Immune Network最新文献

Immune checkpoint inhibitors (ICIs) offer tremendous promise as therapeutic targets for a range of tumor types, and their development is advancing rapidly in cancer treatment. Nevertheless, the limited efficacy of anti-PD-1/PD-L1 immunotherapy in several cancers has driven researchers to explore other immune checkpoints as potential therapeutic targets. The inhibitory V-domain Ig suppressor of T-cell activation (VISTA) appears to be a captivating candidate. As a member of the B7 family, VISTA is expressed on hematopoietic cells and has the ability to significantly suppress T cell function and the anti-tumor immune response. In this review, our objective is to shed light on the multifaceted potential of VISTA as a therapeutic target. We will highlight the expressions and role of VISTA in various cancer types. Subsequently, we will go through distinct potential VISTA ligands, while underscoring the role of the pathway within the tumor microenvironments (TME). Finally, we will conclude with a comprehensive overview of the latest clinical trials, highlighting VISTA's emerging potential in cancer treatment.

Chimeric Ag receptor (CAR)-T cell therapy has demonstrated success primarily in B-cell malignancies, but efficacy in solid tumors remains limited by Ag heterogeneity, immunosuppressive tumor microenvironments, and restricted infiltration. Cytokine engineering has emerged as a promising strategy to overcome these barriers. Fourth-generation CAR-T cells, known as T cells redirected for universal cytokine-mediated killing, demonstrated the feasibility of localized immune modulation through activation-induced IL-12 release, and this concept has been extended to various cytokines. Receptor engineering strategies, including switch/inverted and orthogonal designs, restrict cytokine signaling to CAR-T cells, thereby enhancing both specificity and safety. Beyond CAR-T engineering, external cell-based 'cytokine factories' and immune-cytokines further underscore the versatility of localized cytokine delivery strategies. In addition, fifth-generation CAR-T cells, incorporating approaches that enhance or mimic cytokine-mediated JAK-STAT signaling pathways, highlight a new direction toward programmable intracellular signaling. These strategies remain in the early stages of clinical application due to substantial limitations related to safety and clinical translation, including risks of uncontrolled cytokine activation and complexities in manufacturing. Nevertheless, they offer significant potential to improve therapeutic outcomes not only in hematologic malignancies but also across a broad range of solid tumors.

Tumor-infiltrating CD8⁺ T cells are a key determinant of anti-tumor efficacy in immunotherapy. IL-7 has been explored as a cytokine therapy to expand CD8⁺ T cells, showing promising anti-tumor effects in preclinical models. However, clinical outcomes remain limited, likely due to the immunosuppressive tumor microenvironment. To enhance the efficacy of IL-7 therapy, we reanalyzed publicly available single-cell RNA-sequencing (scRNA-seq) data of tumors treated with IL-7, identifying elevated TGF-β signaling in CD8⁺ T cells following treatment. As TGF-β impairs CD8⁺ T cell function and antagonizes IL-7 signaling, we developed a bifunctional fusion protein, recombinant human IL-7 (rhIL-7)-hyFc-sTBRII (IL7-TBRII), by fusing a TGF-β trap (Fc-TBRII) to rhIL-7-hyFc (IL7-Fc). We evaluated the binding affinities and functionalities of each domain in vitro and in vivo, and assessed anti-tumor effects in the MC38 colon cancer model. IL7-TBRII demonstrated superior anti-tumor efficacy compared to IL7-Fc or Fc-TBRII alone, primarily through increased infiltration of cytotoxic CD8⁺ T cells into tumors. Also, IL7-TBRII expanded the number of activated CD44⁺ CD8⁺ T cells. Furthermore, IL7-TBRII reduced metastasis in the 4T1 breast cancer model by reshaping the immune cell composition, and demonstrated synergistic efficacy when combined with radiotherapy or anti-CTLA-4 therapy in the EMT6 breast tumor model. These findings suggest that dual modulation of the IL-7 and TGF-β pathways by IL7-TBRII effectively reprograms the immune microenvironment in both primary and metastatic tumors, particularly by promoting CD8⁺ T cell activation and infiltration, thus offering a promising strategy to improve clinical responses to immunotherapy.

Several studies have reported the immunoregulatory effects of transplanting mitochondria from mesenchymal stem cells. However, whether similar effects can be achieved using mitochondria derived from human induced pluripotent stem cells (iPSCs; iMito) has not yet been investigated. Here, we examined the protective effects of iMito in a dextran sodium sulfate (DSS)-induced colitis mouse model. To address this, we investigated the effects both in vitro and in vivo. First, iMitos were transferred into mouse splenocytes, and the expression and secretion of IL-17 and FoxP3 were measured. Next, iMitos were transferred into mice with inflammatory bowel disease (IBD) induced by DSS. Intestinal tissues were assessed histologically, and immune cell infiltration was measured. In vitro, iMitos transfer increased mitochondrial function, evidenced by higher ATP synthesis. An immunomodulatory effect was observed, with decreased IL-17 and increased FoxP3 expression. In vivo, iMitos transplantation in IBD mice led to improvements in body weight and intestinal tissue damage; it decreased Th17 cells, increased Tregs, and reduced inflammatory cytokines and fibrosis markers. These data suggest the therapeutic potential of iMitos in treating human inflammatory diseases.

Type 2 innate lymphoid cells (ILC2s) are an important source of innate cytokines that contribute to allergic inflammation. Recent studies have also suggested that ILC2s play a biological role in peripheral tissues such as lung, fat, intestine and skin, controlled by alarmins, neuropeptides and environmental factors. Furthermore, emerging studies have shown that tissues including the pancreas, uterus and meninges contain ILC2s that contribute to normal biological function. Here, we review recent studies on the physiological function of ILC2s in multiple tissues, emphasizing their importance not only in type 2 immune responses, but also in maintaining biological homeostasis.

Kidney-resident macrophages (KRMs) are long-lived immune cells crucial for maintaining kidney homeostasis, with roles that vary depending on kidney condition. Their phenotypes can exert different effects on kidney status, but how the phenotypes of KRMs evolve in aged kidneys and the resulting impacts on kidney homeostasis remain poorly understood. Through single-cell RNA sequencing, we identified a phenotypic shift in KRMs within aged kidneys characterized by increased oxidative phosphorylation (OXPHOS), which stemmed from crosstalk with surrounding tubules. Among these interactions, thrombospondin-1 (THBS1), derived from tubules, has emerged as a pivotal factor driving OXPHOS in KRMs. Experiments confirmed that THBS1 increased OXPHOS in cultured macrophages, polarizing them toward an inflammatory phenotype marked by the production of IL-1β and IL-10. This shift contributes to the inflammatory state of aged kidneys. Finally, we validated these findings in human kidney tissues from elderly individuals. In conclusion, aged kidneys harbor phenotypically altered KRMs that promote an inflammatory microenvironment, with THBS1 playing a central role in this process. These results underscore the importance of exploring therapeutic strategies targeting this pathway to mitigate the inflammatory shift in aged kidneys.

An effective respiratory syncytial virus (RSV) vaccine should elicit neutralizing Abs and confer protection without causing vaccine-enhanced disease. Virus-like particle (VLP) is a safe vaccine platform that can display multivalent Ags similar to a virus and induce potent neutralizing Abs without adjuvant. We investigated the impact of mutations in the furin cleavage site, fusion (F) peptide, and change in the transmembrane (TM) domain of RSV F protein in VLPs on inducing RSV neutralizing Abs and efficacy in a cotton rat model. Palivizumab-binding antigenic site II epitope was preferentially exposed by combination mutations in the furin cleavage sites and F peptide together with a change in the TM domain. A single dose of mutant F protein VLP containing these combination mutations effectively induced IgG Ab responses to post-F and pre-F proteins, neutralizing activities, and protection without apparent lung histopathology. The VLP also induced the highest level of INF-γ, indicating the Th1-skewed immune response against the virus infection. A single dose of RSV F mutant exposing an antigenic site II on VLP vaccine could induce RSV-neutralizing Abs, conferring protection without causing vaccine-enhanced disease in cotton rats.

IL-33, a member of the IL-1 cytokine family, is constitutively expressed in the nucleus of various cell types. As an alarmin, IL-33 is released upon tissue damage and activates immune cell populations through its receptor, suppression of tumorigenicity 2 (ST2). Given that ST2 is expressed on diverse immune cells involved in both type 1 and type 2 immunity, IL-33 exerts pleiotropic effects on immune responses. In the tumor microenvironment (TME), IL-33 plays a dual role, promoting both protumor and antitumor TME. In this review, we summarize general characteristics of IL-33 and its immunological functions, with particular emphasis on its role in tumor immunity. Furthermore, we discuss recent advances in utilizing IL-33 in cancer immunotherapies and propose IL-33 as a potential candidate for the development of new cancer therapies.

Colorectal cancer (CRC), one of the most prevalent and lethal malignancies of digestive system, continues to impose a substantial burden on global health due to its high morbidity and mortality. Tumor microenvironment (TME) is a critical regulator for CRC progression and therapeutic response, but the in-depth understanding on the relationship of TME with CRC remains to be elucidated. In this study, we leveraged single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq data to dissect the immune heterogeneity in CRC patients. The differential expression genes analysis, functional enrichment analysis, random forest analysis and the Least Absolute Shrinkage and Selection Operator method were used to construct a molecular immune prognostic model. The molecular model demonstrated robust performance in stratifying patients based on their immune microenvironment characteristics. The experimental results showed that TIMP1 was highly expressed in CRC. Knockdown of TIMP1 gene significantly inhibited RKO cell proliferation and invasion. By integrating scRNA-seq and bulk RNA-seq data, we developed a new prognostic model that effectively predicts clinical outcomes in patients with CRC and identifies TIMP1 as a promising prognostic biomarker for CRC.

Ileal lipid binding protein (Ilbp), encoded by Fabp6 gene, plays a critical role in intracellular transport of bile acids (BAs) from apical to basolateral side of ileal enterocytes, maintaining BA homeostasis within enterohepatic circulation. However, pathophysiological consequences of Ilbp deficiency remain largely unexplored. Here, we demonstrate that disruption of BA balance, caused by intestinal epithelial cell (IEC)-specific Fabp6 gene knockout (Fabp6 ^ΔIEC), exacerbates dextran sulfate sodium (DSS)-induced gut inflammation. Fecal microbiota transplantation from Fabp6 ^ΔIEC mice to germ free recipient mice replicated the adverse effects observed in Fabp6 ^ΔIEC mice, which were mitigated when these mice were co-housed with control (Fabp6 ^f/f) mice. Metagenomic analysis identified Ligilactobacillus murinus as a primarily diminished strain in Fabp6 ^ΔIEC mice. Oral administration of L. murinus isolated from feces of Fabp6 ^f/f mice ameliorated DSS-induced colitis in Fabp6 ^ΔIEC mice by restoring epithelial barrier integrity and lowering pro-inflammatory cytokines IL-1β, IL-6 and TNF-α. Furthermore, daily administration of taurodeoxycholic acid-one of the BAs reduced in Fabp6 ^ΔIEC mice and that promotes the growth of L. murinus in an in vitro growth assay-also exhibited a protective effect against DSS-induced colitis through a similar mechanism. These findings suggest that deficiency of specific BAs due to epithelial Fabp6 deletion leads to gut dysbiosis, predisposing the host to inflammatory disease.