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Background: The immune system plays a pivotal role in cancer progression. Interleukin 22 binding protein (IL-22BP), a natural antagonist of the cytokine interleukin 22 (IL-22) has been shown to control the progression of colorectal cancer (CRC). However, the role of IL-22BP in the process of metastasis formation remains unknown. Methods: We used two different murine in vivo metastasis models using the MC38 and LLC cancer cell lines and studied lung and liver metastasis formation after intracaecal or intrasplenic injection of cancer cells. Furthermore, IL22BP expression was measured in a clinical cohort of CRC patients and correlated with metastatic tumor stages. Results: Our data indicate that low levels of IL-22BP are associated with advanced (metastatic) tumor stages in colorectal cancer. Using two different murine in vivo models we show that IL-22BP indeed controls the progression of liver but not lung metastasis in mice. Conclusions: We here demonstrate a crucial role of IL-22BP in controlling metastasis progression. Thus, IL-22 might represent a future therapeutic target against the progression of metastatic CRC. [ABSTRACT FROM AUTHOR]

Simple Summary: Lymphatic spreading is a main driver of metastasis and, thus, associated death in colon cancer. Therefore, resecting all metastatic lymph nodes is vital for cancer-free survival. Although resection within established resection lines provides a good lymph node yield, aberrant lymphatic drainage pathways may be missed. Lymphatic mapping can compensate for this shortcoming. Different methods for tracing lymphatic drainage exist, such as radiocolloid tracers, ink, and fluorescent tracers. Tracers can be applicated either during surgery or before surgery through colonoscopy, giving the tracer more time to travel through the lymphatic system and highlighting more distant tumor-draining lymph nodes. This review aims to assess which protocol best maps the lymphatic drainage pathway and thus enables an optimized, personalized approach for curative resection. 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. [ABSTRACT FROM AUTHOR]

Cancer is one of the leading causes of death worldwide. When cancer patients are diagnosed with metastasis, meaning that the primary tumor has spread to at least one different site, their life expectancy decreases dramatically. In the past decade, the immune system´s role in fighting cancer and metastasis has been studied extensively. Importantly, immune cells and inflammatory reactions generate potent antitumor responses but also contribute to tumor development. However, the molecular and cellular mechanisms underlying this dichotomic interaction between the immune system and cancer are still poorly understood. Recently, a spotlight has been cast on the distinct subsets of immune cells and their derived cytokines since evidence has implicated their crucial impact on cancer development. T helper 17 cell (TH17) cells, which express the master transcriptional factor Retinoic acid‐receptor‐related orphan receptor gamma t, are among these critical cell subsets and are defined by their production of type 3 cytokines, such as IL‐17A, IL‐17F, and IL‐22. Depending on the tumor microenvironment, these cytokines can also be produced by other immune cell sources, such as T cytotoxic 17 cell, innate lymphoid cells, NKT cells, or γδ T cells. To date, a lot of data have been collected describing the divergent functions of IL‐17A, IL‐17F, and IL‐22 in malignancies. In this comprehensive review, we discuss the role of these TH17‐ and non‐TH17‐derived type 3 cytokines in different tumor entities. Furthermore, we will provide a structured insight into the strict regulation and subsequent downstream mechanisms of these cytokines in cancer and metastasis. [ABSTRACT FROM AUTHOR]

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. [Display omitted] • Il22 -deficient mice are protected against metastasis formation • IL-22 neutralization blocks cancer cell extravasation • IL-22 acts on endothelial cells, promoting cancer cell extravasation via ANPEP induction • Tissue resident iNKT17 cells are the key IL-22 source during cancer cell extravasation Interleukin-22 (IL-22) is produced by immune cells and promotes tissue repair and regeneration; however, in malignancy, IL-22 can promote tumor growth. Giannou et al. find that tissue resident iNKT17 cells produce IL-22 and promote cancer cell extravasation through regulation of aminopeptidase N. Neutralization of IL-22 inhibits metastasis formation, suggesting therapeutic avenues for cancer treatment. [ABSTRACT FROM AUTHOR]

Although T cells can exert potent anti-tumor immunity, a subset of T helper (Th) cells producing interleukin-22 (IL-22) in breast and lung tumors is linked to dismal patient outcome. Here, we examined the mechanisms whereby these T cells contribute to disease. In murine models of lung and breast cancer, constitutional and T cell-specific deletion of Il22 reduced metastases without affecting primary tumor growth. Deletion of the IL-22 receptor on cancer cells decreases metastasis to a degree similar to that seen in IL-22-deficient mice. IL-22 induced high expression of CD155, which bound to the activating receptor CD226 on NK cells. Excessive activation led to decreased amounts of CD226 and functionally impaired NK cells, which elevated the metastatic burden. IL-22 signaling was also associated with CD155 expression in human datasets and with poor patient outcomes. Taken together, our findings reveal an immunosuppressive circuit activated by T cell-derived IL-22 that promotes lung metastasis. [Display omitted] • IL-22 from Th cells acts on IL-22RA1+ tumor cells to promote lung metastases • Mechanistically, IL-22 induces overexpression of CD155 on tumor cells • Excessive CD155 promotes internalization of CD226 in NK cells, rendering them inert • IL-22-CD155 signature governs early-stage lung and breast cancer patients' survival Metastatic disease is the terminal and most lethal stage of cancer. Briukhovetska et al. find that interleukin-22 produced by Th cells increases the expression of CD155 in cancer cells, which in turn abrogates NK cell function by promoting the internalization of the activating receptor CD226. This axis promotes an immunosuppressive niche that enables lung metastases. [ABSTRACT FROM AUTHOR]