Higher Frequency Of CD4 Research Articles

Brain temperature, brain metabolites, and immune system phenotypes in temporal lobe epilepsy.

Epileptogenesis is linked to neuroinflammation. We hypothesized that local heat production caused by neuroinflammation can be visualized non-invasively invivo via brain magnetic resonance spectroscopic imaging (MRSI) and MRSI-thermometry (MRSI-t) and that there is a relationship in patients with temporal lobe epilepsy (TLE) between MRSI-t and brain metabolites choline and myo-inositol and between neuroimaging and cellular and serum biomarkers of inflammation. Thirty-six (36) participants, 18 with temporal lobe epilepsy (13 females) and 18 age-matched healthy controls (nine females), were enrolled prospectively and underwent MRSI/MRSI-t; TLE participants also provided blood samples. Temperature was measured using creatine as a reference metabolite. Analysis of Functional NeuroImages 3dttest++ tool was used to analyze voxel-level group differences in temperature, choline, and myo-inositol. Associations with immune cell subsets, cytokines, and chemokines related to inflammation were quantified using correlation coefficients with significant relationships as noted. Patients with TLE showed elevated temperature, choline, and myo-inositol in the temporal lobes. Higher brain temperature was associated with higher levels of cytokines and chemokines, including GM-CSF, TNF, IL-1β, and IL - 12p70, and lower frequency of immune cells including CD3+ T-cells, CD4+ T-cells, CD8+ T-cells, and classical monocytes. Higher choline was associated with higher levels of the cytokines including LT-α, IL-13, and IL-4, and higher myo-inositol was associated with a higher frequency of CD4+ T-cell and CD19+ B-cell subsets and higher levels of cytokines and chemokines including LT-α, IL-13, and CCL3. This study, for the first time, showed that in temporal lobes of patients with TLE temperature and metabolite changes correlate with cellular and serum biomarkers of inflammation. Our results provide support for further development of MRSI-t as a measure of neuroinflammation in epilepsy and potentially other neurological disorders and as an investigative and clinical tool. Neuroinflammation is associated with excessive heat production which can be visualized with magnetic resonance spectroscopic imaging and thermometry (MRSI-t). We prospectively investigated the relationship between MRSI-t and cellular and serum measures of peripheral inflammation in patients with temporal lobe epilepsy (TLE); we compared the results of MRSI-t in patients with TLE to healthy controls. We showed a relationship between the temperature elevations in TLE and elevations of various measures of peripheral inflammation. Our results support further development of MRSI-t as a measure of neuroinflammation in epilepsy and potentially other neurological disorders and as an investigative and clinical tool.

T-Cell Dynamics Predicts Prognosis of Patients with Hepatocellular Carcinoma Receiving Atezolizumab Plus Bevacizumab.

Atezolizumab and bevacizumab show promise for treating hepatocellular carcinoma (HCC), but identifying responsive patients remains challenging, due to tumor heterogeneity. This study explores immune dynamics following this combination therapy. Between 2020 and 2023, 29 patients with advanced HCC who received atezolizumab plus bevacizumab at Severance Hospital, Seoul, were enrolled in this study. Peripheral blood mononuclear cells were analyzed using flow cytometry and statistical methods to assess immune alterations and identify biomarkers. Baseline characteristics showed a diverse HCC cohort with a mean age of 64 years and 82.8% male predominance. Absence of extrahepatic metastasis was associated with better overall survival. Immune responses revealed distinct CD4+ T-cell phenotypes between the 'partial response (PR) + stable disease (SD)' and 'progressive disease (PD)' groups, with an overall increase in CD8+ T-cell phenotypes. Patients with higher frequencies of CD8+PD-1+Ki-67+ T cells experienced significantly improved overall survival, while those with lower frequencies of CD4+Foxp3+PD-1+LAG3+ T cells also had notable survival benefits. These findings enhance the overall understanding of immune responses to this combination therapy, facilitating improved patient stratification and personalized therapeutic approaches for HCC.

Immunoaging at Early Ages Could Drive a Higher Comorbidity Burden in People with HIV on Antiretroviral Therapy Compared with the Uninfected Population.

This is an observational, cross-sectional, comparative case-control, pilot study aimed at assessing the impact of HIV infection and age on immunological markers in people with HIV (PWH) on antiretroviral therapy (ART). The study included 40 PWH on ART, divided into two age groups (40-45 years vs. ≥60 years), and 30 HIV-uninfected controls matched by sex and age. The results show that older PWH on ART had more comorbidities and a higher frequency of CD8 T cells compared to older controls, with a significant decrease in CD8 naïve T cells with age. Additionally, younger PWH on ART exhibited higher frequencies of activated CD8 T cells and elevated levels of inflammatory markers (sCD14, IL-6) compared to age-matched controls, with values similar to those of older PWH on ART. These findings suggest that younger PWH on ART may experience accelerated immunoaging, highlighting the need for early interventions in this population.

Clinicopathologic features and tumor immune microenvironment of lymphocyte-rich hepatocellular carcinoma

Lymphocyte-rich hepatocellular carcinoma (LR-HCC) is a rare variant of HCC characterized by pronounced lymphoid infiltration, providing an opportunity to explore the tumor immune microenvironment (TIME) and its potential impact on disease progression and therapy. This study aimed to describe the clinicopathological features and TIME components of LR-HCC to inform more effective treatment strategies. In this study, we present five novel cases of LR-HCC alongside a comprehensive retrospective analysis of 136 previously documented cases. Immunohistochemical evaluation was utilized to systematically assess TIME components and immune checkpoint inhibitor (ICI) targets. Our findings demonstrated a significant predominance of CD3+ T cells over CD20+ B cells (1.5:1, P < 0.001) and a higher frequency of CD8+ cytotoxic T cells compared to Foxp3+ regulatory T cells (2.4:1, P < 0.001), indicating an immune landscape potentially favorable for immunotherapeutic interventions. Programmed cell death ligand 1 (PD-L1) expression was detected in three out of five cases using the VENTANA SP263 assay, suggesting potential responsiveness to ICIs. A pooled analysis of 38 cases showed a 5-year overall survival rate of 73.6 %, which is notably lower than previously reported rates (>90 %), with 29.4 % of patients experiencing postoperative recurrence or lymph node metastasis. Multivariate analysis identified tumor size as an independent predictor of overall survival. These findings emphasize the relevance of TIME characteristics in understanding LR-HCC and point to promising avenues for targeted and immune-based therapies, contributing to the optimization of clinical management for this distinct cancer subtype.

CD8+ tissue-resident memory T cells are expanded in primary Sjögren’s disease and can be therapeutically targeted by CD103 blockade

ObjectiveTissue-resident memory cells (Trm) are a subset of T cells residing persistently and long-term within specific tissues that contribute to persistent inflammation and tissue damage. We characterised the phenotype and...

IL-6 Inhibition as a Therapeutic Target in Aged Experimental Autoimmune Encephalomyelitis.

Multiple sclerosis (MS) onset at an advanced age is associated with a higher risk of developing progressive forms and a greater accumulation of disability for which there are currently no effective disease-modifying treatments. Immunosenescence is associated with the production of the senescence-associated secretory phenotype (SASP), with IL-6 being one of the most prominent cytokines. IL-6 is a determinant for the development of autoimmunity and neuroinflammation and is involved in the pathogenesis of MS. Herein, we aimed to preclinically test the therapeutic inhibition of IL-6 signaling in experimental autoimmune encephalomyelitis (EAE) as a potential age-specific treatment for elderly MS patients. Young and aged mice were immunized with myelin oligodendrocyte protein (MOG)35-55 and examined daily for neurological signs. Mice were randomized and treated with anti-IL-6 antibody. Inflammatory infiltration was evaluated in the spinal cord and the peripheral immune response was studied. The blockade of IL-6 signaling did not improve the clinical course of EAE in an aging context. However, IL-6 inhibition was associated with an increase in the peripheral immunosuppressive response as follows: a higher frequency of CD4 T cells producing IL-10, and increased frequency of inhibitory immune check points PD-1 and Tim-3 on CD4+ T cells and Lag-3 and Tim-3 on CD8+ T cells. Our results open the window to further studies aimed to adjust the anti-IL-6 treatment conditions to tailor an effective age-specific therapy for elderly MS patients.

Decoding the inflammatory signature of the major depressive episode: insights from peripheral immunophenotyping in active and remitted condition, a case–control study

Depression is a prevalent and incapacitating condition with a significant impact on global morbidity and mortality. Although the immune system’s role in its pathogenesis is increasingly recognized, there is a lack of comprehensive understanding regarding the involvement of innate and adaptive immune cells. To address this gap, we conducted a multicenter case–control study involving 121 participants matched for sex and age. These participants had either an active (or current) major depressive episode (MDE) (39 cases) or a remitted MDE (40 cases), including individuals with major depressive disorder or bipolar disorder. We compared these 79 patients to 42 healthy controls (HC), analyzing their immunological profiles. In blood samples, we determined the complete cell count and the monocyte subtypes and lymphocyte T-cell populations using flow cytometry. Additionally, we measured a panel of cytokines, chemokines, and neurotrophic factors in the plasma. Compared with HC, people endorsing a current MDE showed monocytosis (p = 0.001), increased high-sensitivity C-reactive protein (p = 0.002), and erythrocyte sedimentation rate (p = 0.003), and an altered proportion of specific monocyte subsets. CD4 lymphocytes presented increased median percentages of activation markers CD69+ (p = 0.007) and exhaustion markers PD1+ (p = 0.013) and LAG3+ (p = 0.014), as well as a higher frequency of CD4+CD25+FOXP3+ regulatory T cells (p = 0.003). Additionally, patients showed increased plasma levels of sTREM2 (p = 0.0089). These changes are more likely state markers, indicating the presence of an ongoing inflammatory response during an active MDE. The Random Forest model achieved remarkable classification accuracies of 83.8% for MDE vs. HC and 70% for differentiating active and remitted MDE. Interestingly, the cluster analysis identified three distinct immunological profiles among MDE patients. Cluster 1 has the highest number of leukocytes, mainly given by the increment in lymphocyte count and the lowest proinflammatory cytokine levels. Cluster 3 displayed the most robust inflammatory pattern, with high levels of TNFα, CX3CL1, IL-12p70, IL-17A, IL-23, and IL-33, associated with the highest level of IL-10, as well as β-NGF and the lowest level for BDNF. This profile is also associated with the highest absolute number and percentage of circulating monocytes and the lowest absolute number and percentage of circulating lymphocytes, denoting an active inflammatory process. Cluster 2 has some cardinal signs of more acute inflammation, such as elevated levels of CCL2 and increased levels of proinflammatory cytokines such as IL-1β, IFNγ, and CXCL8. Similarly, the absolute number of monocytes is closer to a HC value, as well as the percentage of lymphocytes, suggesting a possible initiation of the inflammatory process. The study provides new insights into the immune system’s role in MDE, paving the ground for replication prospective studies targeting the development of diagnostic and prognostic tools and new therapeutic targets.

The presence of cytotoxic CD4 and exhausted-like CD8+ T-cells is a signature of active tuberculosis

Chronic infections induce CD4+ T-cells with cytotoxic functions (CD4 CTLs); at present, it is still unknown whether latent tuberculosis (LTB) and active tuberculosis (ATB) induce CD4 CTLs. Plasma and cells from four patient groups—uninfected contact (UC), LTB, and ATB (divided as sensitive [DS-TB]- or resistant [DR-TB]-drug)—were evaluated by flow cytometry, q-PCR, and proteomics. The data showed that ATB patients had an increased frequency of CD4+ T-cells and a decreased frequency of CD8+ T-cells. The latter displays an exhausted-like profile characterized by CD39, CD279, and TIM-3 expression. ATB had a high frequency of CD4 + perforin+ cells, suggesting a CD4 CTL profile. The expression (at the transcriptional level) of granzyme A, granzyme B, granulysin, and perforin, as well as the genes T-bet (Tbx21) and NKG2D (Klrk1), in enriched CD4+ T-cells, confirmed the cytotoxic signature of CD4+ T-cells during ATB (which was stronger in DS-TB than in DR-TB). Moreover, proteomic analysis revealed the presence of HSP70 (in DS-TB) and annexin A5 (in DR-TB), which are molecules that have been associated with favoring the CD4 CTL profile. Finally, we found that lipids from Mycobacterium tuberculosis increased the presence of CD4 CTLs in DR-TB patients. Our data suggest that ATB is characterized by exhausted-like CD8+ T-cells, which, together with a specific microenvironment, favor the presence of CD4 CTLs.

The tumor microenvironment of benign and malignant salivary gland tumors.

Treatment of salivary gland tumors (SGTs) remains challenging. Little is known about the immune landscape of SGTs. We aimed to characterize the tumor microenvironment in benign and malignant SGTs. Eleven benign and nine malignant tumors were collected from patients undergoing curative intent surgery. Specimens were analyzed using mass cytometry by time-of-flight. Immune cell populations were manually gated, and T cells were clustered using the FlowSOM algorithm. Population frequencies were compared between high-grade and low-grade malignancies, corrected for multiple hypothesis testing. There were trends towards increased CD4+ and CD8+ T cells among malignant tumors. High-grade malignancies exhibited trends towards higher frequencies of CD8+ PD-1+ CD39+ CD103+ exhausted T cells, CD4+ FoxP3+ TCF-1+ CD127- Tregs, and CD69+ CD25- CD4+ T cells compared to low-grade malignancies. SGTs exhibit significant immunologic diversity. High-grade malignancies tended to have greater infiltration of exhausted CD8+ T cells and Tregs, which may guide future studies for immunotherapy strategies.

Cellular Immune Responses Against γ-Inactivated Antigen in the Recovered Cases of Kyasanur Forest Disease.

Kyasanur Forest Disease Virus (KFDV) is a tick-borne flavivirus that causes life-threatening hemorrhagic fever in humans with case fatality rates of 3-5%. Relatively little is known about the mechanism of its pathogenesis or host immune responses to KFDV infection. Here, we investigated KFDV-specific cellular immune responses in the recovered cases of Kyasanur Forest Disease (KFD). Peripheral blood mononuclear cells of the recovered KFD cases and healthy controls were exposed to γ-inactivated KFDV antigen ex vivo. The proliferation index was determined using an enzyme-linked immunosorbent assay-based lymphoproliferative assay. The frequencies of CD4+ and CD8+ T cells expressing intracellular interferon (IFN)-γ in response to stimulation with γ-inactivated KFDV antigen were determined using flow cytometry. A significant increase in lymphoproliferation and a high frequency of CD4+ and CD8+ T cells secreting IFN-γ against γ-inactivated KFDV antigen were found in the recovered KFD group compared to the healthy control group. In conclusion, the study indicated the generation of cellular immune responses in individuals who recovered from KFD and can be used as indicators of cellular immunity in KFD vaccine studies.

Lower frequencies of circulating suppressive regulatory T cells and higher frequencies of CD4+ naïve T cells at baseline are associated with severe immune-related adverse events in immune checkpoint inhibitor-treated melanoma

BackgroundImmune-related adverse events (irAEs) are major barriers of clinical management and further development of immune checkpoint inhibitors (ICIs) for cancer therapy. Therefore, biomarkers associated with the onset of severe irAEs...

Synergistic B and T lymphocyte interaction: prognostic implications in non-small cell lung cancer.

While T-cell-mediated immune responses in solid tumors have been well-established and have driven major therapeutic advances, our understanding of B-cell biology in cancer is comparatively less developed. A total of 60 lung cancer patients were included, of which 53% were diagnosed at an early stage while 47% were diagnosed at an advanced stage. Flow cytometry was used to analyze the proportion of T and B cells in all blood samples, and the levels of human serum cytokines were also assessed. Compared to the control group, cancer patients showed lower frequencies of IgD+CD27+ marginal B cells and CD32+ B cells, and higher frequencies of T cells with lower CD8+ T cells and higher central memory and naïve CD4+ T cells. Additionally, advanced-stage cancer patients exhibited higher levels of cytokines, a higher proportion of effector memory CD8+ T cells, and a lower frequency of CD27+CD28+CD4+/CD8+ T cells. Linear regression analysis revealed significant correlations between cancer stage and the frequency of B and T cell subsets, leukocyte count, and cytokine levels. Survival analysis demonstrated that patients with higher frequency of class-switched B cells had a worse prognosis, while patients with higher frequency of CD8+ effector T cells and lower frequency of CD4+57+ T cells appeared to have a better survival rate. These findings provide valuable insight into the immunological changes that occur during lung cancer progression and have the potential to inform the development of new immunotherapeutic strategies.

Infliximab aggregates produced in severe and mild elevated temperature stress conditions induce an extended specific CD4 T-cell response

Aggregation has been widely described as a factor contributing to therapeutic antibody immunogenicity. Although production of high-affinity anti-drug antibodies depends on the activation of CD4 T lymphocytes, little is known about the T-cell response induced by antibody aggregates, especially for aggregates produced in mild conditions resulting from minor handling errors of vials. Large insoluble infliximab (IFX) aggregates produced in severe elevated temperature stress conditions have been previously shown to induce human monocyte-derived dendritic cell (moDC) maturation. We here showed that large IFX aggregates recruit in vitro a significantly higher number of CD4 T-cells compared to native IFX. Moreover, a larger array of T-cell epitopes encompassing the entire variable regions was evidenced compared to the native antibody. We then compared the responses of moDCs to different types of aggregates generated by submitting IFX to mild conditions of various times of incubation at an elevated temperature. Decreasing stress duration reduced aggregate size and quantity, and subsequently altered moDC activation. Of importance, IFX aggregates generated in mild conditions and not altering moDC phenotype generated an in vitro T-cell response with a higher frequency of CD4 T cells compared to native IFX. Moreover, cross-reactivity studies of aggregate-specific T cells showed that some T cells could recognize both native and aggregated IFX, while others responded only to IFX aggregates. Taken together, our results suggest that aggregation of antibodies in mild elevated temperature stress conditions is sufficient to alter moDC phenotype in a dose-dependent manner and to increase T-cell response.

Longitudinal Correlative Profiles of Responders, Nonresponders, and Those with Relapse on Treatment with Teclistamab in the Phase 1/2 MajesTEC-1 Study of Patients with Relapsed/Refractory Multiple Myeloma

Introduction: Teclistamab (tec) is the only approved B-cell maturation antigen (BCMA) × CD3 bispecific antibody with a personalized, weight-based dosing schedule for the treatment of triple-class exposed relapsed/refractory multiple myeloma (RRMM). In the phase 1/2 MajesTEC-1 study (NCT03145181/NCT04557098), tec demonstrated deep and durable responses. To better understand mechanisms of resistance and relapse in MajesTEC-1, we assessed longitudinal BCMA expression and immune profiles. Methods: Patients (N=165) with RRMM received subcutaneous tec 1.5 mg/kg weekly after step-up doses of 0.06 and 0.3 mg/kg, with the option to switch to every-other-week dosing if they achieved at least a partial response after ≥4 cycles of therapy in phase 1 or a complete response or better for ≥6 months in phase 2. Bone marrow and peripheral blood samples at baseline, on treatment, and at disease progression (PD) were analyzed by flow cytometry for BCMA expression and immune cell populations. Bone marrow aspirates were analyzed by cytometry by time of flight (CyTOF) for immune cell populations. Soluble BCMA (sBCMA) was analyzed in serum samples by electrochemiluminescence ligand binding. Results: Patients who responded to tec had a greater recovery of CD3+ T cells in the periphery and bone marrow during the first treatment cycles, which was sustained over time compared with nonresponders. Greater activation during the first cycle was observed in responders, indicated by a transient increase in CD38 on CD8+ T cells. In contrast, an exhausted T-cell phenotype in the blood and bone marrow was observed longitudinally in nonresponders vs responders, indicated by increasing and sustained levels of activation and exhaustion markers including persistence of CD38+ T cells and expression of LAG-3, PD-1 (Figure 1A), PD-1/LAG-3, and PD-1/TIM-3 on CD4+ or CD8+ T cells. Higher levels of immunosuppressive regulatory T cells (Tregs), including CD38+ Tregs, were also sustained in the periphery in nonresponders compared with responders. BCMA expression and sBCMA levels were assessed in a subset of patients who initially responded then relapsed on tec, who had matched baseline and end-of-treatment/PD samples. There were no significant changes in the frequency of BCMA+ plasma cells, BCMA receptor density, or sBCMA levels at PD relative to baseline, suggesting BCMA loss was not a mechanism of relapse in these patients. In contrast, higher proportions of peripheral CD4+ and/or CD8+ T cells expressing CD38, TIM-3, PD-1, and PD-1/TIM-3 were observed at relapse vs baseline. Analysis of bone marrow progression samples using CyTOF in patients who relapsed showed significantly lower CD28 expression on CD8+ T cells, significantly higher expression of exhaustion markers (CD38, PD-1, TIM-3, EOMES, and TOX) and perforin on CD4+ and/or CD8+ T cells, a higher frequency of CD4+ and CD8+ T cells expressing TIM-3 and co-expressing CD38/TOX, PD-1/TIM-3, and TOX/TIM-3 (Figure 1B), and significantly higher CD38 expression on T-cell receptor gamma delta T cells, at PD than at baseline. PD-1 and TIGIT expression was also significantly higher at PD than at baseline across CD25hiCD127dim and/or CD25hiCD127dimFoxP3+ Tregs in patients who relapsed. Conclusions: Patients responding to tec exhibited a differential immune profile in early cycles compared with nonresponders, with greater transient T-cell activation. In contrast, an exhausted T-cell phenotype was sustained in nonresponders during the first 2 treatment cycles. While mutations in BCMA cannot be excluded, we did not detect BCMA loss as a mechanism of relapse, but observed a dysfunctional immune phenotype at PD, with increased T-cell exhaustion and higher frequency of gamma delta T cells and immunosuppressive Tregs. These results suggest the importance of immune fitness and T-cell function in achieving and maintaining a response to tec. Ongoing studies will evaluate these correlatives in earlier treatment lines, where patients may have more favorable immune profiles.

Rheumatoid arthritis synovial fluid shows enrichment of T-cells producing GMCSF which are polyfunctional for TNFα and IFNγ.

GMCSF+T-cells may be involved in pathogenesis of rheumatoid arthritis (RA), and polyfunctionality may be a marker of pathogenicity. Although, higher frequencies of CD4+GMCSF+ T-cells have been reported, there are no data on CD8+GMCSF+ T-cells or polyfunctionality.Our objective was to enumerate frequencies of CD8+GMCSF+ T cells in RA blood and synovial fluid (SF), and assess their polyfunctionality, memory phenotype and cytotoxic ability. This study included RA patients (blood samples,in some with paired synovial fluid (SF)), healthy controls (HC) (blood) and SpA patients (SF). In some RA patients' blood was sampled twice, before and 16-24 weeks after methotrexate (MTX) treatment. After mononuclear cell isolation from blood and SF, ex-vivo stimulation using PMA/Ionomycin was done, and cells were stained (surface and intracellular after permeabilisation/fixation). Subsequently, frequencies of GMCSF+CD8+ and CD4+ T-cells, polyfunctionality (TNFα, IFNγ, IL-17), phenotype (memory) and perforin/granzyme expression were assessed by flowcytometry. There was no significant difference in frequencies of GMCSF+CD8+ (3.7, 4.1%, p=0.540) or GMCSF+CD4+ T-cells (4.5, 5.2%, p=0.450) inblood of RA and HC. However, there was significant enrichment of both CD8+GMCSF+ (5.8, 3.9%, p=0.0045) and CD4+GMCSF+ (8.5, 4.5%, p=0.0008) T-cells inSF compared to blood in RA patients. Polyfunctional triple cytokine positive TNFα+IFNγ+GMCSF+CD8+T-cells (81, 36%, p=0.049) and CD4+T-cells (48, 32%, p=0.010) was also higher in SF compared to blood in RA. CD8+ T cells showed higher frequency of effector-memory phenotype and granzyme-B expression in RA-SF. On longitudinal follow-up, blood CD4+GMCSF+ T-cells significantly declined (4.6, 2.9%, p=0.0014) post-MTX. We report a novel finding of enrichment of CD8+GMCSF+ in addition to CD4+GMCSF+ T-cells in RA-SF. These cells showed higher polyfunctionality for TNFα and IFNγ, and effector memory phenotype suggesting their involvement in RA pathogenesis.

Reduced numbers of naïve CD4+T cells and an altered CD4/CD8 balance in depressed common variable immune deficiency (CVID) patients. Is thymosin-α1 a possible treatment?

In the 1990's the macrophage-T-cell-theory of depression was posed stating that low grade inflammation and an abnormal T cell system destabilize the development and function of the emotional brain in such a way, that individuals become ultrasensitive to stress. Recently we gathered evidence that indeed higher frequencies of CD4+ memory T cells, lower frequencies of naive CD4+T cells, higher frequencies of CD8+T cells (the latter two in part elicited by Cytomegalovirus, CMV, infection) are a characteristic of Major Depressive Disorder (MDD). In MDD patients with a history of childhood trauma and severe depression monocytes are inflammatory activated. Low grade inflammation and T cell system defects have also been reported in patients with Common Variable Immune Deficiency (CVID) (next to antibody production defects). CVID patients show a higher prevalence of mild depression. The aim of this study was to determine T cell frequencies and monocyte inflammatory activation in CVID patients with and without depression. This study confirms that CVID patients have CMV independent decreases in the frequency of naïve CD4+T cells and it de novo shows a CMV dependent increase in the expression of inflammatory genes in monocytes. CVID patients with depression are additionally characterized by a CMV independent increase in the frequency of naïve CD8+T cells, while lacking monocyte inflammatory activation. In conclusion, depressed CVID patients have T cell abnormalities comparable to that of patients with regular MDD. These abnormalities are presently targeted by thymosin α1 in an open-label proof of concept trial.

The Probable Role of Tregs in Improved Heat Tolerance in Heat-acclimated Mice

Abstract Heatstroke is a life-threatening illness related to systematic inflammation-induced multiple organ dysfunction. The severity of systematic inflammatory response may be related to the changes in immune regulation triggered by heat acclimation. However, the mechanisms of heat acclimation and its effect on immune regulation are unclear. Here, we assessed the differences in immunocyte subsets in the spleen and lymph nodes of heat-acclimated mice. Higher frequencies of CD4 +Foxp3 +regulatory T cells (Tregs) were observed in the heat-acclimated mice. Our results indicate that the improvement in heat tolerance during acute heat stress correlates with the increase in the number of Tregs. These Tregs mitigated the recruitment of neutrophils, inhibited their activation, and suppressed the severity of acute inflammation. The increased differentiation and development of Tregs might stem from an enhanced expression of Foxp3 and PD-L1. Our results strongly suggest that the increase of Tregs has a regulatory effect on neutrophils, and that the PD-1/PD-L1 pathway may be involved in this regulation. The anti-inflammatory effects of Tregs have never been studied in the context of heat stress-induced systemic inflammation. Thus, the results of our study are significant for devising a potential treatment for systemic inflammatory response syndrome and heatstroke. National Natural Science Foundation of China (grant number 81570497)

Abstract 6633: T regulatory cell subsets in colorectal cancer: friends or foes

Abstract T cells in the tumor microenvironment (TME) have diverse roles in anti-tumor immunity. Different T cell subsets may have opposing roles in tumor progression, especially in inflammatory cancers such as colorectal cancer (CRC). In different series of studies, we performed extensive characterization and critical analyses of T regulatory cell (Treg)-related markers and key inhibitory immune checkpoints (ICs) in CD4+ and CD8+ T cell subsets in the TME and periphery of CRC patients. We found a significant increase in levels of CD4+FoxP3+Helios+ T cells, which represent potentially highly immunosuppressive Tregs, in the TME. Additionally, tumor-infiltrating CD4+ T cells upregulated PD-1, CTLA-4, TIM-3 and LAG-3 immune checkpoints. CTLA-4, TIM-3, and LAG-3 were mainly co-expressed on FoxP3+Helios+ Tregs in the TME. Additionally, we found that FoxP3 expression and ICs including PD-1, CTLA-4, TIM-3, and LAG-3 were significantly upregulated in tumor-infiltrating CD8+ T cells. We then investigated associations between different tumor-infiltrating CD4+ and CD8+ T cell subpopulations and disease-free survival (DFS). Interestingly, a high frequency of circulating CD4+FoxP3+ Tregs was associated with poorer DFS, while higher frequency of these cells in the TME was associated with better DFS. Additionally, high frequencies of circulating CD4+FoxP3+Helios+ Tregs and tumor-infiltrating CD4+FoxP3-Helios- T cells were associated with poorer DFS. Moreover, a high frequency of CD4+FoxP3+Helios-PD-1+ Tregs in circulation was associated with worse DFS. In contrast, high frequencies of CD4+TIM-3+ T cells, FoxP3+Helios+TIM-3+ Tregs, and FoxP3-Helios+TIM-3+ CD4+ T cells in circulation were associated with longer DFS. Additionally, we found that high levels of certain circulating CD8+ T cell subsets (TIM-3+, FoxP3-Helios-TIM-3+ and FoxP3-Helios+TIM-3+ cells) were associated with longer DFS. In the TME, elevated levels of CD25+ and TIM-3+ CD8+ T cells, and FoxP3+Helios-TIM-3+ CD8+ Tregs were associated with better DFS. These data show that circulating and tumor-infiltrating immune checkpoint-expressing CD4+ and CD8+ Treg/T cell subsets play different roles in disease prognoses, and certain subsets could serve as independent predictive biomarkers in CRC patients. Citation Format: Eyad Elkord. T regulatory cell subsets in colorectal cancer: friends or foes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6633.

Abstract PD9-04: Immunological and clinical consequences of durvalumab treatment in combination to neoadjuvant chemotherapy in triple-negative breast cancer patients

Abstract Background: The implementation of immune checkpoint inhibitors in the therapy of different cancer types has provided promising results, but only a limited number of patients respond. Therefore, biomarkers to identify these responding patients are urgently needed. Methods: The GeparNuevo was a randomized, double-blind phase II trial in which triple-negative breast cancer (TNBC) patients were treated with neoadjuvant chemotherapy (NACT) consisting of nanoparticle albumin-bound paclitaxel in an initial phase followed by treatment with epirubicin and cyclophosphamide. Placebo or durvalumab were given throughout the neo-adjuvant treatment and in the “window” sub-cohort also prior to chemotherapy. Primary objective of this report was to evaluate changes in the blood immune cell repertoires of TNBC patients receiving durvalumab (anti-PD-L1) versus placebo in combination with NACT. At up to 4 different time points during therapy, blood samples were taken and underwent immunomonitoring using multicolor flow cytometry. The absolute counts of the major immune cell subtypes in the blood as well as the frequencies of different immune cell subpopulations and their functional phenotypes along treatment were determined and correlated to clinico-pathologic characteristics of the patients and to treatment response. Results: 120 out of 174 patients included in the GeparNuevo trial underwent blood immunomonitoring; 63 patients belonged to the “window” sub-cohort. Durvalumab administration almost completely blocked the detection of the inhibitory ligand PD-L1 and induced changes in the composition of the immune cell subpopulations. Evaluation of the “window” sub-cohort, in which an enhanced, but not significant pathological clinical response was observed within the immunomonitored patients, identified different markers correlating with clinical response to durvalumab. Higher frequencies of CD4+ T cells at recruitment as well as increased frequencies of T cells bearing the gamma delta TCR along treatment were some of the characteristics of patients responding to durvalumab treatment. Conclusions: The flow cytometry-based immunomonitoring of the clinical trial identified different immune-relevant biomarkers at recruitment as well as during treatment that predict clinical response to durvalumab. After validation of this data in an independent patient cohort, these markers could be implemented for an improved patient stratification to immunotherapy. Citation Format: Chiara Massa, Thomas Karn, Karsten Weber, Andreas Schneeweiss, Claus Hanusch, Jens-Uwe Blohmer, Dirk-Michael Zahm, Christian Jackisch, Marion van Mackelenbergh, Jörg Thomalla, Frederik Marmé, Jens Huober, Volkmar Müller, Christian Schem, Anja Müller, Elmar Stickeler, Katharina Biehl, Peter A. Fasching, Michael Untch, Sibylle Loibl, Carsten Denkert, Barbara Seliger. Immunological and clinical consequences of durvalumab treatment in combination to neoadjuvant chemotherapy in triple-negative breast cancer patients [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD9-04.

Bacillus Calmette-Guérin Tokyo-172 vaccine provides age-related neuroprotection in actively induced and spontaneous experimental autoimmune encephalomyelitis models.

Multiple sclerosis is the most common immune-mediated disorder affecting the central nervous system in young adults but still has no cure. Bacillus Calmette-Guérin (BCG) vaccine is reported to have non-specific anti-inflammatory effects and therapeutic benefits in autoimmune disorders including multiple sclerosis. However, the precise mechanism of action of BCG and the host immune response to it remain unclear. In this study, we aimed to investigate the efficacy of the BCG Tokyo-172 vaccine in suppressing experimental autoimmune encephalomyelitis (EAE). Groups of young and mature adult female C57BL/6J mice were BCG-vaccinated 1 month prior or 6 days after active EAE induction using myelin oligodendrocyte glycoprotein (MOG)35-55 peptide. Another group of 2D2 TCRMOG transgenic female mice was BCG-vaccinated before and after the onset of spontaneous EAE. BCG had an age-associated protective effect against active EAE only in wild-type mice vaccinated 1 month before EAE induction. Furthermore, the incidence of spontaneous EAE was significantly lower in BCG vaccinated 2D2 mice than in non-vaccinated controls. Protection against EAE was associated with reduced splenic T-cell proliferation in response to MOG35-55 peptide together with high frequency of CD8+ interleukin-10-secreting T cells in the spleen. In addition, microglia and astrocytes isolated from BCG-vaccinated mice showed polarization to anti-inflammatory M2 and A2 phenotypes, respectively. Our data provide new insights into the cell-mediated and humoral immune mechanisms underlying BCG vaccine-induced neuroprotection, potentially useful for developing better strategies for the treatment of MS.