Summary Cytokines play a pivotal role in regulating tumor immunogenicity and antitumor immunity. IL-36γ is important for the IL-23/IL-17-dominated inflammation and anti-BCG Th1 immune responses. However, the impact of IL-36γ on tumor immunity is unknown. Here, we found IL-36γ stimulated CD8+ T cells, NK cells, and γδ T cells synergistically with TCR signaling and/or IL-12. Importantly, IL-36γ exerted profound antitumor effects in vivo and transformed the tumor microenvironment in favor of tumor eradication. Furthermore, IL-36γ strongly increased the efficacy of tumor vaccination. Moreover, IL-36γ expression inversely correlated with progression of human melanoma and lung cancer. Our study establishes a role of IL-36γ in promoting antitumor immune responses and suggests its potential clinical translation in cancer immunotherapy.

Subset selection, i.e., to select a limited number of items optimizing some given objective function, is a fundamental problem with various applications such as unsupervised feature selection and sparse regression. By employing a multi-objective evolutionary algorithm (EA) with mutation only to optimize the given objective function and minimize the number of selected items simultaneously, the recently proposed POSS algorithm achieves state-of-the-art performance for subset selection. In this paper, we propose the PORSS algorithm by incorporating recombination, a characterizing feature of EAs, into POSS. We prove that PORSS can achieve the optimal polynomial-time approximation guarantee as POSS when the objective function is monotone, and can find an optimal solution efficiently in some cases whereas POSS cannot. Extensive experiments on unsupervised feature selection and sparse regression show the superiority of PORSS over POSS. Our analysis also theoretically discloses that recombination from diverse solutions can be more likely than mutation alone to generate various variations, thereby leading to better exploration; this may be of independent interest for understanding the influence of recombination.

Use of a 2 μm CW thulium laser is feasible and effective in treating primary NMIBC. With a cystoscopic biopsy of the bladder muscle, 2 μm CW thulium laser could retrieve sufficient diagnostic and prognostic specimens.

In the INO80 chromatin remodeling complex, all of the accessory subunits are assembled on the following three domains of INO80: N-terminal domain, HSA domain, and ATPase domain. Although the ATPase and HSA domains and their interacting accessory subunits are known to be responsible for chromatin remodeling, it is largely unknown how the accessory subunits that interact with the INO80 N-terminal domain regulate chromatin status. Here, we identify both conserved and non-conserved accessory subunits that interact with the three domains in the INO80 complex in Arabidopsis thaliana. While the accessory subunits that interact with all the three INO80 domains can mediate transcriptional repression, the INO80 N-terminal domain and the accessory subunits interact with it can contribute to transcriptional activation even when the ATPase domain is absent, suggesting that INO80 has an ATPase-independent role. A subclass of the COMPASS histone H3K4 methyltransferase complexes interact with the INO80 N-terminal domain in the INO80 complex and function together with the other accessory subunits that interact with the INO80 N-terminal domain, thereby facilitating H3K4 trimethylation and transcriptional activation. This study suggests that the opposite effects of the INO80 complex on transcription are required for the balance between vegetative growth and flowering under diverse environmental conditions.

With recent advances in single-cell RNA sequencing, enormous transcriptome datasets have been generated. These datasets have furthered our understanding of cellular heterogeneity and its underlying mechanisms in homogeneous populations. Single-cell RNA sequencing (scRNA-seq) data clustering can group cells belonging to the same cell type based on patterns embedded in gene expression. However, scRNA-seq data are high-dimensional, noisy, and sparse, owing to the limitation of existing scRNA-seq technologies. Traditional clustering methods are not effective and efficient for high-dimensional and sparse matrix computations. Therefore, several dimension reduction methods have been introduced. To validate a reliable and standard research routine, we conducted a comprehensive review and evaluation of four classical dimension reduction methods and five clustering models. Four experiments were progressively performed on two large scRNA-seq datasets using 20 models. Results showed that the feature selection method contributed positively to high-dimensional and sparse scRNA-seq data. Moreover, feature-extraction methods were able to promote clustering performance, although this was not eternally immutable. Independent component analysis (ICA) performed well in those small compressed feature spaces, whereas principal component analysis was steadier than all the other feature-extraction methods. In addition, ICA was not ideal for fuzzy C-means clustering in scRNA-seq data analysis. K-means clustering was combined with feature-extraction methods to achieve good results.

Regulatory T cells (Tregs) play a pivotal role in suppressing specific antiviral immune responses during the progression of chronic hepatitis B virus infection (CHB) as well as tumorigenesis. Programmed death-1 ligand-1 (PD-L1) expressed on Tregs can transduce an inhibitory signal into effector T cells through interacting with programmed death-1 (PD-1). However, in CHB patients, the clinical significance of PD-L1 expression on Tregs has not been clearly described. This study investigated the frequency of circulating Tregs and PD-L1 expression on Tregs and analyzed their correlations with clinical parameters. The data show that both the frequency of CD4+CD25+FoxP3+ Tregs and PD-L1 expression on Tregs in the peripheral blood increased significantly in CHB patients when compared with healthy controls. At the same time, it is shown that PD-L1 expression on Tregs was positively correlated with the percentage of Tregs in CHB patients. Moreover, the results demonstrated that both Treg frequency and PD-L1 expression on Tregs positively correlated with the levels of alanine aminotransaminase (ALT) and aspartate aminotransferase (AST), both of which are indicators of the extent of liver injury. Taken together, these findings suggest that PD-L1 on Tregs might contribute to progression of hepatitis B virus infection through mediating the inhibitory function of Tregs. Thereby, blockade of interaction between Treg-expressing PD-L1 and PD-1 on effector T cells may be adopted as a potential therapeutic approach in CHB.

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Cytokine-amplified functional CD8 + T cells ensure effective eradication of tumors. Interleukin 36α (IL-36α), IL-36β, and IL-36γ share the same receptor complex, composed of the IL-36 receptor (IL-36R), and IL-1RAcP. Recently, we revealed that IL-36γ greatly promoted CD8 + T cell activation, contributing to antitumor immune responses. However, the underlying mechanism of IL-36-mediated CD8 + T cell activation remains understood. In the current study, we proved that IL-36β had the same effect on CD8 + T cell as IL-36γ, and uncovered that IL-36β significantly activated mammalian target of rapamycin complex 1 (mTORC1) of CD8 + T cells. When mTORC1 was inhibited by rapamycin, IL-36β-stimulated CD8 + T cell activation and expansion was drastically downregulated. Further, we elucidated that IL-36β-mediated mTORC1 activation was dependent on the pathway of phosphatidylinositol 3 kinase (PI3K)/Akt, IκB kinase (IKK) and myeloid differentiation factor 88 (MyD88). Inhibition of PI3K or IKK by inhibitor, or deficiency of MyD88, respectively, suppressed mTORC1 signal, causing arrest of CD8 + T cell activation. Additionally, it was validated that IL-36β significantly promoted mTORC1 activation and antitumor function of CD8 + tumor-infiltrating lymphocytes (TILs) in vivo , resulting in inhibition of tumor growth and prolongation of survival of tumor-bearing mice. Taken together, we substantiated that IL-36β could promote CD8 + T cell activation through activating mTORC1 dependent on PI3K/Akt, IKK and MyD88 pathways, leading to enhancement of antitumor immune responses, which laid the foundations for applying IL-36β into tumor immunotherapy.