Tfh Cells Research Articles

MiR‐149‐5p in Tfh Cell‐Derived Exosomes Promotes B Cell Proliferation and Maturation Through the Wnt3a/Axin2 Axis in Allergic Rhinitis

ABSTRACTAllergic rhinitis (AR) is one of the most frequently observed diseases in otorhinolaryngology, a global issue that alters the quality of life of patients. Both B cells and follicular helper T cells (Tfhs) have important roles in allergic diseases. However, how Tfhs and B cells interact to modulate allergic rhinitis pathogenesis remains unclear. In this study, two models of allergic rhinitis were examined, including the co‐culture of follicular helper T cells (Tfhs) isolated from mouse spleen with B cells. To further define the mechanism, exosomes from Tfh cells were isolated and added to B cells. Bulk RNA sequencing (RNA‐seq) analysis was used to compare exosomes derived from Tfhs cells in a mouse model of allergic rhinitis and exosomes derived from Tfhs cells in wild‐type mice. Among them, miR‐149‐5p was observed to be lowly expressed in the allergic rhinitis group, which was confirmed using qPCR. miR‐149‐5p mimics or inhibitors were utilised to overexpress or knock down miR‐149‐5p in Tfhs, which were then co‐cultured with B cells, demonstrating that miR‐149‐5p is negatively correlated with B cell proliferation and maturation. The function of WNT3A, a target gene of miR‐149‐5p, and the downstream effector AXIN2 on the proliferation and maturation of B cells were predicted and verified. We show that miR‐149‐5p packaged in Tfhs‐derived exosomes induces B cell proliferation and maturation through the WNT3A/AXIN2 axis. The discovery will contribute to new ideas for the treatment of allergic rhinitis.

Impaired SARS-CoV-2-specific responses via activated T follicular helper cells in immunocompromised kidney transplant recipients

Activated T follicular helper (aTfh) cells are likely important in host immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccination. We characterized the immune responses of aTfh cells to the second (D2) and third (booster; D3) doses of an mRNA vaccine in the peripheral blood of 40 kidney transplant recipients (KTRs) and 17 healthy control volunteers (HCs). A significant increase in SARS-CoV-2-specific IgG antibody was seen after D3 in the KTRs; nonetheless, the levels after D2 and D3 were significantly lower than in the HCs. After D2, dramatic increases in activated CD45RA-CXCR5+ICOS+PD1+ circulating Tfh (acTfh) cells were observed in the HCs, as well as the seropositive patients among the KTRs, when compared with the seronegative patients among the KTRs. Unlike the HCs, KTRs had less prominent immune responses, including the acTfh and T cells that produce interferon gamma, tumor necrosis factor alpha, and interleukin 21. In addition, the increase in acTfh cells was significantly associated with anti-IgG antibody levels after D3. These results indicate impaired SARS-CoV-2-specific responses via acTfh cells in KTRs, and they suggest that acTfh cells in peripheral blood may play an important role in antibody maintenance following SARS-CoV-2 mRNA vaccination.

Mechanism of biliary atresia caused by T follicular helper cells-induced immune injury

BackgroundBiliary atresia (BA) has diverse and unclear pathogenesis, which may be related to immune response in response to a foreign stimulus. T follicular helper (Tfh) cells have been found to play an important role in various immune diseases.AimsTo investigate the expression of Tfh cells in BA and non-BA cholestatic diseases in children.MethodsTranscriptome sequencing and Gene Ontology (GO) enrichment analysis were performed to investigate the differences in gene expression between the BA group and the non-BA cholestasis group. Study the distribution of Tfh cells in liver tissues of the BA and non-BA cholestatic groups through single sample gene set enrichment analysis (ssGSEA). Tfh cells (CD3+Bcl6+) in liver tissues from BA patients were labeled by double immunofluorescent staining to verify their distribution in the liver.ResultsTranscriptome sequencing showed differences in gene expression between the BA group and the non-BA cholestasis group. A total of 808 genes were up-regulated and 405 genes were down-regulated in BA, suggesting that there might be a specific immune response in BA. GO enrichment analysis showed that BA group had augmented response to foreign stimulus and increased metabolic process compared to the non-BA cholestatic group. The relative proportion of immune cells was analyzed by ssGSEA method. The proportions of Tfh cells, activated B cells, CD4+ T cells, memory B cells and Th2 cells were higher in the BA group than in the non-BA cholestatic group. Fluorescence immunostaining showed that Tfh cells were significantly increased in liver tissue samples of the BA group compared to the non-BA cholestasis group, which was consistent with the transcriptome sequencing results.ConclusionTfh cells share in immune cascade involvement in BA. Our work support immune pathogenesis of the in response to a stimulus that might be foreign in BA.

Cutting Edge: Low-dose Recombinant IL-2 Treatment Prevents Autoantibody Responses in Systemic Lupus Erythematosus via Regulatory T Cell-independent Depletion of T Follicular Helper Cells.

The expansion of T follicular helper (Tfh) cells correlates with disease progression in human and murine systemic lupus erythematosus (SLE). Unfortunately, there are no therapies to deplete Tfh cells. Importantly, low-dose rIL-2-based immunotherapy shows potent immunosuppressive effects in SLE patients and lupus-prone mice, primarily attributed to the expansion of regulatory T cells (Tregs). However, IL-2 can also inhibit Tfh cell differentiation. In this study, we investigate the potential of low-dose rIL-2 to deplete Tfh cells and prevent autoantibody responses in SLE. Our data demonstrate that low-dose rIL-2 efficiently depletes autoreactive Tfh cells and prevents autoantibody responses in lupus-prone mice. Importantly, this immunosuppressive effect was independent of the presence of Tregs. The therapeutic potential of eliminating Tfh cells was confirmed by selectively deleting Tfh cells in lupus-prone mice. Our findings demonstrate the critical role of Tfh cells in promoting autoantibody responses and unveil, (to our knowledge), a novel Treg-independent immunosuppressive function of IL-2 in SLE.

Quercetin ameliorates lupus symptoms by promoting the apoptosis of senescent Tfh cells via the Bcl-2 pathway

Systemic lupus erythematosus (SLE) is an autoimmune disorder that commonly affects the skin, kidneys, joints, and various other systemic tissues, with its development intricately linked to the process of immunosenescence. Quercetin (QC), a phytochemical that occurs naturally, demonstrates many different biological capabilities, such as antibacterial, antioxidant, and anti-inflammatory activities. Our investigation found that QC effectively reduced kidney damage and relieved mesenteric lymph nodes (mLNs) swelling in MRL/lpr lupus mice. Moreover, QC has been found to decrease the number of senescent follicular helper T (Tfh) cells, a pivotal kind of T cells that contribute to the progression of SLE. In vitro, QC exhibited the capacity to modulate mRNA expression levels, with the downregulation of IL-6, IL21-AS1, IL-27, BCL6, and BCL2L12, and the upregulation of FOXP1 and BIM. This modulation resulted in the suppression of Tfh cells differentiation and the enhancement of apoptosis in senescent CD4+ T cells. In addition, the HuProtTM Human Proteome Microarray revealed that QC can directly bind to BCL-2 protein and therefore promote the apoptosis of senescent CD4+ T cell. As a result, our investigative elucidate the potent inhibitory action of QC on the ontogeny of Tfh cells, along with its capacity to abrogate the immunosenescent phenotype. This positions QC as a promising therapeutic strategy for treating SLE.

B Cell Lymphoma 6 (BCL6): A Conserved Regulator of Immunity and Beyond

B cell lymphoma 6 (BCL6) is a conserved multi-domain protein that functions principally as a transcriptional repressor. This protein regulates many pivotal aspects of immune cell development and function. BCL6 is critical for germinal center (GC) formation and the development of high-affinity antibodies, with key roles in the generation and function of GC B cells, follicular helper T (Tfh) cells, follicular regulatory T (Tfr) cells, and various immune memory cells. BCL6 also controls macrophage production and function as well as performing a myriad of additional roles outside of the immune system. Many of these regulatory functions are conserved throughout evolution. The BCL6 gene is also important in human oncology, particularly in diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL), but also extending to many in other cancers, including a unique role in resistance to a variety of therapies, which collectively make BCL6 inhibitors highly sought-after.

A small molecule BCL6 inhibitor effectively suppresses diffuse large B cell lymphoma cells growth.

The B-cell lymphoma 6 (BCL6) transcription factor plays a key role in establishment of germinal center (GC) formation. Diffuse large B cell lymphoma (DLBCL) originates from the GC reaction due to dysregulation of BCL6. Disrupting BCL6 and its corepressors interaction has become the foundation for rationally designing lymphoma therapies. However, BCL6 inhibitors with good activities in vitro and in vivo are rare and there are no clinically approved BCL6 inhibitors. Here, we discovered and developed a novel range of [1,2,4] triazolo[1,5-a] pyrimidine derivatives targeting BCL6/SMRT interaction. The analogue WK692 directly bound BCL6BTB, disrupted BCL6BTB/SMRT interaction and activated the expression of BCL6 downstream genes inside cells, inhibited DLBCL growth and induced apoptosis in vitro, inhibited GC formation, decreased proportion of follicular helper T (Tfh) cells and impaired immunoglobulin affinity maturation. Further studies showed that WK692 inhibited the DLBCL growth without toxic effects in vivo and synergizes with the EZH2 and PRMT5 inhibitors. Our results demonstrated that WK692 as a BCL6 inhibitor may be developed as a novel potential anticancer agent against DLBCL.

Differential Tfh cell phenotypes distinguish IgE-mediated milk allergy from eosinophilic esophagitis in children

IgE-mediated food allergy and eosinophilic esophagitis (EoE) are diseases commonly triggered by milk. Milk-responsive CD4+ T cells producing type 2 cytokines are present in both diseases, yet the clinical manifestation of disease in milk allergy (MA) and EoE are distinct. To identify CD4+ T cell differences between EoE and MA that may be responsible for distinct disease manifestations. The total and milk-specific CD4+ T cell phenotype of children with milk allergy (MA), EoE (active or in remission) and controls was measured using spectral flow cytometry of peripheral blood (all groups) or esophageal biopsies (EoE and control). Circulating milk-responsive T cells could be identified in active (A)-EoE and MA. An increased frequency of Th2A cells was also noted in MA and EoE. In circulating T cells, type 2 cytokine production was elevated in MA, but not EoE. Within the milk-responsive Tfh subset, a dichotomy of phenotype was noted: Tfh13 cells predominated in MA, while IL-10-producing Tfh cells predominated in EoE. In the esophagus, CD4+ T cells were constitutively activated and expressed not only type 2 cytokines, but also IL-10 and IL-21 in A-EoE. There was production of IgG4 from CD38+ plasma cells in close proximity to CD4+ T cells. In vitro activation studies demonstrated that IL-10 and IL-21 elicited strong IgG4 responses in B lymphocytes, while IL-4 and IL-13 promoted IgE production. Our studies demonstrate a dichotomy of Tfh responses that may be the basis for the different clinical manifestations to milk in EoE and MA.

Pathogenic Th17 cells are a potential therapeutic target for tacrolimus in AChR-myasthenia gravis patients

In our study, we investigated the impact of tacrolimus (TAC) on CD4+ T cell subsets in 41 AChR-MG patients over 12 weeks. Twenty-seven patients were classified as the response group (RG) (improved myasthenia gravis composite scores ≥3), while 14 were non-response. We found that TAC treatment significantly reduced Th17 and pathogenic Th17 cells, along with IL-17 levels in RG, while Th1 and Tfh cells slightly decreased without affecting Th2 or Treg subsets. This indicates that TAC's clinical benefits may be due to its inhibitory effect on the Th17 response, enhancing our insight into its immunomodulatory mechanisms in MG management.

Variable clinical presentation of hypomorphic DCLRE1C deficiency from childhood to adulthood.

In this study, we aimed to report long-term follow-up of our pediatric and adult patients with DCLRE1C (DNA cross-link repair 1C) hypomorphic mutation who were diagnosed leaky severe combined immunodeficiency (SCID). Eighteen patients (13 children and five adults), aged between 6 and 29 years were included. Clinical and immunological features, including immunoglobulin levels, T and B cells, natural killer cell subsets, regulator T (Treg) cell ratios/markers, and cytokines, were assessed before and after hematopoietic stem cell transplantation (HSCT) and compared with healthy controls. Recurrent infections (78%) and skin manifestations (61%) such as granulomatous skin lesions, warts, and vitiligo were the most common clinical findings. Autoimmune diseases were observed in 33% and malignancy in 17%. Most patients had low serum IgA and B- and T-cell lymphopenia at the first admission. Recent thymic emigrants (RTE), Tnaive, Bnaive, CD56dimCD16+ cell ratios were significantly lower in the patients than in control; however, follicular helper T TFH and Th1 [interferon gamma (IFN-γ)] cell ratios were significantly higher than the control. Although, Treg ratio and its functional receptors tend to be high but not significant. Eleven patients (61.1%) were treated with HSCT. Median follow-up times of transplant patients was 56 (9-67) months. Patients with hypomorphic DCLRE1C mutations may present with variable clinical and laboratory findings at different ages. Our study showed a helper T (Th)1-dominant immune response before and after HSCT. Increased IFN-γ and TFH cells ratio could be a reason of chronic inflammation and autoimmunity developing before and after HSCT. Long-term follow-up of these patients after HSCT will help to better understand the disease and its pathophysiology.

Interleukin 9 mediates T follicular helper cell activation to promote antibody responses.

Antigen-specific humoral responses are orchestrated through complex interactions among immune cells in lymphoid tissues, including the collaboration between B cells and T follicular helper (Tfh) cells. Accumulating evidence indicates a crucial role for interleukin-9 (IL-9) in the formation of germinal centers (GCs), enhancing the generation of class-switched high-affinity antibodies. However, the exact function of IL-9 in Tfh cell regulation remains unclear. In this study, we examined the humoral immune responses of CD4Cre/+Il9rafl/fl mice, which lack an IL-9-specific receptor in Tfh cells. Upon intraperitoneal immunization with sheep red blood cells (SRBCs), CD4Cre/+Il9rafl/fl mice displayed diminished levels of SRBC-specific IgG antibodies in their sera, along with reduced levels of GC B cells and plasma cells. Notably, Il9ra-deficient Tfh cells in the spleen exhibited decreased expression of their signature molecules such as B-cell lymphoma 6, C-X-C chemokine receptor 5, IL-4, and IL-21 compared to control mice. In models of allergic asthma induced by house dust mite (HDM) inhalation, CD4Cre/+Il9rafl/fl mice failed to elevate serum levels of HDM-specific IgE and IgG. This was accompanied by reductions in Tfh cells, GC B cells, and plasma cells in mediastinal lymph nodes. Furthermore, group 2 innate lymphoid cells (ILC2s) were identified as producers of IL-9 under immunizing conditions, possibly induced by leukotrienes released by activated IgD+ B cells around the T-B border. These observations may indicate the critical role of IL-9 receptor signaling in the activation of Tfh cells, with ILC2s potentially capable of supplying IL-9 in organized lymphoid tissues.

Exploring the prognostic value of T follicular helper cell levels in chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) presents with heterogeneous clinical outcomes, suggesting varied underlying pathogenic mechanisms. This study aims to elucidate the impact of T follicular helper (Tfh) cells on CLL progression and prognosis. Gene expression profile data for CLL were collected from GSE22762 and GSE39671 datasets. Patients were divided into high and low groups using Tfh levels using the optimal cutoff value based on overall survival (OS) and time-to-first treatment (TTFT). Differential expression analysis was performed between these groups, followed by co-expression network analysis and single-sample Gene Set Enrichment Analysis (ssGSEA). Marker genes of Tfh cells were used to construct prognostic models. Additionally, 40 CLL patients were recruited and categorized based on median Tfh levels. Marker gene expression was assessed using RT-qPCR and Western Blot, and immune cell levels were determined through flow cytometry. The high group showed better prognosis compared to the low group. Among the 1121 differentially expressed genes identified, five co-expression networks were constructed, with the turquoise module showing the highest correlation with Tfh cells. Genes within this module significantly participate in cytokine-cytokine receptor interaction, PI3K-Akt signaling pathway, and natural killer cell mediated cytotoxicity. Tfh cells were significantly negatively correlated with activated B cells and positively correlated with Tregs. The Random Survival Forest (RSF) model identified 10 marker genes, and further analysis using Lasso regression and nomogram selected CLEC4A, RAE1, CD84, and PRDX1 as prognostic markers. In the high group, levels of CLEC4A and RAE1 were higher than in the low group, whereas CD84 and PRDX1 were lower. Flow cytometry revealed that the level of activated B cells in the high Tfh group was significantly lower than in the low Tfh group, while the level of Tregs is significantly higher in the high Tfh group. This study seeks to contribute to a more detailed understanding of the pathogenesis of CLL, delving into the prognostic significance of Tfh.

BAFF promotes follicular helper T cell development and germinal center formation through BR3 signal.

T follicular helper (Tfh) cells represent an important subset of CD4+ T cells that is crucial to the maturation and differentiation of B cells and the production of high-affinity antibodies. Since BAFF, a vital B cell survival factor, is also crucial to B cell maturation and differentiation, we assessed the effects of BAFF on Tfh cell development and function. We demonstrate that deficiency of BAFF, but not of APRIL, markedly inhibits Tfh cell development, germinal center (GC) formation, and antigen-specific antibody production. The promoting effect of BAFF on Tfh cell development is dependent on expression of BR3 on T cells, and its promoting effect on GC formation is dependent on expression of BR3 on both T cells and B cells. BAFF directly promotes expression of the Tfh cell-characteristic genes via NF-κB signaling. This effect does need BR3 expression. Thus, BAFF not only has direct effects on B cells, but it also has direct effects on Tfh cell differentiation via engagement of BR3 which collectively promote GC formation and production of high-affinity antibodies. This dual effect of BAFF on B cells and Tfh cells may help explain the clinical utility of BAFF antagonists in the management of certain autoimmune diseases.

In vitro modulation of T cells in myasthenia gravis by low-dose IL-2.

Follicular helper (Tfh), peripheral helper (Tph), and regulatory (Treg) T cells are involved in myasthenia gravis (MG) pathogenesis, an autoimmune disorder arising from autoantibodies targeting neuromuscular junction proteins. This study explores the impact of low-dose IL-2 on Tfh, Tph, and Treg cells in vitro in MG. Acetylcholine-receptor antibody-positive MG (AChR-MG), muscle-specific kinase antibody-positive MG (MuSK-MG) patients, and healthy controls (HC) were studied. Blood cells were cultured with/without IL-2 and compared by the ratios of IL-2 stimulated/unstimulated cultures. In both AChR-MG and MuSK-MG patients, CD25+FoxP3+Tregs were lower, while CXCR5+PD-1+ or ICOS+Tfh and CXCR5-PD-1+ or ICOS+Tph cells were higher compared with HC. Among the MG group, the FoxP3+ Treg cells in AChR-MG patients were even lower compared with MuSK-MG patients. In vitro IL-2 stimulation increased Tregs in all groups while decreasing PD-1+/ICOS+Tfh and PD-1+/ICOS+Tph populations. The fold-increase ratio of Tregs and the fold-decrease ratio of PD-1+ or ICOS+Tfh and ICOS+Tph cells in AChR-MG and MuSK-MG patients were greater than in HCs. Low-dose IL-2 treatment may balance Tfh, Tph, and Treg cells in MG patients, offering a potential opportunity for disease modulation.

In vivo CAR T cell therapy against angioimmunoblastic T cell lymphoma

BackgroundFor angioimmunoblastic T cell lymphoma (AITL), a rare cancer, no specific treatments are available and survival outcome is poor. We previously developed a murine model for AITL that mimics closely human disease and allows to evaluate new treatments. As in human AITL, the murine CD4+ follicular helper T (Tfh) cells are drivers of the malignancy. Therefore, chimeric antigen receptor (CAR) T cell therapy might represent a new therapeutic option.MethodsTo prevent fratricide among CAR T cells when delivering an CD4-specific CAR, we used a lentiviral vector (LV) encoding an anti-CD4 CAR, allowing exclusive entry into CD8 T cells.ResultsThese anti-CD4CAR CD8-targeted LVs achieved in murine AITL biopsies high CAR-expression levels in CD8 T cells. Malignant CD4 Tfh cells were eliminated from the mAITL lymphoma, while the CAR + CD8 T cells expanded upon encounter with the CD4 receptor and were shaped into functional cytotoxic cells. Finally, in vivo injection of the CAR + CD8-LVs into our preclinical AITL mouse model carrying lymphomas, significantly prolonged mice survival. Moreover, the in vivo generated functional CAR + CD8 T cells efficiently reduced neoplastic T cell numbers in the mAITL tumors.ConclusionThis is the first description of in vivo generated CAR T cells for therapy of a T cell lymphoma. The strategy described offers a new therapeutic concept for patients suffering from CD4-driven T cell lymphomas.

Activation of circulating TFH17 cells associated with activated naive and double negative 2 B cell expansion, and disease activity in systemic lupus erythematosus patients

BackgroundSystemic lupus erythematosus (SLE) is the quintessential autoimmune disease, as it is characterized by hyperactivity of CD4+ T cells and subsequently drives lupus pathology. Follicular helper T (TFH) cells play an important role in B cell maturation and antibody production. However, which specific subset of cTFH cells drives B cell function and contributes to the development of anti-dsDNA antibodies and SLE pathogenesis remains unclear.MethodsPeripheral blood mononuclear cells from SLE patients with inactive (n = 11) and active (n = 21) were used to determine and detect frequencies and phenotypes of circulating TFH cells (cTFH), memory cTFH, and B cell subsets. The correlations among cTFH cell subsets and phenotypes, B cell subsets, anti-dsDNA autoantibodies, and clinical parameters were analyzed.ResultsIn subjects with active SLE, cTFH1 and cTFH17 cells were significantly expanded and activated. These expanded cTFH cells expressed memory phenotypes; cTFH1 cells were predominantly central memory (CM) type, while cTFH17 cells were largely effector memory (EM) type. Phenotyping B cell subsets in these patients showed increased frequencies of aNAV and DN2 B cells. Clinically, ICOS+ cTFH1, ICOS+ cTFH17 cells, and SLEDAI-2k scores were found to be correlated. Analysis of cTFH-B cell relationship revealed positive correlations among ICOS+ cTFH1 cells, aNAV B cells, and anti-dsDNA antibodies. Activation of ICOS+ cTFH17 cells was significantly related to the expansion of aNAV and DN2 B cells. The presence of CM cells in cTFH1 and cTFH17 subsets was correlated with aNAV and DN2 B cell frequencies.ConclusionSLE cTFH cells were found to be polarized toward cTFH1 and cTFH17 cells; activation of these cTFH subsets was significantly associated with disease activity score, aNAV, DN2 B cell expansion, and anti-dsDNA antibody level. Thus, the interactions among cTFH1, cTFH17, and B cells likely contribute to the development of autoantibodies and the pathogenesis in SLE.

Polarization of circulating Follicular Helper T cells correlates with the severity of Bullous Pemphigoid.

T-follicular-helper (Tfh) cells form a distinct population of T-helper cells with different polarizations (type 1, type 2 and type 17) that regulates humoral responses and may participate in the pathophysiology of B-cell mediated autoimmune diseases, such as bullous pemphigoid (BP), a dermatosis mediated by auto-antibodies specific for hemidesmosomal proteins. The aim was to evaluate the impact of superpotent topical corticosteroid (TCS) treatment, which is more effective and safer than high doses of oral corticosteroids and recommended first-line treatment of BP, on circulating Tfh cells. We compared by flow cytometry the frequency, polarization and activation of blood Tfh cells from patients with BP at baseline and longitudinally after initiation of TCS treatment to age- and sex-matched healthy subjects. We observed that circulating Tfh cells were more frequent in patients with BP at baseline than in healthy subjects and exhibited an activated phenotype. We further showed a decrease of type 1 and an increase of type 17 Tfh cells in the blood of patients, which resulted in a higher (type 2+type 17) to type 1 Tfh cell ratio. This ratio correlated positively with disease severity as measured by the Bullous Pemphigoid Disease Area Index. Remarkably, along TCS treatment, although the frequency of Tfh cells returned to a level similar to control, the activated phenotype persisted. Interestingly serum IL-21 levels and the Tfh cell subset ratio, similarly to disease activity and serum anti-BP180 and anti-BP230 auto-antibodies, were decreased under the TCS treatment. Overall, our findings suggest an involvement of the polarization of Tfh cells in the pathophysiology of BP and open the door to a modulation of their activity for therapeutic purposes.

Chemotherapy drives tertiary lymphoid structures that correlate with ICI-responsive TCF1+CD8+ T cells in metastatic ovarian cancer.

Patients with high-grade serous ovarian carcinoma (HGSOC) are virtually insensitive to immune checkpoint inhibitors (ICIs) employed as standalone therapeutics, at least in part reflecting microenvironmental immunosuppression. Thus, conventional chemotherapeutics and targeted anticancer agents that not only mediate cytotoxic effects but also promote the recruitment of immune effector cells to the HGSOC microenvironment stand out as promising combinatorial partners for ICIs in this oncological indication. We harnessed a variety of transcriptomic, spatial and functional assays to characterize the differential impact of neo-adjuvant paclitaxel-carboplatin on the immunological configuration of paired primary and metastatic HGSOC biopsies as compared to NACT-naïve HGSOC samples from 5 independent patient cohorts. We found neo-adjuvant chemotherapy (NACT)-driven endoplasmic reticulum stress and calreticulin exposure in metastatic HGSOC lesions culminates with the establishment of a dense immune infiltrate including follicular T cells (TFH cells), a prerequisite for mature tertiary lymphoid structure (TLS) formation. In this context, TLS maturation was associated with an increased intratumoral density of ICI-sensitive TCF1+PD-1+ CD8+ T cells over their ICI-insensitive TIM-3+PD-1+ counterparts. Consistent with this notion, chemotherapy coupled with a PD-1-targeting ICI provided a significant survival benefit over either therapeutic approach in syngeneic models of HGSOC bearing high (but not low) tumor mutational burden. Altogether, our findings suggest that NACT promotes TLS formation and maturation in HGSOC lesions, de facto preserving an intratumoral ICI-sensitive T-cell phenotype. These observations emphasize the role of rational design, especially relative to the administration schedule, for clinical trials testing chemotherapy plus ICIs in patients with HGSOC.

Changes in Circulating CD44+CD62L− Treg Subsets and CD44−CD62L+ Treg Subsets Reflect the Clinical Status of Patients with Allergic Rhinitis

Introduction: This study clarified the expression changes and clinical significance of CD44+CD62L− Treg and CD44−CD62L+ Treg subsets in the peripheral blood of patients with allergic rhinitis (AR). Methods: The peripheral blood of 39 patients with AR and 42 healthy controls was collected. Clinical data, such as sex, age, IgE titer, allergen screening information and visual analogue scale (VAS) score, were recorded. Changes in serum IL-2, IL-4, IL-6, IL-10, TNF-α, and IFN-γ were detected using the cytometric bead array method. Flow cytometry was used to detect the proportions of Th1, Th2, Th17, TFH, and Th9 cells and the proportions of CD44+CD62L− Treg and CD44−CD62L+ Treg subsets. Correlation analysis was performed between the CD44+CD62L− Treg subsets and the CD44−CD62L+ Treg subsets with clinical indicators (VAS score, total IgE titer), cytokines (IL-2, IL-4, IL-6, IL-10, TNF-α, IFN-γ), and Th1/Th2/Th17/TFH/Th9 cell proportions. Results: Compared to the control group, the proportion of total Treg cells and CD44+CD62L− Treg cells in the AR group decreased, and the proportion of CD44−CD62L+ Treg cells increased (p < 0.05). The proportions of CD44+CD62L− Treg cells significantly negatively correlated with Th2 cells (R = −0.5270, p < 0.05) and positively correlated with Treg cytokine IL-10 (R = 0.6447, p < 0.05). In addition, CD44+CD62L− Treg cells negatively correlated with the VAS score (R = −0.4956, p < 0.05), total IgE level (R = −0.4177, p < 0.05) and Th2 cytokine IL-6 level (R = −0.3034, p < 0.05) but positively correlated with the Th1 cytokine IL-2 (R = 0.4331, p < 0.05). In contrast, the proportion of CD44+CD62L− Treg cells significantly positively correlated with the Th2 cells (R = 0.6187, p < 0.05). Moreover, the proportion of CD44−CD62L+ Treg cells positively correlated with the VAS score (R = 0.4060, p < 0.05), total IgE level (R = 0.5224, p < 0.05) and Th2 cytokine IL-4 (R = 0.2647, p < 0.05) and IL-6 levels (R = 0.3824, p < 0.05) but negatively correlated with Th1 cytokine IL-2 (R = −0.3451, p < 0.05) and IL-10 (R = −0.3277, p < 0.05). Conclusion: A greater proportion of CD44+CD62L− Tregs correlated with better reversal of the Th1/Th2 imbalance and milder clinical symptoms in AR patients. The presence of more CD44−CD62L+ Tregs correlated with a weaker immunosuppressive effect on Th2 cells and more severe clinical symptoms in AR patients. These findings provide new perspectives for the treatment and disease monitoring of AR.

2D Differential Metallic Immunopotentiators Drive High Diversity and Capability of Antigen-specific Immunity Against Tumor.

The therapeutic efficacy of vaccines for treating cancers in clinics remains limited. Here, a rationally designed cancer vaccine by placing immunogenically differential and clinically approved aluminum (Al)or manganese (Mn) in a 2D nanosheet (NS) architecture together with antigens is reported. Structurally optimal NS with a high molar ratio of Mn to Al (MANS-H) features distinctive immune modulation, markedly promoting the influx of heterogeneous innate immune cells at the injection site. Stimulation of multiple subsets of dendritic cells (DCs) significantly increases the levels, subtypes, and functionalities of antigen-specific T cells. MANS-H demonstrates even greater effectiveness in the production of antigen-specific antibodies than the commercial adjuvant (Alhydrogel) by priming T helper (Th)2 cells rather than T follicular helper (Tfh) cells. Beyond humoral immunity, MANS-H evokes high frequencies of antigen-specific Th1 and CD8+ cell immunity, which are comparable with Quil-A that is widely used in veterinary vaccines. Immunized mice with MANS-H adjuvanted vaccines exert strong potency in tumor regression by promoting effector T cells infiltrating at tumor and overcoming tumor resistance in multiple highly aggressive tumor models. The engineered immunogen with an intriguing NS architecture and safe immunopotentiators offers the next clinical advance in cancer immunotherapy.