Over the recent decades the market potential of biologics has substantially expanded, and many of the top-selling drugs worldwide are now monoclonal antibodies or antibody-like molecules. The common gamma chain (γc) cytokines, Interleukin (IL-)2, IL-4, IL-7, IL-9, IL-15, and IL-21, play pivotal roles in regulating immune responses, from innate to adaptive immunity. Dysregulation of cell signaling by these cytokines is strongly associated with a range of immunological disorders, which includes cancer as well as autoimmune and inflammatory diseases. Given the essential role of γc cytokines in maintaining immune homeostasis, the development of therapeutic interventions targeting these molecules poses unique challenges. Here, we provide an overview of current biologics targeting either single or multiple γc cytokines or their respective receptor subunits across a spectrum of diseases, primarily focusing on antibodies, antibody-like constructs, and antibody-cytokine fusions. We summarize therapeutic biologics currently in clinical trials, highlighting how they may offer advantages over existing therapies and standard of care, and discuss recent advances in this field. Finally, we explore future directions and the potential of novel therapeutic intervention strategies targeting this cytokine family.

Antibodies against immune checkpoints are now routinely administered as a first line of treatment against metastatic lung cancer. Resistance to immune checkpoint inhibitors is, however, frequent, underscoring the need to find alternative treatments. Adoptive T-cell therapy has recently proven effective in treating patient's refractory to immune checkpoint inhibitors. This provides impetus to characterize the T-cell subsets best able to tackle tumors. The anticancer activities of IL-9-producing CD4 T helper cells (TH9 cells) were identified in melanoma in 2012. TH9 cells feature strong antimelanoma effects thanks to their production of interleukin (IL)-9 and the activation of innate and adaptive immune effectors. The ability of TH9 cells to prevent the growth of triple-negative breast cancer (TNBC) and osteosarcoma (OS), which commonly metastasize to the lungs, is elusive. In this commentary, we discuss the findings of Chen et al reported in the JITC demonstrating that TH9 cells are lung-tropic and eliminate TNBC and OS cells developing in the lungs. We also highlight how these investigations are in line with recent studies indicating that the adoptive transfer of IL-9-producing T cells eliminate aggressive cancers, including hematological tumors like leukemia and solid tumors such as glioblastoma. Altogether, these findings over the past 13 years support the clinical evaluation of TH9 cells in the adoptive therapy of cancer.

T helper (Th) cell subsets play pivotal roles in regulating immune responses within the tumor microenvironment, influencing both tumor progression and anti-tumor immunity. Among these subsets, Th1 cells promote cytotoxic responses through the production of IFN-γ, while Th2 cells and regulatory T cells (Tregs) exert immunosuppressive effects that support tumor growth. Th9 and Th17 cells have context-dependent roles, contributing to both pro-inflammatory and regulatory processes in tumor immunity. Tumor antigen-specific T cells within the tumor microenvironment often exhibit a dysfunctional phenotype due to increased expression of inhibitory receptors such as CTLA-4 and PD-1, leading to reduced antitumor activity. Monoclonal antibodies that block these inhibitory signals-collectively known as immune checkpoint inhibitors (ICIs)-can reactivate these T cells, enhancing their ability to target and destroy cancer cells. Recent advancements have highlighted the critical role of T helper subsets in modulating responses to ICIs, with their interactions remaining a focus of ongoing research. Both positive and negative effects of ICIs have been reported in relation to Th cell subsets, with some effects depending on the type of tumor microenvironment. This review summarizes the crucial roles of different T helper cell subsets in tumor immunity and their complex relationship with immune checkpoint inhibitor therapy.

BackgroundGiven the differences between malignancies arising from different segments of the colon, specific theranostic biomarkers can be linked to either Right-sided (RCC) or Left-sided colon cancer (LCC).ObjectiveAnalysis of 65 serum proteins to identify panels of theranostic biomarkers for LCC and RCC.MethodsSerum levels of 65 immunomodulators were measured in CC, LCC, and RCC patients, as well as healthy controls with the ProcartaPlex Human Immune Monitoring 65-Plex Panel.ResultsIL-27 may be used for early detection in LCC. CD-30 was up-regulated in metastatic CC, BLC was up-regulated in metastatic LCC and CD-40L was down-regulated in metastatic RCC. MDC and MMP-1 were positively associated, while IL-9 and VEGF-A were negatively associated with lymph nodes invasion in CC. Up-regulation of IL-12p70 and MMP-1 in LCC with lymph nodes invasion contrasted with down-regulation of IL-9 and MIP-1beta. IL-23, I-TAC, and SDF-1α were negatively associated with resistant CC to Folfox chemotherapy, and I-TAC was down-regulated in resistant LCC. IL-2 and FGF-2 were down-regulated, while APRIL was up-regulated in resistant RCC.ConclusionsOur study revealed significant differences in serum protein levels between LCC and RCC emphasizing the importance to explore novel theranostic biomarkers for CC, associated with resistance or sensitivity to chemotherapy.

CD4+ T cells play essential roles in adaptive immunity. Distinct CD4+ T-cell subsets-TH1, TH2, TH17, TH22, T follicular helper, and regulatory T cells-have been identified, and their contributions to host defense and immune regulation are increasingly well defined. IL-9-producing TH9 cells were first described in 2008 and appear to play both protective and pathogenic roles in human immunity. However, key requirements for generating human TH9 cells remain incompletely defined.

We sought to define signaling pathways that regulate IL-9 production by human CD4+ T cells.

Human naive and memory CD4+ T cells were cultured under different conditions, and the molecular mechanisms regulating IL-9 induction were determined by assessing the ability of CD4+ T cells from a broad range of patients (n = 92) with pathogenic variants in key immune genes (n = 21) to differentiate into IL-9+ cells.

We identified 2 culture conditions that yielded IL-9-expressing cells from naive CD4+ T cells and amplified IL-9 production by in vivo-generated memory CD4+ T cells: TGF-β plus IL-4 (ie, TH9 polarizing condition), and the combination of IL-21, IL-23, IL-6, IL-1β, and TGF-β (ie, TH17 polarizing condition). Combining these conditions had a synergistic effect in generating IL-9+CD4+ T cells. IL-9 induction required STAT3-activating cytokines as well as intact signaling via the T-cell receptor and STAT5. Importantly, IL-9 induction was restrained by IFN-γ/STAT1 and IL-10.

Our findings revealed critical molecules involved in inducing/restraining IL-9 production by human CD4+ T cells, thereby identifying pathways that could be targeted to modulate IL-9 in health and disease.

Staphylococcus aureus (S. aureus) is a Gram-positive bacterium of significant clinical importance, known for its versatility and ability to cause a wide array of infections, such as osteoarticular, pulmonary, cardiovascular, device-related, and hospital-acquired infections. This review describes the most recent evidence of the pathogenic potential of S. aureus, which is commonly part of the human microbiota but can lead to severe infections. The prevalence of pathogenic S. aureus in hospital and community settings contributes to substantial morbidity and mortality, particularly in individuals with compromised immune systems. The immunopathogenesis of S. aureus infections involves intricate interactions with the host immune and non-immune cells, characterized by various virulence factors that facilitate adherence, invasion, and evasion of the host's defenses. This review highlights the complexity of S. aureus infections, ranging from mild to life-threatening conditions, and underscores the growing public health concern posed by multidrug-resistant strains, including methicillin-resistant S. aureus (MRSA). This article aims to provide an updated perspective on S. aureus-related infections, highlighting the main diseases linked to this pathogen, how the different cell types, virulence factors, and signaling molecules are involved in the immunopathogenesis, and the future perspectives to overcome the current challenges to treat the affected individuals.

While much is known about the functional effects of type 2 cytokines interleukin (IL)-4, IL-5 and IL-13 in homeostasis and disease, we still poorly understand the functions of IL-9. Chronic inflammation seen in allergic diseases, autoimmunity and cancer is however frequently accompanied by overproduction of this elusive type 2 cytokine. Initially identified as a T cell and mast cell growth factor, and later as the hallmark cytokine defining TH9 cells, we now know that IL-9 is produced by multiple innate and adaptive immune cells. Recent evidence suggests that IL-9 controls discrete aspects of the allergic cascade, cellular responses of immune and stromal cells, cancer progression, tolerance and immune escape. Despite functioning as a pleiotropic cytokine in mucosal environments, like the lungs, the direct and indirect cellular targets of IL-9 are still not well characterized. Here, we discuss IL-9's cellular senders and receivers, focusing on asthma and cancer. Moreover, we review current research directions and the outlook of targeted therapy centered around the biology of IL-9.

Chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable clinical success in treating hematological malignancies. However, its clinical efficacy in solid tumors is less satisfactory, partially due to poor in vivo expansion and the limited persistence of CAR-T cells. Here, we demonstrated that the overexpression of GITR ligand enhances the anti-tumor activity of CAR-T cells. Compared to prostate-specific membrane antigen-BB-Z (PSMA-BB-Z) CAR-T, PSMA-BB-Z-GITRL CAR-T cells have much more interferon (IFN)-γ, TNF-α, and interleukin (IL)-9 secretion, a higher proportion of central memory T (TCM) cells and T helper 9 (Th9) cells, less expression of exhaustion markers, and robust proliferation capacity. Consequently, PSMA-BB-Z-GITRL CAR-T cells exhibited more potent anti-tumor activity against established solid tumors in vivo than PSMA-BB-Z CAR-T cells. The results of the in vivo persistence experiment also indicated that PSMA-BB-Z-GITRL CAR-T cells exhibited much more retention in mouse blood, spleen, and tumor tissue than PSMA-BB-Z CAR-T cells 15 days after CAR-T cell therapy. In addition, PSMA-BB-Z-GITRL CAR-T cells produce higher levels of IFN-γ, TNF-α, and IL-9 in mouse blood, exhibiting a higher proportion of TCM cells and a lower proportion of Treg cells compared to PSMA-BB-Z CAR-T cells. Our results demonstrate that the overexpression of GITRL has important implications for improving CAR-T cell-based human solid tumor immunotherapy.

Lung metastasis remains the primary cause of tumor-related mortality, with limited treatment options and unsatisfactory efficacy. In preclinical studies, T helper 9 (TH9) cells have shown promise in treating solid tumors. However, it is unclear whether TH9 cells can tackle more challenging situations, such as established lung metastases. Moreover, comprehensive exploration into the nuanced biological attributes of TH9 cells is imperative to further unravel their therapeutic potential.

We adoptively transferred TH1, TH9, and TH17 cells into subcutaneous, in situ, and established lung metastases models of osteosarcoma and triple-negative breast cancer, respectively, comparing their therapeutic efficacy within each distinct model. We employed flow cytometry and an in vivo imaging system to evaluate the accumulation patterns of TH1, TH9, and TH17 cells in the lungs after transfusion. We conducted bulk RNA sequencing on in vitro differentiated TH9 cells to elucidate the chemokine receptor CXCR4, which governs their heightened pulmonary tropism relative to TH1 and TH17 cell counterparts. Using Cd4 cre Cxcr4 flox/flox mice, we investigate the effects of CXCR4 on the lung tropism of TH9 cells. We performed mass spectrometry to identify the E3 ligase responsible for CXCR4 ubiquitination and elucidated the mechanism governing CXCR4 expression within TH9 cellular milieu. Ultimately, we analyzed the tumor immune composition after TH9 cell transfusion and evaluated the therapeutic efficacy of adjunctive anti-programmed cell death protein-1 (PD-1) therapy in conjunction with TH9 cells.

In this study, we provide evidence that TH9 cells exhibit higher lung tropism than TH1 and TH17 cells, thereby exhibiting exceptional efficacy in combating established lung metastases. CXCR4-CXCL12 axis is responsible for lung tropism of TH9 cells as ablating CXCR4 in CD4+ T cells reverses their lung accumulation. Mechanistically, tumor necrosis factor receptor-associated factor 6 (TRAF6)-driven hyperactivation of NF-κB signaling in TH9 cells inhibited ITCH-mediated ubiquitination of CXCR4, resulting in increased CXCR4 accumulation and enhanced lung tropism of TH9 cells. Besides, TH9 cells' transfusion significantly improved the immunosuppressed microenvironment. TH9 cells and anti-PD-1 exhibit synergistic effects in tumor control.

Our findings emphasized the innate lung tropism of TH9 cells driven by the activation of TRAF6, which supports the potential of TH9 cells as a promising therapy for established lung metastases.

Sphingosylphosphorylcholine (SPC) is one of sphingomyelin-derived sphingolipids. SPC levels are increased in ascitic fluids of ovarian cancer patients and stratum corneum of atopic dermatitis (AD) patients. SPC has antitumor activity against several cancer cells by reducing proliferation and migration and increasing apoptosis in vitro. SPC can also cause scratching, potentially exacerbating symptoms of AD. However, the role of SPC in modulating immune responses, particularly in the differentiation of Th9 cells, which carry the most powerful antitumor activity among CD4+ T cells, has yet to be investigated. In this study, we found that SPC is another inducer of Th9 cell differentiation by replicating TGF-β. SPC upregulated Smad3, STAT5, and β-catenin signaling pathways. Increased Smad3 and STAT5 signaling pathways by SPC promoted the differentiation of Th9 cells and increased β-catenin signaling pathway resulted in a less-exhausted, memory-like phenotype of Th9 cells. Increased Smad3, STAT5 and β-catenin signaling pathways by SPC were mediated by increased mitochondrial ROS. These results suggest that SPC is an important endogenous inducer of Th9 cell differentiation and may be one of the targets for treating Th9-related diseases, and that enhancing Th9 differentiation by SPC may be helpful in adoptive T cell therapy for cancer treatment.

IL-9-producing T cells (T9) regulate immunological responses that affect various cellular biological processes, though their precise function remains fully understood. Previous studies have linked T9 cells to conditions such as allergic disorders, parasitic infection clearance, and various types of cancers. While the functional heterogeneity of IL-9 and T9 cells in cancer development has been documented, these cells present promising therapeutic opportunities for treating solid tumors. This review highlights the roles of IL-9 and T9 cells in cancer progression and treatment responses, focusing on potential discrepancies in IL-9/IL-9R signaling between murine tumors and cancer patients. Additionally, we discuss the regulation of tumor-specific Th9/Tc9 cell differentiation, the therapeutic potential of these cells, and current strategies to enhance their anti-tumor activities.

Nonalcoholic fatty liver disease (NAFLD) is reaching pandemic proportions due to overnutrition. The understanding of advanced stages that recapitulate the human pathology is of great importance to get a better mechanistic insight. We hypothesized that feeding of WT (C57BL) mice with a diet containing a high content of fat (21%), sugar (41.5%) and 1.25% of cholesterol (called from now on high fat, sucrose and cholesterol diet, HFSCD) will reproduce the characteristics of disease severity. Analysis of 16 weeks HFSCD-fed mice demonstrated increased liver weight and plasmatic liver damage markers compared with control diet (CD)-fed mice. HFSCD-fed mice developed greater hepatic triglyceride, cholesterol and NEFA content, inflammation and NAFLD activity score (NAS) indicating an advanced disease. HFSCD-fed mice displayed augmented hepatic total CD3+ T and Th9 lymphocytes, as well as reduced Th2 lymphocytes and CD206 anti-inflammatory macrophages. Moreover, T cells and anti-inflammatory macrophages correlated positively and inversely, respectively, with intrahepatic cholesterol content. Consistently, circulating cytotoxic CD8+ T lymphocytes, Th1, and B cell levels were elevated in HFSCD-fed WT mice. Hepatic and adipose tissue expression analysis demonstrated changes in fibrotic and metabolic genes related with cholesterol, triglycerides, and fatty acid synthesis in HFSCD-fed WT. These mice also exhibited reduced antioxidant capacity and autophagy and elevated ERK signaling pathway activation and CHOP levels. Our results indicate that the feeding with a cholesterol-enriched diet in WT mice produces an advanced NAFLD stage with fibrosis, characterized by deficient autophagy and ER stress along with inflammasome activation partially via ERK pathway activation.

T helper 9 (Th9) cells are interleukin 9 (IL-9)-producing cells that have diverse functions ranging from antitumor immune responses to allergic inflammation. Th9 cells differentiate from naïve CD4+ T cells in the presence of IL-4 and transforming growth factor-beta (TGF-β); however, our understanding of the molecular basis of their differentiation remains incomplete. Previously, we reported that the differentiation of another subset of TGF-β-driven T helper cells, Th17 cells, is highly dependent on de novo lipid biosynthesis. On the basis of these findings, we hypothesized that lipid metabolism may also be important for Th9 cell differentiation. We therefore investigated the differentiation and function of mouse and human Th9 cells in vitro under conditions of pharmacologically or genetically induced deficiency of the intracellular fatty acid content and in vivo in mice genetically deficient in acetyl-CoA carboxylase 1 (ACC1), an important enzyme for fatty acid biosynthesis. Both the inhibition of de novo fatty acid biosynthesis and the deprivation of environmental lipids augmented differentiation and IL-9 production in mouse and human Th9 cells. Mechanistic studies revealed that the increase in Th9 cell differentiation was mediated by the retinoic acid receptor and the TGF-β-SMAD signaling pathways. Upon adoptive transfer, ACC1-inhibited Th9 cells suppressed tumor growth in murine models of melanoma and adenocarcinoma. Together, our findings highlight a novel role of fatty acid metabolism in controlling the differentiation and in vivo functions of Th9 cells.

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.

Retinoic-acid-related orphan receptors (RORs) are transcription factors belonging to the nuclear receptor subfamily consisting of RORα, RORβ, and RORγ. By binding to the ROR response elements (ROREs) on target gene promoters, RORs regulate a wide variety of cellular processes, including autophagy, mitophagy, oxidative stress, and inflammation. The regulatory roles of RORs are observed in cardiac cells, hepatocytes, pulmonary epithelial cells, renal cells, immune cells, and cancer cells. A growing body of clinical and experimental evidence suggests that ROR expression levels are markedly reduced under different pathological and stress conditions, suggesting that RORs may play a critical role in the pathogenesis of a variety of disease states, including myocardial infarction, immune disorders, cancer, and metabolic syndrome. Reductions in RORs are also associated with inhibition of autophagy, increased reactive oxygen species (ROS), and increased cell death, underscoring the importance of RORs in the regulation of these processes. Herein, we highlight the relationship between RORs and homeostatic processes that influence cell viability. Understanding how these intricate processes are governed at the cellular level is of high scientific and clinical importance to develop new therapeutic strategies that modulate ROR expression and disease progression.

T lymphocytes that infiltrate the tumor microenvironment (TME) often fail to function as effective anti-cancer agents. Within the TME, cell-to-cell inhibitory interactions play significant roles in dampening their anti-tumor activities. Recent studies have revealed that soluble factors released in the TME by immune and non-immune cells, as well as by tumor cells themselves, contribute to the exacerbation of T cell exhaustion. Our understanding of the cytokine landscape of the TME, their interrelationships, and their impact on cancer development is still at its early stages. In this review, we aim to shed light on Interleukin (IL) -6, IL-9, and IL-10, a small group of JAK/STAT signaling-dependent cytokines harboring T cell-suppressive effects in the TME and summarize their mechanisms of action. Additionally, we will explore how advancements in scientific research can help us overcoming the obstacles posed by cytokines that suppress T cells in tumors, with the ultimate objective of stimulating further investigations for the development of novel therapeutic strategies to counteract their tumor-promoting activities.

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.

TTK spindle assembly checkpoint kinase is an emerging cancer target. This preclinical study explored the antitumor mechanism of TTK inhibitor OSU13 to define a strategy for clinical development. We observed prominent antitumor activity of OSU13 in melanoma, colon and breast cancer cells, organoids derived from patients with melanoma, and mice bearing colon tumors associated with G2 cell cycle arrest, senescence, and apoptosis. OSU13-treated cells displayed DNA damage and micronuclei that triggered the cytosolic DNA-sensing cGAS/STING pathway. STING was required for the induction of several proteins involved in T cell recruitment and activity. Tumors from OSU13-treated mice showed an increased proportion of T and NK cells and evidence of PD-1/PD-L1 immune checkpoint activation. Combining a low-toxicity dose of OSU13 with anti-PD-1 checkpoint blockade resulted in prominent STING- and CD8+ T cell-dependent tumor inhibition and improved survival. These findings provide a rationale for utilizing TTK inhibitors in combination with immunotherapy in STING-proficient tumors.

Th9 cells, a subset of T-helper cells producing interleukin-9 (IL-9), play a vital role in the adaptive immune response and have diverse effects in different diseases. Regulated by transcription factors like PU.1 and IRF4, and cytokines such as IL-4 and TGF-β, Th9 cells drive tissue inflammation. This review focuses on their emerging role in immunopathophysiology. Th9 cells exhibit immune-mediated cancer cell destruction, showing promise in glioma and cervical cancer treatment. However, their role in breast and lung cancer is intricate, requiring a deeper understanding of pro- and anti-tumor aspects. Th9 cells, along with IL-9, foster T cell and immune cell proliferation, contributing to autoimmune disorders. They are implicated in psoriasis, atopic dermatitis, and infections. In allergic reactions and asthma, Th9 cells fuel pro-inflammatory responses. Targeting Foxo1 may regulate innate and adaptive immune responses, alleviating disease symptoms. This comprehensive review outlines Th9 cells' evolving immunopathophysiological role, emphasizing the necessity for further research to grasp their effects and potential therapeutic applications across diseases.

Basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs) are high-incidence, non-melanoma skin cancers (NMSCs). The success of immune-targeted therapies in advanced NMSCs led us to anticipate that NMSCs harbored significant populations of tumor-infiltrating lymphocytes with potential anti-tumor activity. The main aim of this study was to characterize T cells infiltrating NMSCs. Flow cytometry and immunohistochemistry were used to assess, respectively, the proportions and densities of T cell subpopulations in BCCs (n = 118), SCCs (n = 33), and normal skin (NS, n = 30). CD8+ T cells, CD4+ T cell subsets, namely, Th1, Th2, Th17, Th9, and regulatory T cells (Tregs), CD8+ and CD4+ memory T cells, and γδ T cells were compared between NMSCs and NS samples. Remarkably, both BCCs and SCCs featured a significantly higher Th1/Th2 ratio (~four-fold) and an enrichment for Th17 cells. NMSCs also showed a significant enrichment for IFN-γ-producing CD8+T cells, and a depletion of γδ T cells. Using immunohistochemistry, NMSCs featured denser T cell infiltrates (CD4+, CD8+, and Tregs) than NS. Overall, these data favor a Th1-predominant response in BCCs and SCCs, providing support for immune-based treatments in NMSCs. Th17-mediated inflammation may play a role in the progression of NMSCs and thus become a potential therapeutic target in NMSCs.

Interleukin-9 (IL-9) is a multifunctional cytokine with roles in a broad cross-section of human diseases. Like many cytokines, IL-9 is transcriptionally regulated by a group of noncoding regulatory elements (REs) surrounding the IL9 gene. These REs modulate IL-9 transcription by forming 3D loops that recruit transcriptional machinery. IL-9-promoting transcription factors (TFs) can bind REs to increase locus accessibility and permit chromatin looping, or they can be recruited to already accessible chromatin to promote transcription. Ample mechanistic and genome-wide association studies implicate this interplay between IL-9-modulating TFs and IL9 cis-REs in human physiology, homeostasis, and disease.

The tumor microenvironment is closely linked to the initiation, promotion, and progression of solid tumors. Among its constitutions, immunologic cells emerge as critical players, facilitating immune evasion and tumor progression. Apart from their indirect impact on anti-tumor immunity, immunocytes directly influence neoplastic cells, either bolstering or impeding tumor advancement. However, current therapeutic modalities aimed at alleviating immunosuppression from regulatory cells on effector immune cell populations may not consistently yield satisfactory results in various solid tumors, such as breast carcinoma, colorectal cancer, etc. Therefore, this review outlines and summarizes the direct, dualistic effects of immunocytes such as T cells, innate lymphoid cells, B cells, eosinophils, and tumor-associated macrophages on tumor cells within the tumor microenvironment. The review also delves into the underlying mechanisms involved and presents the outcomes of clinical trials based on these direct effects, aiming to propose innovative and efficacious therapeutic strategies for addressing solid tumors.

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.

T helper 9 (Th9) cells, a subset of CD4+ T helper cells, have emerged as a valuable target for immune cell therapy due to their potential to induce immunomodulation and tolerance. The Th9 cells mainly produce interleukin (IL)-9 and are known for their defensive effects against helminth infections, allergic and autoimmune responses, and tumor suppression. This paper explores the mechanisms involved in the generation and differentiation of Th9 cells, including the cytokines responsible for their polarization and stabilization, the transcription factors necessary for their differentiation, as well as the role of Th9 cells in inflammatory and autoimmune diseases, allergic reactions, and cancer immunotherapies. Recent research has shown that the differentiation of Th9 cells is coregulated by the transcription factors transforming growth factor β (TGF-β), IL-4, and PU.1, which are also known to secrete IL-10 and IL-21. Multiple cell types, such as T and B cells, mast cells, and airway epithelial cells, are influenced by IL-9 due to its pleiotropic effects.

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.

Immune cell-derived IL-17A is one of the key pathogenic cytokines in psoriasis, an immunometabolic disorder. Although IL-17A is an established regulator of cutaneous immune cell biology, its functional and metabolic effects on nonimmune cells of the skin, particularly keratinocytes, have not been comprehensively explored. Using multiomics profiling and systems biology-based approaches, we systematically uncover significant roles for IL-17A in the metabolic reprogramming of human primary keratinocytes (HPKs). High-throughput liquid chromatography-tandem mass spectrometry and nuclear magnetic resonance spectroscopy revealed IL-17A-dependent regulation of multiple HPK proteins and metabolites of carbohydrate and lipid metabolism. Systems-level MitoCore modeling using flux-balance analysis identified IL-17A-mediated increases in HPK glycolysis, glutaminolysis, and lipid uptake, which were validated using biochemical cell-based assays and stable isotope-resolved metabolomics. IL-17A treatment triggered downstream mitochondrial reactive oxygen species and HIF1α expression and resultant HPK proliferation, consistent with the observed elevation of these downstream effectors in the epidermis of patients with psoriasis. Pharmacological inhibition of HIF1α or reactive oxygen species reversed IL-17A-mediated glycolysis, glutaminolysis, lipid uptake, and HPK hyperproliferation. These results identify keratinocytes as important target cells of IL-17A and reveal its involvement in multiple downstream metabolic reprogramming pathways in human skin.

Tuberculosis remains an international health threat partly because of limited protection from pulmonary tuberculosis provided by standard intradermal vaccination with Bacillus of Calmette and Guérin (BCG); this may reflect the inability of intradermal vaccination to optimally induce pulmonary immunity. In contrast, respiratory Mycobacterium tuberculosis infection usually results in the immune-mediated bacillary containment of latent tuberculosis infection (LTBI). Here we present RNA-Seq-based assessments of systemic and pulmonary immune cells from LTBI participants and recipients of intradermal and oral BCG. LTBI individuals uniquely display ongoing immune activation and robust CD4 T cell recall responses in blood and lung. Intradermal BCG is associated with robust systemic immunity but only limited pulmonary immunity. Conversely, oral BCG induces limited systemic immunity but distinct pulmonary responses including enhanced inflammasome activation potentially associated with mucosal-associated invariant T cells. Further, IL-9 is identified as a component of systemic immunity in LTBI and intradermal BCG, and pulmonary immunity following oral BCG.

T helper type 9 (Th9) cells play important roles in immune responses by producing interleukin-9 (IL-9). Several transcription factors are responsible for Th9 cell differentiation; however, transcriptional regulation of Th9 cells is not fully understood. Here, it is shown that Id1 is an essential transcriptional regulator of Th9 cell differentiation. Id1 is induced by IL-4 and TGF-β. Id1-deficient naïve CD4 T cells fail to differentiate into Th9 cells, and overexpression of Id1 induce expression of IL-9. Mass spectrometry analysis reveals that Id1 interacts with Tcf3 and Tcf4 in Th9 cells. In addition, RNA-sequencing, chromatin immunoprecipitation, and transient reporter assay reveal that Tcf3 and Tcf4 bind to the promoter region of the Il9 gene to suppress its expression, and that Id1 inhibits their function, leading to Th9 differentiation. Finally, Id1-deficient Th9 cells ameliorate airway inflammation in an animal model of asthma. Thus, Id1 is a transcription factor that plays an essential role in Th9 cell differentiation by inhibiting Tcf3 and Tcf4.

Adoptive cell therapy (ACT) can successfully treat hematopoietic cancers but lacks efficacy against solid tumors. This is due to insufficient T cell infiltration, high tumor heterogeneity, frequent antigen loss with subsequent tumor escape, and the immunosuppressive tumor microenvironment (TME). Alternative methods to boost the anticancer efficacy of adoptively transferred cells are actively pursued. Among adjuvants that are utilized to stimulate anticancer immune responses, ligands of the stimulator of interferon genes (STING) pathway have received increasing attention. STING activation can trigger dendritic cell (DC) activation and endogenous immune responses, thereby preventing tumor escape. Activation of the STING pathway in the context of ACT was accordingly associated with improved T cell trafficking and persistence in the TME combined with the reduced presence of immunosuppressive cells. Recent findings also suggest cell-intrinsic effects of STING ligands on T cells. Activation of the STING signaling pathway was in this regard shown to enhance effector functions of CD4+ and CD8+ T cells, suggesting that the STING signaling could be exploited to harness T cell anticancer functions. In this review, we will discuss how the STING signaling can be used to enhance the anticancer efficacy of ACT.

Immunotherapies are mainly aimed to promote a CD8+ T cell response rather than a CD4+ T cell response as cytotoxic T lymphocytes (CTLs) can directly kill target cells. Recently, CD4+ T cells have received more attention due to their diverse roles in tumors and chronic viral infections. In antitumor and antichronic viral responses, CD4+ T cells relay help signals through dendritic cells to indirectly regulate CD8+ T cell response, interact with B cells or macrophages to indirectly modulate humoral immunity or macrophage polarization, and inhibit tumor blood vessel formation. Additionally, CD4+ T cells can also exhibit direct cytotoxicity toward target cells. However, regulatory T cells exhibit immunosuppression and CD4+ T cells become exhausted, which promote tumor progression and chronic viral persistence. Finally, we also outline immunotherapies based on CD4+ T cells, including adoptive cell transfer, vaccines, and immune checkpoint blockade. Overall, this review summarizes diverse roles of CD4+ T cells in the antitumor or protumor and chronic viral responses, and also highlights the immunotherapies based on CD4+ T cells, giving a better understanding of their roles in tumors and chronic viral infections.

Th9 cells are powerful effector T cells for cancer immunotherapy. However, the underlying antitumor mechanism of Th9 cells still needs to be further elucidated. Here, we show that Th9 cells express high levels of not only IL-9, but also IL-24. We found that knockout of Il24 gene in Th9 cells promotes Th9 cell proliferation in vitro, but decreases Th9 cell survival in vitro and in vivo. Interestingly, knockout of Il24 gene in Th9 cells decreases the tumor-specific cytotoxicity of Th9 cells in vitro. In addition, immunotherapy with Il24 knockout Th9 cells exhibit less tumor inhibition than regular Th9 cells in mouse tumor models. We found that inhibition of Foxo1 by a specific inhibitor downregulates IL-24 expression in Th9 cells and decreases Th9 cell antitumor efficacy in vivo. Our results identify IL-24 as a powerful antitumor effector of Th9 cells and provide a target in Th9 cell-mediated tumor therapy.

Cell mediated immune escape, a microenvironment factor, induces tumorigenesis and metastasis. The purpose of this study was to display the characteristics of T cell populations in immune microenvironments for colorectal cancer (CRC) metastasis. Unsupervised cluster analysis was conducted to identify functionally distinct T cell clusters from 3,003 cells in peripheral blood and 4,656 cells in tissues. Subsequently, a total of 8 and 4 distinct T cell population clusters were identified from tumor tissue and peripheral blood, respectively. High levels of CD8+TEX, CD4+TRM, TH1-like T cells, CD8+TEM, tumor-Treg from tissues, and CD4+TN from peripheral blood are essential components of immune microenvironment for the prediction of CRC metastasis. Moreover, exhausted T cells are characterized by higher expression of multiple inhibitory receptors, including PDCD1 and LAG3. Some genes such as PFKFB3, GNLY, circDCUN1D4, TXNIP and NR4A2 in T cells of cluster were statistically different between CRC metastasis and non-metastasis. The ligand-receptor interactions identified between different cluster cells and metastases-related DEGs identified from each cluster revealed that the communications of cells, alterations of functions, and numbers of T subsets may contribute to the metastasis of CRC. The mutation frequency of KiAA1551, ATP8B4 and LNPEP in T cells from tissues and SOR1 from peripheral blood were higher in metastatic CRC than that in non-metastatic CRC. In conclusion, the discovery of differential genes in T cells may provide potential targets for immunotherapy of CRC metastasis and relevant insights into the clinical prediction and prognosis of CRC metastasis.

Among the cytokines regulating immune cells, IL-9 has gained considerable attention for its ability to act on multiple cell types as a regulator of beneficial and pathologic immune responses. Yet, it is still not clearly defined how IL-9 impacts immune responses. IL-9 demonstrates a remarkable degree of tissue-specific functionality and has cellular sources that vary by tissue site and the context of the inflammatory milieu. Here, we provide perspective to summarize the biological activities of IL-9 and highlight cell type-specific roles in the immune pathogenesis of diseases. This perspective will be important in defining the diseases where targeting IL-9 as a therapeutic strategy would be beneficial and where it has the potential to complicate clinical outcomes.

T cells are crucial for immune functions to maintain health and prevent disease. T cell development occurs in a stepwise process in the thymus and mainly generates CD4+ and CD8+ T cell subsets. Upon antigen stimulation, naïve T cells differentiate into CD4+ helper and CD8+ cytotoxic effector and memory cells, mediating direct killing, diverse immune regulatory function, and long-term protection. In response to acute and chronic infections and tumors, T cells adopt distinct differentiation trajectories and develop into a range of heterogeneous populations with various phenotype, differentiation potential, and functionality under precise and elaborate regulations of transcriptional and epigenetic programs. Abnormal T-cell immunity can initiate and promote the pathogenesis of autoimmune diseases. In this review, we summarize the current understanding of T cell development, CD4+ and CD8+ T cell classification, and differentiation in physiological settings. We further elaborate the heterogeneity, differentiation, functionality, and regulation network of CD4+ and CD8+ T cells in infectious disease, chronic infection and tumor, and autoimmune disease, highlighting the exhausted CD8+ T cell differentiation trajectory, CD4+ T cell helper function, T cell contributions to immunotherapy and autoimmune pathogenesis. We also discuss the development and function of γδ T cells in tissue surveillance, infection, and tumor immunity. Finally, we summarized current T-cell-based immunotherapies in both cancer and autoimmune diseases, with an emphasis on their clinical applications. A better understanding of T cell immunity provides insight into developing novel prophylactic and therapeutic strategies in human diseases.

Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease (sAIBD). In addition to disease causing autoantibodies, several leukocyte subsets, including mast cells and eosinophils, play key roles in mediating skin inflammation. Detailed immunophenotyping and, more recently, the therapeutic effects of interleukin-4 (IL-4) receptor alpha inhibition in BP pointed to a prominent role of T helper 2 (Th2) cells. Among other cell types, IL-9 is expressed by Th2 and mast cells and potentially drives allergic, Th2-dominated inflammation. Although cytokines in BP have been relatively well investigated, the role of IL-9 has remained enigmatic. This study aimed to evaluate the effect of IL-9 in BP. Serum IL-9 levels were significantly elevated in patients with BP and decreased upon induction of remission. Serum IL-9 levels were not elevated in epidermolysis bullosa acquisita, another sAIBD. The time-course analysis using serum sets from four patients with BP revealed that serum IL-9 was a sensitive biomarker of BP. IL-9-positive cells infiltrated dominantly in BP lesions, especially in the blister fluid, and Th9 cells were abundant. Therefore, IL-9 was elevated in the serum and lesions of BP, which could be a biomarker of BP.

Interleukin 9 (IL-9) is a cytokine with potent proinflammatory properties that plays a central role in pathologies such as allergic asthma, immunity to parasitic infection, and autoimmunity. More recently, IL-9 has garnered considerable attention in tumor immunity. Historically, IL-9 has been associated with a protumor function in hematological malignancies and an antitumor function in solid malignancies. However, recent discoveries of the dynamic role of IL-9 in cancer progression suggest that IL-9 can act as both a pro- or antitumor factor in various hematological and solid malignancies. This review summarizes IL-9-dependent control of tumor growth, regulation, and therapeutic applicability of IL-9 blockade and IL-9-producing cells in cancer.

Protein phosphatase 2A (PP2A) is a serine-threonine phosphatase that plays an important role in the regulation of cell proliferation and signal transduction. The catalytic activity of PP2A is integral in the maintenance of physiological functions which gets severely impaired in its absence. PP2A plays an essential role in the activation, differentiation, and functions of T cells. PP2A suppresses Th1 cell differentiation while promoting Th2 cell differentiation. PP2A fosters Th17 cell differentiation which contributes to the pathogenesis of systemic lupus erythematosus (SLE) by enhancing the transactivation of the Il17 gene. Genetic deletion of PP2A in Tregs disrupts Foxp3 expression due to hyperactivation of mTORC1 signaling which impairs the development and immunosuppressive functions of Tregs. PP2A is important in the induction of Th9 cells and promotes their antitumor functions. PP2A activation has shown to reduce neuroinflammation in a mouse model of experimental autoimmune encephalomyelitis (EAE) and is now used to treat multiple sclerosis (MS) clinically. In this review, we will discuss the structure and functions of PP2A in T cell differentiation and diseases and therapeutic applications of PP2A-mediated immunotherapy.

Mast cells (MCs) are evolutionarily ancient innate immune cells with important roles in protective immunity against bacteria, parasites, and venomous animals. They can be found in most organs of the body, where they also contribute to normal tissue functioning, for example by engaging in crosstalk with nerves. Despite this, they are most widely known for their detrimental roles in allergy, anaphylaxis, and atopic disease. Just like macrophages, mast cells were conventionally thought to originate from the bone marrow. However, they are already present in fetal tissues before the onset of bone marrow hematopoiesis, questioning this dogma. In recent years, our view of myeloid cell ontogeny has been revised. We now know that the first mast cells originate from progenitors made in the extra-embryonic yolk sac, and later get supplemented with mast cells produced from subsequent waves of hematopoiesis. In most connective tissues, sizeable populations of fetal-derived mast cells persist into adulthood, where they self-maintain largely independently from the bone marrow. These developmental origins are highly reminiscent of macrophages, which are known to have critical functions in development. Mast cells too may thus support healthy development. Their fetal origins and longevity also make mast cells susceptible to genetic and environmental perturbations, which may render them pathological. Here, we review our current understanding of mast cell biology from a developmental perspective. We first summarize how mast cell populations are established from distinct hematopoietic progenitor waves, and how they are subsequently maintained throughout life. We then discuss what functions mast cells may normally have at early life stages, and how they may be co-opted to cause, worsen, or increase susceptibility to disease.