor (CAR) Tcells in the ROS-rich TME. Here, we demonstrated that tumor growth in Nrf2-/- mice was significantly controlled and was reversed by Tcell depletion and further confirmed that Nrf2 deficiency in Tcells promotes anti-tumor responses using an adoptive transfer model of antigen-specific CD8+ Tcells. Nrf2-deficient CTLs are resistant to ROS, and their effector functions are sustained in the TME. Furthermore, Nrf2 knockdown in human CAR-Tcells enhanced the survival and function of intratumoral CAR-Tcells in a solid tumor xenograft model and effectively controlled tumor growth. ROS-sensing Nrf2 inhibits the anti-tumor Tcell responses, indicating that Nrf2 may be a potential target for Tcell immunotherapy strategies against solid tumors.

Hypocortisolemic ASIA: a vaccine- and chronic infection-induced syndrome behind the origin of long COVID and myalgic encephalomyelitis.

Myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), long COVID (LC) and post-COVID-19 vaccine syndrome show similarities in their pathophysiology and clinical manifestations. These disorders are related to viral or adjuvant persistence, immunological alterations, autoimmune diseases and hormonal imbalances. A developmental model is postulated that involves the interaction between immune hyperactivation, autoimmune hypophysitis or pituitary hypophysitis, and immune depletion. This process might begin with a deficient CD4 T-cell response to viral infections in genetically predisposed individuals (HLA-DRB1), followed by an uncontrolled immune response with CD8 T-cell hyperactivation and elevated antibody production, some of which may be directed against autoantigens, which can trigger autoimmune hypophysitis or direct damage to the pituitary, resulting in decreased production of pituitary hormones, such as ACTH. As the disease progresses, prolonged exposure to viral antigens can lead to exhaustion of the immune system, exacerbating symptoms and pathology. It is suggested that these disorders could be included in the autoimmune/adjuvant-induced inflammatory syndrome (ASIA) because of their similar clinical manifestations and possible relationship to genetic factors, such as polymorphisms in the HLA-DRB1 gene. In addition, it is proposed that treatment with antivirals, corticosteroids/ginseng, antioxidants, and metabolic precursors could improve symptoms by modulating the immune response, pituitary function, inflammation and oxidative stress. Therefore, the purpose of this review is to suggest a possible autoimmune origin against the adenohypophysis and a possible improvement of symptoms after treatment with corticosteroid replacement therapy.

Sialic acids on T cells are crucial for their maintenance and survival.

Sialic acids are found as terminal sugars on glycan structures on cellular surfaces. T cells carry these sialoglycans abundantly, and they are thought to serve multiple functions in cell adhesion, cell migration, and protection from complement attack. We studied the role of sialoglycans on T cells in a mouse model with a T cell-specific deletion of cytidine monophosphate-sialic acid synthase (CMAS), the enzyme that is crucial for the synthesis of sialoglycans. These mice showed a T-cell deficiency in peripheral lymphoid organs. Many T cells with an undeleted Cmas allele were found in the periphery, suggesting that they escaped the Cre-mediated deletion. The remaining peripheral T cells of T cell-specific Cmas KO mice had a memory-like phenotype. Additional depletion of the complement factor C3 could not rescue the phenotype, showing that the T-cell defect was not caused by a host complement activity. Cmas-deficient T cells showed a high level of activated caspase 3, indicating an ongoing apoptosis. In bone marrow chimeric cellular transfer experiments, we observed a strong competitive disadvantage of Cmas-deficient T cells compared to wild-type T cells. These results show that sialoglycans on the surface of T cells are crucial for T-cell survival and maintenance. This function has not been recognized before and is similar to the function of sialoglycans on B cells.

IGATE analysis improves the interpretability of single-cell immune landscape of influenza infection.

Influenza poses a persistent health burden worldwide. To design equitable vaccines effective across all demographics, it is essential to better understand how host factors such as genetic background and aging affect the single-cell immune landscape of influenza infection. Cytometry by time-of-flight (CyTOF) represents a promising technique in this pursuit, but interpreting its large, high-dimensional data remains difficult. We have developed a new analytical approach, in silico gating annotating training elucidating (iGATE), based on probabilistic support vector machine classification. By rapidly and accurately "gating" tens of millions of cells in silico into user-defined types, iGATE enabled us to track 25 canonical immune cell types in mouse lung over the course of influenza infection. Applying iGATE to study effects of host genetic background, we show that the lower survival of C57BL/6 mice compared with BALB/c was associated with a more rapid accumulation of inflammatory cell types and decreased IL-10 expression. Furthermore, we demonstrate that the most prominent effect of aging is a defective T cell response, reducing survival of aged mice. Finally, iGATE reveals that the 25 canonical immune cell types exhibited differential influenza infection susceptibility and replication permissiveness in vivo, but neither property varied with host genotype or aging. The software is available at https://github.com/UmichWenLab/iGATE.

Advancing CAR T-cell therapy for chronic lymphocytic leukemia: exploring resistance mechanisms and the innovative strategies to overcome them.

Chimeric antigen receptor (CAR) T-cell therapy has ushered in substantial advancements in the management of various B-cell malignancies. However, its integration into chronic lymphocytic leukemia (CLL) treatment has been challenging, attributed largely to the development of very effective chemo-free alternatives. Additionally, CAR T-cell responses in CLL have not been as high as in other B-cell lymphomas or leukemias. However, a critical void exists in therapeutic options for patients with high-risk diseases who are resistant to the current CLL therapies, underscoring the urgency for adoptive immunotherapies in these patients. The diminished CAR T-cell efficacy within CLL can be traced to factors such as compromised T-cell fitness due to persistent antigenic stimulation inherent to CLL. Resistance mechanisms encompass tumor-related factors like antigen escape, CAR T-cell-intrinsic factors like T-cell exhaustion, and a suppressive tumor microenvironment (TME). New strategies to combat CAR T-cell resistance include the concurrent administration of therapies that augment CAR T-cell endurance and function, as well as the engineering of novel CAR T-cells targeting different antigens. Moreover, the concept of "armored" CAR T-cells, armed with transgenic modulators to modify both CAR T-cell function and the tumor milieu, is gaining traction. Beyond this, the development of readily available, allogeneic CAR T-cells and natural killer (NK) cells presents a promising countermeasure to innate T-cell defects in CLL patients. In this review, we explore the role of CAR T-cell therapy in CLL, the intricate tapestry of resistance mechanisms, and the pioneering methods studied to overcome resistance.

T-Large Granular Lymphocytic Leukemia with Hepatosplenic T-Cell Lymphoma? A Rare Case of Simultaneous Neoplastic T-Cell Clones Highlighted by Flow Cytometry and Review of Literature.

Lymphoproliferative diseases are a heterogeneous set of malignant clonal proliferations of lymphocytes. Despite well-established diagnostic criteria, the diagnosis remains difficult due to their variety in clinical presentation and immunophenotypic profile. Lymphoid T-cell disorders are less common than B-cell entities, and the lack of a clear immunophenotypic characteristic makes their identification hard. Flow cytometry turned out to be a useful tool in diagnosing T-cell disorders and to resolve complicated cases, especially if the number of analyzable neoplastic cells is small. We present a case of a 55-year-old man with simultaneous lymphoproliferative neoplastic T-cell clones, one αβ and the other γδ, identified and characterized by flow cytometry (FC), exploiting the variable expression intensity of specific markers. However, the patient's rapid decline made it impossible to define a differential diagnosis in order to confirm the identity of the γδ clone, which remains uncertain. This case is added to the few other cases already documented in the literature, characterized by the co-existence of T-large granular lymphocytic leukemia (T-LGLL)-αβ and T-LGLL-γδ/Hepatosplenic T-cell lymphoma (HSTCL). Our case underlines the key role of sensitive diagnostic tools in the assessment of potential relationship between the diagnosis, prognosis, and treatment in the two pathologies.

The complexities of T-cell dysfunction in chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is a B-cell malignancy characterized by profound alterations and defects in the T-cell compartment. This observation has gained renewed interest as T-cell treatment strategies, which are successfully applied in more aggressive B-cell malignancies, have yielded disappointing results in CLL. Despite ongoing efforts to understand and address the observed T-cell defects, the exact mechanisms and nature underlying this dysfunction remain largely unknown. In this review, we examine the supporting signals from T cells to CLL cells in the lymph node niche, summarize key findings on T-cell functional defects, delve into potential underlying causes, and explore novel strategies for reversing these deficiencies. Our goal is to identify strategies aimed at resolving CLL-induced T-cell dysfunction which, in the future, will enhance the efficacy of autologous T-cell-based therapies for CLL patients.

170 Celiac disease in selective IgA deficiency patients is associated with T-cell defects

170 Celiac disease in selective IgA deficiency patients is associated with T-cell defects

The natural history of neurolymphomatosis

BackgroundNeurolymphomatosis is a lymphoid malignancy of the peripheral nervous system and its natural history is poorly understood.MethodsWe performed PubMed search and extracted clinical data for Kaplan-Meier statistics to determine outcome parameters over time. Kruskal-Wallis test was performed to compare prognostic factors.ResultsOur search identified 559 patients and their median age was 61 years. Median overall survival (OS) was 12.0 (range 10.0–15.0) months. Diffuse large B-cell lymphoma was the most frequent histology, involving the brachial plexus, cranial nerves, and sciatic nerve. None had molecular profiling. There was a progressive lengthening of OS in successive decades, from 0.5 (95% CI 0.0–0.8) to 26.4 (95% CI 18.0–34.8) months between 1951 and 2022 (r2 = 0.0528, p < 0.00001). Time from first treatment (treatment 1) to progression increased from 2.0 to 36.0 (95% CI 6.5–50.7) months (r2 = 0.0961, p = 0.00236). Time from symptom onset to diagnosis remained unchanged (r2 = 0.0000556, p = 0.939). Patients were most frequently treated with methotrexate, rituximab, and/or radiation either alone or in combination. Primary neurolymphomatosis had a better prognosis than secondary neurolymphomatosis. No OS difference was noted between B- and T-cell disease, but low-grade B-cell performed better than Burkitt’s lymphoma.DiscussionBetter outcome for patients with neurolymphomatosis is noted over time. But timely diagnosis remains a major problem that needs improvement.

Rapamycin Controls Lymphoproliferation and Reverses T-Cell Responses in a Patient with a Novel STIM1 Loss-of-Function Deletion

PurposeDeficiency of stromal interaction molecule 1 (STIM1) results in combined immunodeficiency accompanied by extra-immunological findings like enamel defects and myopathy. We here studied a patient with a STIM1 loss-of-function mutation who presented with severe lymphoproliferation. We sought to explore the efficacy of the mTOR inhibitor rapamycin in controlling disease manifestations and reversing aberrant T-cell subsets and functions, which has never been used previously in this disorder.MethodsClinical findings of the patient were collected over time. We performed immunological evaluations before and after initiation of rapamycin treatment, including detailed lymphocyte subset analyses, alterations in frequencies of circulating T follicular helper (cTFH) and regulatory T (Treg) cells and their subtypes as well as T cell activation and proliferation capacities.ResultsA novel homozygous exon 2 deletion in STIM1 was detected in a 3-year-old girl with severe lymphoproliferation, recurrent infections, myopathy, iris hypoplasia, and enamel hypoplasia. Lymphoproliferation was associated with severe T-cell infiltrates. The deletion resulted in a complete loss of protein expression, associated with a lack of store-operated calcium entry response, defective T-cell activation, proliferation, and cytokine production. Interestingly, patient blood contained fewer cTFH and increased circulating follicular regulatory (cTFR) cells. Abnormal skewing towards TH2-like responses in certain T-cell subpopulations like cTFH, non-cTFH memory T-helper, and Treg cells was associated with increased eosinophil numbers and serum IgE levels. Treatment with rapamycin controlled lymphoproliferation, improved T-cell activation and proliferation capacities, reversed T-cell responses, and repressed high IgE levels and eosinophilia.ConclusionsThis study enhances our understanding of STIM1 deficiency by uncovering additional abnormal T-cell responses, and reveals for the first time the potential therapeutic utility of rapamycin for this disorder.

The dysfunction of CD8+ T cells triggered by endometriotic stromal cells promotes the immune survival of endometriosis.

Endometriosis is defined as an oestrogen-dependent and inflammatory gynaecological disease of which the pathogenesis remains unclear. This study aimed to investigate the cellular heterogeneity and reveal the effect of CD8+ T cells on the progress of endometriosis. Three ovarian endometriosis patients were collected, and single-cell RNA sequencing (scRNA-seq) progressed and delineated the cellular landscape of endometriosis containing five cell clusters. The endometrial cells (EMCs) were the major component, of which the mesenchymal cells were preponderant and characterized with increased inflammation and oestrogen synthesis in endometriosis. The proportion of T cells, mainly CD8+ T cells rather than CD4+, was reduced in endometriotic lesions, and the cytokines and cytotoxicity of ectopic T cells were depressed. CD8+ T cells depressed the proliferation of ESCs through inhibiting CDK1/CCNB1 pathway to arrest the cell cycle and triggered inflammation through activating STAT1 pathway. Correspondingly, the coculture with ESCs resulted in the dysfunction of CD8+ T cells through upregulating STAT1/PDCD1 pathway and glycolysis-promoted metabolism reprogramming. The endometriotic lesions were larger in nude mouse models with T-cell deficiency than the normal mouse models. The inhibition of T cells via CD90.2 or CD8A antibody increased the endometriotic lesions in mouse models, and the supplement of T cells to nude mouse models diminished the lesion sizes. In conclusion, this study revealed the global cellular variation of endometriosis among which the cellular count and physiology of EMCs and T cells were significantly changed. The depressed cytotoxicity and aberrant metabolism of CD8+ T cells were induced by ESCs with the activation of STAT1/PDCD1 pathway resulting in immune survival to promote endometriosis.

Abstract 2703: Targeting STING pathway as a therapeutic strategy against β-catenin driven immune escape and resistance to anti-PD1 therapy in hepatocellular carcinoma

Abstract β-catenin mutation occurs in around 40% of hepatocellular carcinoma(HCC); yet no precision therapies are available to treat this tumor subset. Immune checkpoint inhibitors (ICIs) are now widely used for the treatment of patients with advanced HCC. Unfortunately, preliminary evidence showed that β-catenin mutation drives resistance to anti-PD1 immunotherapy in HCC. In this study, we studied the molecular mechanisms underlying β-catenin mutation during HCC pathogenesis to develop novel therapeutics targeting β-Catenin-driven HCC. Firstly, three HCC cohorts were examined, including 70 untreated, 20 treated patients with nivolumab, and patients from a public TCGA database. By single-cell RNA sequencing analysis, we identified that anti-PD-1 treatment displayed effectiveness with the increase of CD27+CD8+ T-cell infiltration, correlating to improved prognosis with longer progression-free survival (PFS) and OS. Importantly, multiplex IHC staining showed that β-catenin activation is associated with significantly reduced CD8+CD27+ T cell infiltration in tumors (n=70), demonstrating that β-catenin promoted immune escape and resistance to anti-PD-1 treatment involved defective cytotoxic T-cell activity. Subsequently, we found that the interaction of β-Catenin with sirtuin 1 (SIRT1) mediated suppression of IRF3/IRF7 activity, resulting in inhibition of Type I interferon (IFN-I) production. However, by CRISPRi screening, we found that disruption of β-catenin-SIRT1 interaction via STING caused persistent high-level IFN-I response which increased the transcription of T-cell costimulatory molecule CD27 via IL10/STAT3/BATF signaling on infiltrated CD8+ T cells. This effect was also confirmed in the STING null mice, emphasizing that STING signaling is a therapeutic target to overcome β-catenin driven immune escape. Further, using hydrodynamic tail-vein injection murine HCC models, we found that the STING agonist inhibited β-catenin-SIRT1 activity, restored IFN signaling to rescue T-cell cytotoxic capacities, and enhanced the anti-PD-1 therapy efficacy. In conclusion, we demonstrated that STING reprogrammed β-Catenin mutated the HCC tumor microenvironment and a combination of STING and anti-PD-1 treatment represents an effective novel therapeutic strategy for HCC patients with β-Catenin mutation. Citation Format: Qingmei Zhang, Jiacheng Bi, Oscar Wai-Ho Yeung, Tao Ding, Wing-Lim Chan, Yueqin Zhu, Jiang Liu, Kevin Tak-Pan Ng, Kwan Man. Targeting STING pathway as a therapeutic strategy against β-catenin driven immune escape and resistance to anti-PD1 therapy in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2703.

CXCL9/10-engineered dendritic cells promote T cell activation and enhance immune checkpoint blockade for lung cancer

Immune checkpoint blockade (ICB) with PD-1/PD-L1 inhibition has revolutionized the treatment of non-small cell lung cancer (NSCLC). Durable responses, however, are observed only in a subpopulation of patients. Defective antigen presentation and an immunosuppressive tumor microenvironment (TME) can lead to deficient Tcell recruitment and ICB resistance. We evaluate intratumoral (IT) vaccination with CXCL9- and CXCL10-engineered dendritic cells (CXCL9/10-DC) as a strategy to overcome resistance. IT CXCL9/10-DC leads to enhanced Tcell infiltration and activation in the TME and tumor inhibition in murine NSCLC models. The antitumor efficacy of IT CXCL9/10-DC is dependent on CD4+ and CD8+ Tcells, as well as CXCR3-dependent Tcell trafficking from the lymph node. IT CXCL9/10-DC, in combination with ICB, overcomes resistance and establishes systemic tumor-specific immunity in murine models. These studies provide a mechanistic understanding of CXCL9/10-DC-mediated host immune activation and support clinical translation of IT CXCL9/10-DC to augment ICB efficacy in NSCLC.

Key candidate genes and pathways in T lymphoblastic leukemia/lymphoma identified by bioinformatics and serological analyses.

T-cell acute lymphoblastic leukemia (T-ALL)/T-cell lymphoblastic lymphoma (T-LBL) is an uncommon but highly aggressive hematological malignancy. It has high recurrence and mortality rates and is challenging to treat. This study conducted bioinformatics analyses, compared genetic expression profiles of healthy controls with patients having T-ALL/T-LBL, and verified the results through serological indicators. Data were acquired from the GSE48558 dataset from Gene Expression Omnibus (GEO). T-ALL patients and normal T cells-related differentially expressed genes (DEGs) were investigated using the online analysis tool GEO2R in GEO, identifying 78 upregulated and 130 downregulated genes. Gene Ontology (GO) and protein-protein interaction (PPI) network analyses of the top 10 DEGs showed enrichment in pathways linked to abnormal mitotic cell cycles, chromosomal instability, dysfunction of inflammatory mediators, and functional defects in T-cells, natural killer (NK) cells, and immune checkpoints. The DEGs were then validated by examining blood indices in samples obtained from patients, comparing the T-ALL/T-LBL group with the control group. Significant differences were observed in the levels of various blood components between T-ALL and T-LBL patients. These components include neutrophils, lymphocyte percentage, hemoglobin (HGB), total protein, globulin, erythropoietin (EPO) levels, thrombin time (TT), D-dimer (DD), and C-reactive protein (CRP). Additionally, there were significant differences in peripheral blood leukocyte count, absolute lymphocyte count, creatinine, cholesterol, low-density lipoprotein, folate, and thrombin times. The genes and pathways associated with T-LBL/T-ALL were identified, and peripheral blood HGB, EPO, TT, DD, and CRP were key molecular markers. This will assist the diagnosis of T-ALL/T-LBL, with applications for differential diagnosis, treatment, and prognosis.