Th17 lymphocytes are a distinct subpopulation of T cells that are characterized by the production of interleukins IL-17, IL-21, IL-22, and IL-26, and high expression of RORγt. These cells play an important role in inflammation and autoimmune diseases. Recent studies using rodent and human models have also highlighted their promising properties as agents in cellular immunotherapy for cancer. However, much less is known about the properties of canine Th17 lymphocytes, despite the domestic dog being an important model used in comparative medicine. In this study, we developed methods of activation and differentiation of canine CD4+ T lymphocytes towards the Th17 phenotype. Additionally, we targeted the Wnt/β-catenin signaling pathway to modulate the efficiency of Th17 cells differentiation. CD4+ T cells were successfully activated with magnetic EpoxyBeads, and in combination with the appropriate programming medium, they acquired the Th17 phenotype. Furthermore, indomethacin, an inhibitor of the Wnt/β-catenin pathway, significantly increased the efficiency of differentiation, causing elevated production of IL-17 and changed T cell metabolism by promoting oxidative phosphorylation. The protocol elaborated in our study provides an efficient method of canine Th17 lymphocyte differentiation. Our findings also suggested that the modification of the Wnt/β-catenin signaling pathway could be a valuable strategy for optimizing canine Th17 cell differentiation and advancing cell-based immunotherapy.

Breast cancer remains a leading cause of mortality among women, highlighting the need for improved diagnostic and treatment approaches. This study aims to analyze the expression levels of key immunologic factors in the peripheral blood mononuclear cell (PBMC) population of breast cancer patients and assess their relationship with various disease characteristics. A total of 48 treatment-naive breast cancer patients were enrolled, with blood samples collected prior to surgery for PBMC isolation. Gene expression of Foxp3, RORγt, GATA3, and T-bet was measured using quantitative real-time PCR. Gene expressions of Foxp3, RORγt, and GATA3 were significantly elevated in breast cancer patients compared to controls. Logistic regression revealed a strong association between elevated RORγt levels and larger tumor sizes. Subgroup analysis indicated that Foxp3 related to lymphovascular invasion (LVI), RORγt correlated with lymph node involvement and tumor size, GATA3 was associated with tumor size alone, and T-bet was linked to disease stage. ROC analysis demonstrated T-bet and Foxp3 as sensitive indicators for disease stage, while RORγt was notable for lymph node involvement. The study indicates that T-helper cell-related transcription factors in PBMCs reflect important clinical characteristics of breast cancer, supporting the role of T cell immune responses in disease progression. PBMCs emerge as a promising and accessible resource for diagnostic information in breast cancer.

Elderly individuals face heightened susceptibility to infectious diseases and diminished vaccine responses. Vaccine adjuvants offer a solution. Despite aluminum adjuvant's long history, its limitations in inducing strong cellular immunity and protecting immunocompromised individuals restrict its application. Building upon our previous development of zinc salt particle-based risedronate (Zn-RS), we systematically investigated the immunoenhancing effects of Zn-RS in aged mice and thoroughly explored the underlying mechanisms responsible for these observations in this study.

Compared to formulations using aluminum adjuvant, Zn-RS combined with either varicella-zoster virus glycoprotein E (gE) or SARS-CoV-2 monovalent STFK protein (STFK) elicited significantly higher IgG and neutralization titers, as well as superior long-term humoral immunity. Moreover, Zn-RS induced greater quantities of dendritic cells (DCs), antigen-presenting cells (APCs), follicular helper T (TFH) cells, Th1/Th2/Th9/Th17 type immune cells, germinal center B cells (GCBs) and plasma cells.

These findings support Zn-RS as a promising adjuvant candidate for elderly populations, warranting further exploration of its mechanisms and potential applications.

Th17 cells can perform either regulatory or inflammatory functions depending on the cytokine microenvironment. These plastic cells can transdifferentiate into Tregs during inflammation resolution, in allogenic heart transplantation models, or in cancer through mechanisms that remain poorly understood. Here, we demonstrated that NLRP3 expression in Th17 cells is essential for maintaining their immunosuppressive functions through an inflammasome-independent mechanism. In the absence of NLRP3, Th17 cells produce more inflammatory cytokines (IFNγ, Granzyme B, TNFα) and exhibit reduced immunosuppressive activity toward CD8+ cells. Moreover, the capacity of NLRP3-deficient Th17 cells to transdifferentiate into Treg-like cells is lost. Mechanistically, NLRP3 in Th17 cells interacts with the TGF-β receptor, enabling SMAD3 phosphorylation and thereby facilitating the acquisition of immunosuppressive functions. Consequently, the absence of NLRP3 expression in Th17 cells from tumor-bearing mice enhances CD8 + T-cell effectiveness, ultimately inhibiting tumor growth.

Interleukin, a noninvasive biomarker, holds huge potential for providing valuable insights into the management of inflammatory conditions and tumor diseases. This systematic review and meta-analysis aimed to evaluate the prognostic role of interleukin in bladder cancer (BCa) patients.

A comprehensive search of six English and Chinese databases (PubMed, Embase, Web of Science, Chinese National Knowledge Infrastructure (CNKI), Wanfang, and Chinese Biomedical Literature Service System) was conducted from inception to July 10, 2024. Studies investigating the association between serum interleukin levels and BCa were included. Outcome measures encompassed disease-free survival (DFS), overall survival (OS), and disease-specific survival (DSS). Statistical analyses were performed using RevMan 5.4.1, employing random or fixed-effects models as appropriate. Sensitivity, subgroup, and descriptive analyses were also conducted.

A total of seven studies involving 1,505 patients were included. Four studies reported the association between serum interleukin-6/17 (IL-6/17) and OS in BCa. Patients with elevated serum IL levels exhibited a worse OS (HR = 2.28; 95% CI [1.03-5.05]; P = 0.04); however, subgroup analysis revealed that only high serum IL-17 levels were significantly associated with shorter OS, while IL-6 levels showed no association with OS. Six studies examined the relationship between serum IL-6/17 and DFS in BCa. Patients with elevated serum IL levels were associated with poorer DFS (HR = 2.57; 95% CI [1.55-4.26]; P < 0.001). This association remained consistent across subgroup analyses based on interleukin type, publication country, and surgical methods. Only two studies investigated the relationship between serum IL-6/17 and DSS in BCa, with no significant association found (HR = 1.58; 95% CI [1.00-2.51]; P = 0.05).

This meta-analysis demonstrates a strong association between serum interleukin levels and survival outcomes in BCa, suggesting that serum interleukin testing may be a valuable clinical tool for predicting patient outcomes and guiding treatment decisions.

The relationship between psoriasis, immunomodulatory therapies, and the risk of malignancies is complex and still debated. The scarcity of evidence in this field makes clinicians hesitate to prescribe biological therapies for 'difficult-to-treat' patients.

Based on a comprehensive MEDLINE/PUBMED search of articles published up to November 2024, this review synthesizes the current evidence on the association between psoriasis and cancer. This review specifically addresses four key aspects: the overall cancer risk in psoriatic patients, the potential role of cytokines involved in psoriasis pathogenesis in tumor development, the association between biological therapies and the incidence of new malignancies in this population, and the risk of cancer recurrence or progression in patients with a history of malignancy who are treated with biologics.

Biological therapies do not significantly elevate malignancy risk compared to non-biological treatments or the general population. Evidence is also reassuring for patients with prior malignancy, showing no tumor progression or recurrence. These findings support the timely use of biological treatments in 'difficult-to-treat' patients. Regular cancer screenings and risk-factor minimization should always be recommended for psoriatic patients undergoing immunomodulatory therapies. Multidisciplinary management involving oncologists is suggested, particularly for patients with active and advanced oncological disease.

Breast cancer, a predominant contributor to cancer-related mortality worldwide, is increasingly managed through the application of neoadjuvant chemotherapy (NAC). Analyzing the dynamic changes in peripheral blood lymphocyte subsets, granzyme B and perforin are crucial for investigating their roles in tumorigenesis, development and treatment; this study aimed to use these analyses to diagnose malignant breast tumor, assess the anti-tumor immunity and predict chemotherapy efficacy in breast cancer patients.

To address this objective, a total of 582 peripheral blood samples were collected from healthy controls (n=47), benign breast disease patients (n=401) and breast cancer patients (n=134). Lymphocyte subsets, along with granzyme B and perforin expression, were assessed using flow cytometry. Changes before and after NAC were also monitored.

Breast cancer patients exhibited reduced proportions and absolute counts of CD3+ and CD8+ T cells, increased NK cell percentage and CD4+/CD8+ ratio, and higher levels of granzyme B and perforin in CD3+, CD8+ T cells and NK cells. Post-NAC, the percentages of CD3+, CD4+, CD8+ T cells and NK cells increased, along with a higher CD4+/CD8+ ratio, while B cell percentages decreased compared to pre-NAC. Furthermore, the effective group showed higher percentages of CD3+, CD8+ T cells and lower percentages of B cells than the ineffective group post-NAC. Incidentally, Granzyme B and perforin expression in CD3+ and CD8+ T cells was elevated following postoperative chemotherapy.

These findings indicated that peripheral blood lymphocyte subsets, along with granzyme B and perforin levels, could serve as potential biomarkers for differentiating benign from malignant breast tumors, assessing anti-tumor immunity and predicting chemotherapy efficacy.

Dietary behaviors significantly influence tumor progression, with increasing focus on high-salt diets (HSD) in recent years. Traditionally, HSD has been regarded as a major risk factor for multiple health issues, including hypertension, cardiovascular disease, kidney disease, cancer, and osteoporosis. However, recent studies have uncovered a novel aspect of HSD, suggesting that HSD may inhibit tumor growth in specific pathological conditions by modulating the activity of immune cells that infiltrate tumors and enhancing the effectiveness of PD-1 immunotherapy. This review focused on the duel molecular mechanisms of HSD in cancer development, which are based on the tumor microenvironment, the gut microbiota, and the involvement of sodium transporter channels. The objective of this review is to explore whether HSD could be a potential future oncological therapeutic strategy under specific situation.

Cytokines are proteins used by immune cells to communicate with each other and with cells in their environment. The pleiotropic effects of cytokine networks are determined by which cells express cytokines and which cells express cytokine receptors, with downstream outcomes that can differ based on cell type and environmental cues. Certain cytokines, such as interferon (IFN)-γ, have been clearly linked to anti-tumor immunity, while others, such as the innate inflammatory cytokines, promote oncogenesis. Here we provide an overview of the functional roles of cytokines in the tumor microenvironment. Although we have a sophisticated understanding of cytokine networks, therapeutically targeting cytokine pathways in cancer has been challenging. We discuss current progress in cytokine blockade, cytokine-based therapies, and engineered cytokine therapeutics as emerging cancer treatments of interest.

Colorectal Cancer (CRC) is widely prevalent worldwide and its incidence is increasing. Chemotherapy is an important treatment method for colorectal cancer in addition to surgery, but it often causes physical and mental pain to patients due to its side effects. TCM emphasizes evidence-based treatment and a holistic concept, and the combination of TCM and chemotherapy can reduce chemotherapy side effects, improve chemotherapy efficacy, and enhance patients' immunity. Yiqi Jianpi Kangai Decoction (YQJP) has been used clinically to treat patients with advanced colorectal cancer and may improve their immune function and prognosis. However, its mechanism has not been elucidated.

The study aims to explore the effect and mechanism of YQJP on enhancing the therapeutic effect of chemotherapy on spleen qi deficiency type CRC mice.

We used HPLC/MS to characterize the active substance components in YQJP. We established the spleen qi deficiency model induced by using the compound methods of diarrhea of bitter and cold, starvation, and full and excessive labor. and then inoculated CT-26 mouse colon cancer cells subcutaneously to establish the CRC Mice. We also evaluated the efficacy and mechanism of YQJP by using oral Yiqi Jianpi Kangai Decoction combined with an intraperitoneal injection of chemotherapeutic drugs (FOLFOX regimen). We evaluated the efficacy and safety of YQJP by observing the general condition (body weight, tumor size, food intake, hair condition, stool condition), HE staining, blood routine, and organ index of the mice. The expression of CD8+, CD4+ T cells, Th17 cells, and Treg cells in the tumor and spleen were detected by flow cytometry, and the levels of IL-17, IL-10, IFN-γ and TGF-β in the tumor were detected by ELISA; the expression of Ki-67, PCNA, RORγt and FOXP3 proteins in the tumor was detected by immunohistochemistry.

YQJP contains 7 herbal compounds, which can effectively improve body weight, spleen condition, and bone marrow suppression in tumor-bearing mice inhibit tumor growth, and do not damage tissues and organs, which initially confirmed the anti-cancer effect and safety of YQJP. Further experiments showed that YQJP could elevate the proportion of CD8+, CD4+ T cells in the spleen, increase the proportion of Th17 cells in the tumor tissue of mice, and decrease the level of Treg cells. It can inhibit the expression of Ki-67 and PCNA. Meanwhile, it promotes the expression of IL-17 and IFN-γ and inhibits the expression of IL-10 and TGF-β. In addition, it can reduce the relative expression of FOXP3 and increase the relative expression of RORγt.

The combination of YQJP with chemotherapy had the effect of tumor suppression and enhanced chemotherapeutic efficacy in the spleen qi deficiency CRC mice. The related mechanism may be related to inhibiting proliferation, promoting apoptosis of tumor cells, increasing Th17 cells in tumor tissues, and decreasing Treg cell expression to improve the tumor microenvironment.

Psoriasis and psoriatic arthritis are chronic inflammatory conditions that constitute a significant global health burden due to their prevalence and impact on quality of life. A deeper comprehension of psoriasis and psoriatic arthritis pathogenesis has recently led to the emergence of novel classes of biologics targeting the IL-23/Th17 pathway. The specific role of interleukin-12, -23, and -17 in cancer as either promoters or inhibitors is under investigation in various studies. Here, we explore the potential role of interleukin-12, -23, and -17 in the development of skin tumours as well as the safety of using their inhibitors in the treatment of psoriasis and psoriatic arthritis, particularly in relation to the risk of melanoma and non-melanoma skin cancer (NMSC) development.

Identification of early immune signatures associated with acute myeloid leukemia (AML) relapse following hematopoietic stem cell transplant (HSCT) is critical for patient outcomes. We analyzed PBMCs from 58 patients with AML undergoing HSCT, focusing on T cell subsets and functional profiles. High-dimensional flow cytometry coupled with Uniform Manifold Approximation and Projection dimensionality reduction and PhenoGraph clustering revealed distinct changes in CD4+ and CD8+ T cell populations in 16 patients who relapsed within 1 y of HSCT. We observed increased IL-2, IL-10, and IL-17-producing CD4+ T cells, alongside decreased CD8+ T cell function early in relapsing patients. Notably, relapsing patients exhibited increased TCF-1intermediate cells, which lacked granzyme B or IFN-γ production in the CD4+ T cell compartment. We then developed a supervised machine learning algorithm that predicted AML relapse with 90% accuracy within 30 d after HSCT using high-throughput assays. The algorithm leverages condensed immune phenotypic data, alongside the ADASYN algorithm, for data balancing and 100 rounds of XGBoost supervised learning. This approach holds potential for detecting relapse-associated immune signatures months before clinical manifestation. Our findings demonstrate a distinct immunological signature potentially capable of predicting AML relapse as early as 30 d after HSCT.

Overcoming immune suppression is a major barrier to eliciting potent CD8+ T cell responses against cancer. Treatment with anti-CD4 monoclonal antibody is an effective means for eliminating CD4+Foxp3+ regulatory (Treg) cells in preclinical models and has also demonstrated efficacy in early clinical trials. However, the underlying basis for treatment efficacy, more specifically the implications of codepleting other CD4-expressing cell compartments in tumor-bearing hosts, is not well understood.

Tumor-bearing mice were treated with anti-CD4 versus other therapies that preserve helper T cell function, and the priming, tissue distribution, and maintenance of tumor antigen-specific CD8 T cells were assessed. Antibody blockade and transgenic mouse models were used to determine the mechanisms of CD8 T cell priming. Single-cell RNA-sequencing (scRNAseq) was used to further characterize CD8 T cells that are primed by anti-CD4 therapy and to identify immunosuppressive CD4 T cell subsets in human melanoma following immune checkpoint blockade (ICB).

Comparing anti-CD4 to dual ICB therapy, we show that anti-CD4 facilitates more robust priming of TCF-1+, IL-2-producing, tumor-specific CD8+ T cells that disseminate to tissues and form memory. By decoupling priming from homeostatic proliferation and associated cytokines, we find that anti-CD4 functions independently of creating homeostatic space for CD8+ T cells. We also show that depletion of CD4-expressing antigen-presenting cell subsets is not required for anti-CD4 efficacy. Instead, robust tumor-specific CD8+ T cell priming and memory generation required the removal of total antigen-specific CD4+ T cells, including both Tregs and CD4+ Foxp3-negative conventional (Tconv) cells. In particular, the elimination of CD4+ Tconv cells was necessary for the accumulation and maturation of conventional type-1 dendritic cells in tumor-draining LNs, which were required for CD8+ T cell priming. Accordingly, anti-CD4 treatment restored CD8+ T cell responses in mice cotreated with dual ICB. scRNAseq of melanoma tumors from patients who received ICB revealed the presence of Tr1 and Treg subsets, as well as CD4+ Tconv subsets that lacked clear transcriptional evidence of helper differentiation.

These findings underscore the underappreciated benefit of depleting CD4+ Tconv cells to promote systemic primary and memory CD8+ T cell responses against cancer.

Protein/peptide subunit vaccines are promising to promote the tumor therapeutic efficacy of immune checkpoint blockade (ICB). However, current protein/peptide vaccines elicit limited antitumor T cell responses, leading to suboptimal therapeutic efficacy. Here, we present proteolysis-targeting vaccines (PROTAVs) that facilitate antigen proteolytic processing and cross-presentation to potentiate T cell responses for robust ICB combination immunotherapy of melanoma. PROTAVs are modular conjugates of protein/peptide antigens, E3 ligase-binding ligands, and linkers. In antigen-presenting cells (APCs), PROTAVs bind to E3 ligases to rapidly ubiquitinate PROTAV antigens, facilitating antigen proteolytic processing by proteasome, and thereby promoting antigen cross-presentation to T cells and potentiating CD8+ T cell responses. We developed a melanoma PROTAV using a tandem peptide of trivalent melanoma-associated antigens. Co-delivered by lipid nanoparticles (LNPs) with bivalent immunostimulant adjuvants, this PROTAV promotes the quantity and quality of melanoma-specific CD8+ T cells in mice. Further, combining PROTAV and ICB ameliorates the immunosuppressive melanoma microenvironment. As a result, PROTAV and ICB combination enhances melanoma complete regression rates and eradicated 100% large Braf V600E melanoma without recurrence in syngeneic mice. PROTAVs hold the potential for robust tumor combination immunotherapy.

Papillary thyroid carcinoma (PTC) is the most common subtype of thyroid carcinoma. The most effective treatment for PTC is surgical resection, and patients who undergo surgery have good survival outcomes, but some patients have distant metastasis or even multiorgan metastases at the time of initial diagnosis. Distant metastasis is associated with poorer prognosis and a higher mortality rate. Helper T lymphocyte 17 (Th17) cells and regulatory T lymphocytes (Tregs) play different roles in PTC, and the Th17/Treg balance is closely related to the progression of PTC. Th17 cells play anticancer roles, whereas Tregs play cancer-promoting roles. A Th17/Treg imbalance promotes tumor progression and accelerates invasive behaviors such as tumor metastasis. Th17/Treg homeostasis can be regulated by the TGF-β/IL-2 and IL-6 cytokine axes. Immune checkpoint inhibitors contribute to Treg/Th17 cell homeostasis. For PTC, monoclonal antibodies against CTLA-4, PD-1 and PD-L1 inhibit the activation of Tregs, reversing the Th17/Treg cell imbalance and providing a new option for the prevention and treatment of PTC. This article reviews the role of Tregs and Th17 cells in PTC and their potential targets, aiming to provide better treatment options for PTC.

T helper (Th) 17 cells, a distinct subset of Th lymphocytes, are known for their prominent interleukin (IL)-17 production and other pro-inflammatory cytokines. These cells exhibit remarkable plasticity, allowing them to exhibit different phenotypes in the cancer microenvironment. This adaptability enables Th17 cells to promote tumor progression by immunosuppressive activities and angiogenesis, but also mediate anti-tumor immune responses through employing immune cells in tumor setting or even by directly converting toward Th1 phenotype and producing interferon-gamma (IFN-γ). This dual role of Th17 cells in cancer makes it a double-edged sword in encountering cancer. In this review, we aim to elucidate the complexities of Th17 cell function in cancer by summarizing recent studies and, ultimately, to design novel therapeutic strategies, especially targeting Th17 cells in the tumor milieu, which could pave the way for more effective cancer treatments.

The precise conditions by which cytokines drive cancer is relevant to improving immune checkpoint inhibition (ICI) responses while decreasing toxicity. In this issue of the JCI, Kao et al. investigated T helper cell pathways in patients with solid tumors receiving ICI. The authors evaluated T cell populations, cytokine signatures, immune related adverse events (irAEs), and survival outcomes. Patients with a history of autoimmune disorders were more likely to develop irAEs. Notably, blood samples from patients on treatment showed that elevations in IL-5, IL-6, IL-17f, and TNF-α were associated with an increased risk for grade 2 or higher irAEs. Moreover, IL-6 was associated with decreased objective response rate and worse cancer-specific and all-cause mortality. These findings may help guide decisions for optimizing ICI efficacy while minimizing toxicity and suggest that IL-6 blockade may improve response and decrease toxicity in solid tumors.

Melanoma is the deadliest form of skin cancer in the United States, with its incidence rates rising in older populations. As the immune system undergoes age-related changes, these alterations can significantly influence tumor progression and the effectiveness of cancer treatments. Recent advancements in understanding immune checkpoint molecules have paved the way for the development of innovative immunotherapies targeting solid tumors. However, the aging tumor microenvironment can play a crucial role in modulating the response to these immunotherapeutic approaches. This review seeks to examine the intricate relationship between age-related changes in the immune system and their impact on the efficacy of immunotherapies, particularly in the context of melanoma. By exploring this complex interplay, we hope to elucidate potential strategies to optimize treatment outcomes for older patients with melanoma, and draw parallels to other cancers.

Despite therapeutic efficacy observed with immune checkpoint blockade in advanced melanoma, many tumors do not respond to treatment, representing a need for new therapies. Here, we have generated chimeric antigen receptor (CAR) T cells targeting TYRP1, a melanoma differentiation antigen expressed on the surface of melanomas, including rare acral and uveal melanomas. TYRP1-targeted CAR T cells demonstrate antigen-specific activation and cytotoxic activity in vitro and in vivo against human melanomas independent of the MHC alleles and expression. In addition, the toxicity to pigmented normal tissues observed with T lymphocytes expressing TYRP1-targeted TCRs was not observed with TYRP1-targeted CAR T cells. Anti-TYRP1 CAR T cells provide a novel means to target advanced melanomas, serving as a platform for the development of similar novel therapeutic agents and as a tool to interrogate the immunobiology of melanomas.

Cancers eventually kill hosts even when infiltrated by cancer-specific T cells. We examined whether cancer-specific T cell receptors of CD4+ T cells (CD4TCRs) from tumor-bearing hosts can be exploited for adoptive TCR therapy. We focused on CD4TCRs targeting an autochthonous mutant neoantigen that is only presented by stroma surrounding the MHC class II-negative cancer cells. The 11 most common tetramer-sorted CD4TCRs were tested using TCR-engineered CD4+ T cells. Three TCRs were characterized by convergent recombination for which multiple T cell clonotypes differed in their nucleotide sequences but encoded identical TCR α and β chains. These preferentially selected TCRs destroyed tumors equally well and halted progression through reprogramming of the tumor stroma. TCRs represented by single T cell clonotypes were similarly effective only if they shared CDR elements with preferentially selected TCRs in both α and β chains. Selecting candidate TCRs on the basis of these characteristics can help identify TCRs that are potentially therapeutically effective.

Cardiac glycosides, derived from plants and animals, have been recognized since ancient times. These substances hinder the function of the sodium-potassium pump within eukaryotic cells. Many reports have shown that these compounds influence the activity of nuclear receptors. Thus, we assessed the effects of various cardiac glycosides at nontoxic concentrations on RORγ and RORγT. RORγT is a crucial protein involved in the differentiation of Th17 lymphocytes. Sixteen analyzed cardiac glycosides exhibited varying toxicities in HepG2 cells, all of which demonstrated agonistic effects on RORγ, as confirmed in the RORγ-HepG2 reporter cell line. The overexpression of both the RORγ and RORγT isoforms intensified the effects of these compounds. Additionally, these glycosides induced the expression of G6PC, a gene regulated by RORγ, in HepG2 cells. Subsequently, the effects of two endogenous cardiac glycosides (marinobufagenin and ouabain) and the three most potent glycosides (bufalin, oleandrin, and telecinobufagenin) were evaluated in Th17 primary lymphocytes. All of these compounds increased the expression of the IL17A, IL17F, IFNG, and CXCL10 genes, but they exhibited varying effects on GZMB and CCL20 expression. Molecular docking analysis revealed the robust binding affinity of cardiac glycosides for the ligand binding domain of the RORγ/RORγT receptors. Thus, we demonstrated that at nontoxic concentrations, cardiac glycosides have agonistic effects on RORγ/RORγT nuclear receptors, augmenting their activity. This potential can be harnessed to modulate the phenotype of IL17-expressing cells (e.g., Th17 or Tc17 lymphocytes) in adoptive therapy for combating various types of cancer.

Tumor-specific CD8+ T cells are frequently dysfunctional and unable to halt tumor growth. We investigated whether tumor-specific CD4+ T cells can be enlisted to overcome CD8+ T cell dysfunction within tumors. We find that the spatial positioning and interactions of CD8+ and CD4+ T cells, but not their numbers, dictate anti-tumor responses in the context of adoptive T cell therapy as well as immune checkpoint blockade (ICB): CD4+ T cells must engage with CD8+ T cells on the same dendritic cell during the effector phase, forming a three-cell-type cluster (triad) to license CD8+ T cell cytotoxicity and cancer cell elimination. When intratumoral triad formation is disrupted, tumors progress despite equal numbers of tumor-specific CD8+ and CD4+ T cells. In patients with pleural mesothelioma treated with ICB, triads are associated with clinical responses. Thus, CD4+ T cells and triads are required for CD8+ T cell cytotoxicity during the effector phase and tumor elimination.

It's been long thought that CD8+ cytotoxic T cells play a major role in T cell-mediated antitumor responses, whereas CD4+ T cells merely provide some assistance to CD8+ T cells as the "helpers." In recent years, numerous studies support the notion that CD4+ T cells play an indispensable role in antitumor responses. Here, we summarize and discuss the current knowledge regarding the roles of CD4+ T cells in antitumor responses and immunotherapy, with a focus on the molecular and cellular mechanisms behind these observations. These new insights on CD4+ T cells may pave the way to further optimize cancer immunotherapy.

How distinct methods of host preconditioning impact the efficacy of adoptively transferred antitumor T helper cells is unknown.

CD4+ T cells with a transgenic T-cell receptor that recognize tyrosinase-related peptide (TRP)-1 melanoma antigen were polarized to the T helper 17 (Th17) phenotype and then transferred into melanoma-bearing mice preconditioned with either total body irradiation or chemotherapy.

We found that preconditioning mice with a non-myeloablative dose of total body irradiation (TBI of 5 Gy) was more effective than using an equivalently dosed non-myeloablative chemotherapy (cyclophosphamide (CTX) of 200 mg/kg) at augmenting therapeutic activity of antitumor TRP-1 Th17 cells. Antitumor Th17 cells engrafted better following preconditioning with TBI and regressed large established melanoma in all animals. Conversely, only half of mice survived long-term when preconditioned with CTX and infused with anti-melanoma Th17 cells. Interleukin (IL)-17 and interferon-γ, produced by the infused Th17 cells, were detected in animals given either TBI or CTX preconditioning. Interestingly, inflammatory cytokines (granulocyte colony stimulating factor, IL-6, monocyte chemoattractant protein-1, IL-5, and keratinocyte chemoattractant) were significantly elevated in the serum of mice preconditioned with TBI versus CTX after Th17 therapy. The addition of fludarabine (FLU, 200 mg/kg) to CTX (200 mg/kg) improved the antitumor response to the same degree mediated by TBI, whereas FLU alone with Th17 therapy was ineffective.

Our results indicate, for the first time, that the antitumor response, persistence, and cytokine profiles resulting from Th17 therapy are impacted by the specific regimen of host preconditioning. This work is important for understanding mechanisms that promote long-lived responses by adoptive cellular therapy, particularly as CD4+ based T-cell therapies are now emerging in the clinic.

The incidence of head and neck squamous cell carcinoma (HNSCC) is increasing, particularly among younger populations. It is projected that the number of new cases will increase by almost 50% by 2040, with market revenues expected to triple in the same period. Despite the recent introduction of immune checkpoint inhibitors (ICIs) into the therapeutic armamentarium, the vast majority of patients with recurrent and/or metastatic (R/M) HNSCC fail to derive durable benefits from systemic therapy.

This article aims to review the multiple monoclonal antibodies (mAbs) regimens currently under development, targeting various growth factors, immune checkpoints, immune costimulatory receptors, and more.

So far, the combination of anti-EGFR and ICI appears to be the most promising, especially in HPV-negative patients. It will be interesting to confirm whether the arrival of antibody-drug conjugates and bispecific mAb can surpass the efficacy of anti-EGFR, as they are also being tested in combination with ICI. Furthermore, we believe that immune costimulatory agonists and various ICIs combination are worth monitoring, despite some initial setbacks.

The immune system is traditionally classified as a defense system that can discriminate between self and non-self or dangerous and non-dangerous situations, unleashing a tolerogenic reaction or immune response. These activities are mainly coordinated by the interaction between innate and adaptive cells that act together to eliminate harmful stimuli and keep tissue healthy. However, healthy tissue is not always the end point of an immune response. Much evidence has been accumulated over the years, showing that the immune system has complex, diversified, and integrated functions that converge to maintaining tissue homeostasis, even in the absence of aggression, interacting with the tissue cells and allowing the functional maintenance of that tissue. One of the main cells known for their function in helping the immune response through the production of cytokines is CD4+ T lymphocytes. The cytokines produced by the different subtypes act not only on immune cells but also on tissue cells. Considering that tissues have specific mediators in their architecture, it is plausible that the presence and frequency of CD4+ T lymphocytes of specific subtypes (Th1, Th2, Th17, and others) maintain tissue homeostasis. In situations where homeostasis is disrupted, such as infections, allergies, inflammatory processes, and cancer, local CD4+ T lymphocytes respond to this disruption and, as in the healthy tissue, towards the equilibrium of tissue dynamics. CD4+ T lymphocytes can be manipulated by tumor cells to promote tumor development and metastasis, making them a prognostic factor in various types of cancer. Therefore, understanding the function of tissue-specific CD4+ T lymphocytes is essential in developing new strategies for treating tissue-specific diseases, as occurs in cancer. In this context, this article reviews the evidence for this hypothesis regarding the phenotypes and functions of CD4+ T lymphocytes and compares their contribution to maintaining tissue homeostasis in different organs in a steady state and during tumor progression.

To achieve eradication of solid tumors, we examined how many neoantigens need to be targeted with how many T-cell receptors (TCR) by which type of T cells.

Unmanipulated, naturally expressed (autochthonous) neoantigens were targeted with adoptively transferred TCR-engineered autologous T cells (TCR-therapy). TCR-therapy used CD8+ T-cell subsets engineered with TCRs isolated from CD8+ T cells (CD8+TCR-therapy), CD4+ T-cell subsets engineered with TCRs isolated from CD4+ T cells (CD4+TCR-therapy), or combinations of both. The targeted tumors were established for at least 3 weeks and derived from primary autochthonous cancer cell cultures, resembling natural solid tumors and their heterogeneity as found in humans.

Relapse was common with CD8+TCR-therapy even when targeting multiple different autochthonous neoantigens on heterogeneous solid tumors. CD8+TCR-therapy was only effective against homogenous tumors artificially derived from a cancer cell clone. In contrast, a combination of CD8+TCR-therapy with CD4+TCR-therapy, each targeting one neoantigen, eradicated large and established solid tumors of natural heterogeneity. CD4+TCR-therapy targeted a mutant neoantigen on tumor stroma while direct cancer cell recognition by CD8+TCR-therapy was essential for cure. In vitro data were consistent with elimination of cancer cells requiring a four-cell cluster composed of TCR-engineered CD4+ and CD8+ T cells together with antigen-presenting cells and cancer cells.

Two cancer-specific TCRs can be essential and sufficient to eradicate heterogeneous solid tumors expressing unmanipulated, autochthonous targets. We demonstrate that simplifications to adoptive TCR-therapy are possible without compromising efficacy.

Interleukin-21 (IL-21) is an immunostimulatory cytokine which belongs to the common gamma-chain family of cytokines. It plays an import role in the development, differentiation, proliferation, and activation of immune cells, in particular T and natural killer (NK) cells. Since its discovery in 2000, IL-21 has been shown to regulate both adaptive and immune responses associates with key role in antiviral and antitumor responses. Recent advances indicate IL-21 as a promising target for cancer treatment and encouraging results were obtained in preclinical studies which investigated the potency of IL-21 alone or in combination with other therapies, including monoclonal antibodies, checkpoint inhibitory molecules, oncolytic virotherapy, and adoptive cell transfer. Furthermore, IL-21 showed antitumor effects in the treatment of patients with advanced cancer, with minimal side effects in several clinical trials. In the present review, we will outline the recent progress in IL-21 research, highlighting the potential of IL-21 based therapy as single agent or in combination with other drugs to enhance cancer treatment efficiency.

Vitiligo is a chronic skin condition marked by the gradual loss of pigmentation, leading to the emergence of white or depigmented patches on the skin. The exact cause of vitiligo remains not entirely understood, although it is thought to involve a blend of genetic, autoimmune, and environmental factors. While there is currently no definitive cure for vitiligo, diverse treatments exist that may assist in managing the condition and fostering repigmentation in specific instances. Animal models play a pivotal role in comprehending the intricate mechanisms that underlie vitiligo, providing valuable insights into the progression and onset of the disease, as well as potential therapeutic interventions. Although induced experimental models lack the nuanced characteristics observed in natural experimental models, relying solely on a single animal model might not fully capture the intricate pathogenesis of vitiligo. Different animal models simulate specific aspects of human vitiligo pathogenesis to varying degrees. This review extensively explores the array of animal models utilized in vitiligo research, shedding light on their respective advantages, disadvantages, and applications.

The innate immune pathway is receiving increasing attention in cancer therapy. This pathway is ubiquitous across various cell types, not only in innate immune cells but also in adaptive immune cells, tumor cells, and stromal cells. Agonists targeting the innate immune pathway have shown profound changes in the tumor microenvironment (TME) and improved tumor prognosis in preclinical studies. However, to date, the clinical success of drugs targeting the innate immune pathway remains limited. Interestingly, recent studies have shown that activation of the innate immune pathway can paradoxically promote tumor progression. The uncertainty surrounding the therapeutic effectiveness of targeted drugs for the innate immune pathway is a critical issue that needs immediate investigation. In this review, we observe that the role of the innate immune pathway demonstrates heterogeneity, linked to the tumor development stage, pathway status, and specific cell types. We propose that within the TME, the innate immune pathway exhibits multidimensional diversity. This diversity is fundamentally rooted in cellular heterogeneity and is manifested as a variety of signaling networks. The pro-tumor effect of innate immune pathway activation essentially reflects the suppression of classical pathways and the activation of potential pro-tumor alternative pathways. Refining our understanding of the tumor's innate immune pathway network and employing appropriate targeting strategies can enhance our ability to harness the anti-tumor potential of the innate immune pathway and ultimately bridge the gap from preclinical to clinical application.

The success of cancer immunotherapy is largely associated with immunologically hot tumors. Approaches that promote the infiltration of immune cells into tumor beds are urgently needed to transform cold tumors into hot tumors. Oncolytic viruses can transform the tumor microenvironment (TME), resulting in immunologically hot tumors. Cytokines are good candidates for arming oncolytic viruses to enhance their function in this transformation. Here, we used the oncolytic vaccinia virus (oVV) to deliver interleukin-9 (IL-9) into the tumor bed and explored its antitumor effects in colon and lung tumor models. Our data show that IL-9 prolongs viral persistence, which is probably mediated by the up-regulation of IL-10. The vvDD-IL-9 treatment elevated the expression of Th1 chemokines and antitumor factors such as IFN-γ, granzyme B, and perforin. IL-9 expression increased the percentages of CD4+ and CD8+ T cells in the TME and decreased the percentage of oVV-induced immune suppressive myeloid-derived suppressor cells (MDSC), leading to potent antitumor effects compared with parental virus treatment. The vvDD-IL-9 treatment also increased the percentage of regulatory T cells (Tregs) in the TME and elevated the expression of immune checkpoint molecules such as PD-1, PD-L1, and CTLA-4, but not GITR. The combination therapy of vvDD-IL-9 and the anti-CTLA-4 antibody, but not the anti-GITR antibody, induced systemic tumor-specific antitumor immunity and significantly extended the overall survival of mice, indicating a potential translation of the IL-9-expressing oncolytic virus into a clinical trial to enhance the antitumor effects elicited by an immune checkpoint blockade for cancer immunotherapy.

Adoptive transfer of T cell receptor-engineered T cells (TCR-T) is a promising strategy for immunotherapy against solid tumors. However, the potential of CD4+ T cells in mediating tumor regression has been neglected. Nasopharyngeal cancer is consistently associated with EBV. Here, to evaluate the therapeutic potential of CD4 TCR-T in nasopharyngeal cancer, we screened for CD4 TCRs recognizing EBV nuclear antigen 1 (EBNA1) presented by HLA-DP5. Using mass spectrometry, we identified EBNA1567-581, a peptide naturally processed and presented by HLA-DP5. We isolated TCR135, a CD4 TCR with high functional avidity, that can function in both CD4+ and CD8+ T cells and recognizes HLA-DP5-restricted EBNA1567-581. TCR135-transduced T cells functioned in two ways: directly killing HLA-DP5+EBNA1+ tumor cells after recognizing EBNA1 presented by tumor cells and indirectly killing HLA-DP5-negative tumor cells after recognizing EBNA1 presented by antigen-presenting cells. TCR135-transduced T cells preferentially infiltrated into the tumor microenvironment and significantly inhibited tumor growth in xenograft nasopharyngeal tumor models. Additionally, we found that 62% of nasopharyngeal cancer patients showed 50%-100% expression of HLA-DP on tumor cells, indicating that nasopharyngeal cancer is well suited for CD4 TCR-T therapy. These findings suggest that TCR135 may provide a new strategy for EBV-related nasopharyngeal cancer immunotherapy in HLA-DP5+ patients.

Classifying systemic inflammatory disorders as autoinflammatory or autoimmune provides insight into disease pathogenesis and whether treatment should target innate molecules and their signaling pathways or the adaptive immune response. COPA syndrome is a monogenic disorder of immune dysregulation that leads to interstitial lung disease and high-titer autoantibodies. Studies show constitutive activation of the innate immune molecule STING is centrally involved in disease. However, the mechanisms by which STING results in loss of T cell tolerance and autoimmunity in COPA syndrome or more common autoimmune diseases is not understood. Using CopaE241K/+ mice, we uncovered a functional role for STING in the thymus. Single cell data of human thymus demonstrates STING is highly expressed in medullary thymic epithelial cells (mTECs) involved in processing and presenting self-antigens to thymocytes. In CopaE241K/+ mice, activated STING in mTECs triggered interferon signaling, impaired macroautophagy and caused a defect in negative selection of T cells. Wild-type mice given a systemic STING agonist phenocopied the selection defect and showed enhanced thymic escape of a T cell clone targeting a self-antigen also expressed in melanoma. Our work demonstrates STING activation in TECs shapes the T cell repertoire and contributes to autoimmunity, findings important for settings that activate thymic STING.

Several studies describe an inverse statistical relationship between the presence of an allergy and development of cancer. However, the immunological mechanism involved in the relationship between these two degenerative diseases has not been explored.

The main objective of this study was to explore the possibility that the lymphocyte T helper (Th) 2 response, a characteristic of allergy, induces recognition of tumor antigens.

Patients with a clinical diagnosis of breast ductal carcinoma were included. Histopathological markers related to proliferation of tumor cells were determined (Her-2-neu, Ki-67, estrogen receptor, and progesterone receptor). IHC was performed using IgE antibodies purified from an allergy patient and from each biopsy donor patient. Serum concentrations of cytokines representative of Th1 and Th2 inflammatory responses were determined. A total of 14 patients with a confirmed diagnosis of breast ductal carcinoma were included. IHC performed on biopsies showed a weak response when using purified IgE antibodies from an allergy patient; however, IHC using the IgE of each patient as the primary antibody showed an intense and highly specific signal. Serum concentrations of cytokines of the Th2 response, that is, IL-4 (130.5 pg/mL (116-135 pg/mL)), IL-5 (202 pg/mL (191-213 pg/mL)), and IL-13 (105.5 pg/mL (98-117 pg/mL)), were significantly higher than those of the Th1 response, that is, IL-6 (86 pg/mL (79-90 pg/mL)) and INF-γ (93 pg/mL (79-99 pg/mL)).

Purified IgE antibodies specifically recognize tumor cells in breast ductal carcinoma.

Microbes influence cancer initiation, progression and therapy responsiveness. IL-17 signaling contributes to gut barrier immunity by regulating microbes but also drives tumor growth. A knowledge gap remains regarding the influence of enteric IL-17-IL-17RA signaling and their microbial regulation on the behavior of distant tumors. We demonstrate that gut dysbiosis induced by systemic or gut epithelial deletion of IL-17RA induces growth of pancreatic and brain tumors due to excessive development of Th17, primary source of IL-17 in human and mouse pancreatic ductal adenocarcinoma, as well as B cells that circulate to distant tumors. Microbial dependent IL-17 signaling increases DUOX2 signaling in tumor cells. Inefficacy of pharmacological inhibition of IL-17RA is overcome with targeted microbial ablation that blocks the compensatory loop. These findings demonstrate the complexities of IL-17-IL-17RA signaling in different compartments and the relevance for accounting for its homeostatic host defense function during cancer therapy.