The liver is one of the organs most commonly affected by metastasis. The presence of liver metastases has been reported to be responsible for an immunosuppressive microenvironment and diminished immunotherapy efficacy. Herein, we aimed to investigate the role of IL-10 in liver metastasis and to determine how its modulation could affect the efficacy of immunotherapy in vivo. To induce spontaneous or forced liver metastasis in mice, murine cancer cells (MC38) or colon tumor organoids were injected into the cecum or the spleen, respectively. Mice with complete and cell type-specific deletion of IL-10 and IL-10 receptor alpha were used to identify the source and the target of IL-10 during metastasis formation. Programmed death ligand 1 (PD-L1)-deficient mice were used to test the role of this checkpoint. Flow cytometry was applied to characterize the regulation of PD-L1 by IL-10. We found that Il10-deficient mice and mice treated with IL-10 receptor alpha antibodies were protected against liver metastasis formation. Furthermore, by using IL-10 reporter mice, we demonstrated that Foxp3+ regulatory T cells (Tregs) were the major cellular source of IL-10 in liver metastatic sites. Accordingly, deletion of IL-10 in Tregs, but not in myeloid cells, led to reduced liver metastasis. Mechanistically, IL-10 acted on Tregs in an autocrine manner, thereby further amplifying IL-10 production. Furthermore, IL-10 acted on myeloid cells, i.e. monocytes, and induced the upregulation of the immune checkpoint protein PD-L1. Finally, the PD-L1/PD-1 axis attenuated CD8-dependent cytotoxicity against metastatic lesions. Treg-derived IL-10 upregulates PD-L1 expression in monocytes, which in turn reduces CD8+ T-cell infiltration and related antitumor immunity in the context of colorectal cancer-derived liver metastases. These findings provide the basis for future monitoring and targeting of IL-10 in colorectal cancer-derived liver metastases. Liver metastasis diminishes the effectiveness of immunotherapy and increases the mortality rate in patients with colorectal cancer. We investigated the role of IL-10 in liver metastasis formation and assessed its impact on the effectiveness of immunotherapy. Our data show that IL-10 is a pro-metastatic factor involved in liver metastasis formation and that it acts as a regulator of PD-L1. This provides the basis for future monitoring and targeting of IL-10 in colorectal cancer-derived liver metastasis.

Wound healing is a crucial process which protects our body against permanent damage and invasive infectious agents. Upon tissue damage, inflammation is an early event which is orchestrated by a multitude of innate and adaptive immune cell subsets including T_H17 cells. T_H17 cells and T_H17 cell associated cytokines can impact wound healing positively by clearing pathogens and modulating mucosal surfaces and epithelial cells. Injury of the gut mucosa can cause fast expansion of T_H17 cells and their induction from naïve T cells through Interleukin (IL)-6, TGF-β, and IL-1β signaling. T_H17 cells produce various cytokines, such as tumor necrosis factor (TNF)-α, IL-17, and IL-22, which can promote cell survival and proliferation and thus tissue regeneration in several organs including the skin, the intestine, and the liver. However, T_H17 cells are also potentially pathogenic if not tightly controlled. Failure of these control mechanisms can result in chronic inflammatory conditions, such as Inflammatory Bowel Disease (IBD), and can ultimately promote carcinogenesis. Therefore, there are several mechanisms which control T_H17 cells. One control mechanism is the regulation of T_H17 cells via regulatory T cells and IL-10. This mechanism is especially important in the intestine to terminate immune responses and maintain homeostasis. Furthermore, T_H17 cells have the potential to convert from a pro-inflammatory phenotype to an anti-inflammatory phenotype by changing their cytokine profile and acquiring IL-10 production, thereby limiting their own pathological potential. Finally, IL-22, a signature cytokine of T_H17 cells, can be controlled by an endogenous soluble inhibitory receptor, Interleukin 22 binding protein (IL-22BP). During tissue injury, the production of IL-22 by T_H17 cells is upregulated in order to promote tissue regeneration. To limit the regenerative program, which could promote carcinogenesis, IL-22BP is upregulated during the later phase of regeneration in order to terminate the effects of IL-22. This delicate balance secures the beneficial effects of IL-22 and prevents its potential pathogenicity. An important future goal is to understand the precise mechanisms underlying the regulation of T_H17 cells during inflammation, wound healing, and carcinogenesis in order to design targeted therapies for a variety of diseases including infections, cancer, and immune mediated inflammatory disease.

During metastasis, cancer cells invade, intravasate, enter the circulation, extravasate, and colonize target organs. Here, we examined the role of interleukin (IL)-22 in metastasis. Immune cell-derived IL-22 acts on epithelial tissues, promoting regeneration and healing upon tissue damage, but it is also associated with malignancy. Il22-deficient mice and mice treated with an IL-22 antibody were protected from colon-cancer-derived liver and lung metastasis formation, while overexpression of IL-22 promoted metastasis. Mechanistically, IL-22 acted on endothelial cells, promoting endothelial permeability and cancer cell transmigration via induction of endothelial aminopeptidase N. Multi-parameter flow cytometry and single-cell sequencing of immune cells isolated during cancer cell extravasation into the liver revealed iNKT17 cells as source of IL-22. iNKT-cell-deficient mice exhibited reduced metastases, which was reversed by injection of wild type, but not Il22-deficient, invariant natural killer T (iNKT) cells. IL-22-producing iNKT cells promoting metastasis were tissue resident, as demonstrated by parabiosis. Thus, IL-22 may present a therapeutic target for prevention of metastasis.

The lung is a vital organ that incessantly faces external environmental challenges. Its homeostasis and unimpeded vital function are ensured by the respiratory epithelium working hand in hand with an intricate fine-tuned tissue-resident immune cell network. Lung tissue-resident immune cells span across the innate and adaptive immunity and protect from infectious agents but can also prove to be pathogenic if dysregulated. Here, we review the innate and adaptive immune cell subtypes comprising lung-resident immunity and discuss their ontogeny and role in distinct respiratory diseases. An improved understanding of the role of lung-resident immunity and how its function is dysregulated under pathological conditions can shed light on the pathogenesis of respiratory diseases.

The human liver fulfills several vital tasks daily and possesses an impressive ability to self-regenerate. However, the capacity of this self-healing process can be exhausted by a variety of different liver diseases, such as alcoholic liver damage, viral hepatitis, or hepatocellular carcinoma. Over time, all these diseases generally lead to progressive liver failure that can become fatal if left untreated. Thus, a great effort has been directed towards the development of innovative therapies. The most recently discovered therapies often involve modifying the patient’s immune system to enhance a beneficial immune response. Current data suggest that, among others, the cytokine IL-22 might be a promising therapeutical candidate. IL-22 and its endogenous antagonist, IL-22BP, have been under thorough scientific investigation for nearly 20 years. While IL-22 is mainly produced by T_H22 cells, ILC3s, NKT cells, or γδ T cells, sources of IL-22BP include dendritic cells, eosinophils, and CD4⁺ cells. In many settings, IL-22 was shown to promote regenerative potential and, thus, could protect tissues from pathogens and damage. However, the effects of IL-22 during carcinogenesis are more ambiguous and depend on the tumor entity and microenvironment. In line with its capabilities of neutralizing IL-22 in vivo, IL-22BP possesses often, but not always, an inverse expression pattern compared to its ligand. In this comprehensive review, we will summarize past and current findings regarding the roles of IL-22 and IL-22BP in liver diseases with a particular focus on the leading causes of advanced liver failure, namely, liver infections, liver damage, and liver malignancies.

An optimized lymph node yield leads to better survival in colon cancer, but extended lymphadenectomy is not associated with survival benefits. Lymphatic mapping shows several colon cancers feature aberrant drainage pathways inducing local recurrence when not resected. Currently, different protocols exist for lymphatic mapping procedures. This meta-analysis assessed which protocol has the best capacity to detect tumor-draining and possibly metastatic lymph nodes. A systematic review was conducted according to PRISMA guidelines, including prospective trials with in vivo tracer application. The risk of bias was evaluated using the QUADAS-2 tool. Traced lymph nodes, total resected lymph nodes, and aberrant drainage detection rate were analyzed. Fifty-eight studies met the inclusion criteria, of which 42 searched for aberrant drainage. While a preoperative tracer injection significantly increased the traced lymph node rates compared to intraoperative tracing (30.1% (15.4, 47.3) vs. 14.1% (11.9, 16.5), p = 0.03), no effect was shown for the tracer used (p = 0.740) or the application sites comparing submucosal and subserosal injection (22.9% (14.1, 33.1) vs. 14.3% (12.1, 16.8), p = 0.07). Preoperative tracer injection resulted in a significantly higher rate of detected aberrant lymph nodes compared to intraoperative injection (26.3% [95% CI 11.5, 44.0] vs. 2.5% [95% CI 0.8, 4.7], p < 0.001). Analyzing 112 individual patient datasets from eight studies revealed a significant impact on aberrant drainage detection for injection timing, favoring preoperative over intraoperative injection (OR 0.050 [95% CI 0.010–0.176], p < 0.001) while indocyanine green presented itself as the superior tracer (OR 0.127 [95% CI 0.018–0.528], p = 0.012). Optimized lymphatic mapping techniques result in significantly higher detection of aberrant lymphatic drainage patterns and thus enable a personalized approach to reducing local recurrence.