IL-22 is a relatively new cytokine that is characterized by several unique biological properties. In the intestines, the effect of IL-22 is restricted mainly to non-lymphoid cells such as epithelial cells. Interestingly, the expression pattern and major cellular source of IL-22 have distinct difference between large and small intestines. IL-22 possesses an ability to constitutively activate STAT3 for promoting epithelial cell regeneration and reinforcing mucosal barrier integrity through stimulating the expression of anti-bacterial peptide and mucins. Of note, IL-22 is characterized as a two-faced cytokine that can play not only protective but also deleterious roles in the intestinal inflammation depending on the cytokine environment such as the expression levels of IL-23, T-bet, and IL-22 binding protein. Most importantly, clinical relevance of IL-22 to inflammatory bowel disease has been well highlighted. Mucosal healing, which represents the current therapeutic goal for IBD, can be induced by IL-22. Indeed, indigo naturalis, which can activate IL-22 pathway through Ahr, has been shown in a clinical trial to exhibit a strong therapeutic effect on ulcerative colitis. Despite the beneficial effect of IL-22, continuous activation of the IL-22 pathway increases the risk of colitis-associated cancer, particularly in patients with an extended history of IBD. This review article discusses how IL-22 regulates colitis, how beneficial versus deleterious effects of IL-22 is determined, and why IL-22 represents a promising target for IBD therapy.

Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory condition that is mediated by very complex mechanisms controlled by genetic, immune, and environmental factors. More than 74 kinds of genetically engineered mouse strains have been established since 1993 for studying IBD. Although mouse models cannot fully reflect human IBD, they have provided significant contributions for not only understanding the mechanism, but also developing new therapeutic means for IBD. Indeed, 20 kinds of genetically engineered mouse models carry the susceptibility genes identified in human IBD, and the functions of some other IBD susceptibility genes have also been dissected out using mouse models. Cutting-edge technologies such as cell-specific and inducible knockout systems, which were recently employed to mouse IBD models, have further enhanced the ability of investigators to provide important and unexpected rationales for developing new therapeutic strategies for IBD. In this review article, we briefly introduce 74 kinds of genetically engineered mouse models that spontaneously develop intestinal inflammation.

Chimeric antigen receptor (CAR) T cell therapy has attracted attention for its promising therapeutic effects on hematological malignancies. However, there are problems such as relapse during long-term follow-up and limited effect on solid tumors with this therapy. Exhaustion, which impairs in vivo persistence and killing activity of CAR T cells, is one of the causes of these issues. Depending on their structure of extracellular portion, some CARs induce tonic signals in the absence of ligand stimulation and induce exhaustion phenotype in CAR T cells. Analysis of these self-activating CARs is expected to provide key information for understanding and resolving CAR T cell exhaustion. In this review, we introduced examples of self-activating CARs and summarized their phenotypes to figure out how CAR T cell exhaustion occurs. Further, we aimed to review promising solutions to the CAR T cell exhaustion that hampers generalized application of CAR T cell therapy.

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IntroductionImmune checkpoint inhibitors (ICI) have signi cantly improved the prognosis of non-small cell lung cancer (NSCLC). However, only a limited proportion of patients can bene t from this therapy, and clinically useful predictive biomarkers remain to be elucidated. MethodsBlood was collected from 189 patients with NSCLC before and six weeks after the initiation of the ICI treatment (anti-PD-1 or anti-PD-L1 antibody). Soluble PD-1 (sPD-1) and PD-L1 (sPD-L1) in plasma before and after treatment were analyzed for evaluation of their clinical signi cance. ResultsThe Cox regression analysis demonstrated that higher sPD-L1 levels before treatment signi cantly predicted unfavorable progression-free survival (PFS; HR 15.4, 95%CI 1.10-86.7, P = 0.009) and overall survival (OS; HR 11.4, 95%CI 1.19-52.3, P = 0.007) in NSCLC patients treated with ICI monotherapy (n = 122), but not in those treated with ICI combined with chemotherapy (n = 67: P = 0.729 and P = 0.155, respectively). In addition, higher sPD-1 levels after treatment were signi cantly associated with better OS (HR 0.24, 95%CI 0.06-0.91, P = 0.037) in patients treated with anti-PD-1 monotherapy, whereas higher sPD-L1 levels after treatment were signi cantly associated with worse PFS (HR 6.09, 95%CI 1.42-21.0, P = 0.008) and OS (HR 42.6, P < 0.001). The levels of sPD-L1 at baseline were well correlated with those of other soluble factors, such as sCD30, IL-2Ra, sTNF-R1, and sTNF-R2, which are known to be released from the cell surface by zinc-binding proteases ADAM10/17. ConclusionsThese ndings suggest the clinical signi cance of pre-treatment sPD-L1 as well as post-treatment sPD-1 and sPD-L1 in NSCLC patients treated with ICI monotherapy.