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Abstract Background Digital histopathology provides valuable information for clinical decision-making. We hypothesized that a deep risk network (DeepRisk) based on digital pathology signature (DPS) derived from whole-slide images could improve the prognostic value of the tumor, node, and metastasis (TNM) staging system and offer chemotherapeutic benefits for gastric cancer (GC). Methods DeepRisk is a multi-scale, attention-based learning model developed on 1120 GCs in the Zhongshan dataset and validated with two external datasets. Then, we assessed its association with prognosis and treatment response. The multi-omics analysis and multiplex Immunohistochemistry were conducted to evaluate the potential pathogenesis and spatial immune contexture underlying DPS. Results Multivariate analysis indicated that the DPS was an independent prognosticator with a better C-index (0.84 for overall survival and 0.71 for disease-free survival). Patients with low-DPS after neoadjuvant chemotherapy responded favorably to treatment. Spatial analysis indicated that exhausted immune clusters and increased infiltration of CD11b+CD11c+ immune cells were present at the invasive margin of high-DPS group. Multi-omics data from the Cancer Genome Atlas-Stomach adenocarcinoma (TCGA-STAD) hint at the relevance of DPS to myeloid derived suppressor cells infiltration and immune suppression. Conclusion DeepRisk network is a reliable tool that enhances prognostic value of TNM staging and aid in precise treatment, providing insights into the underlying pathogenic mechanisms.

The human ventral occipito-temporal cortex (VOTC) has evolved into specialized regions that process specific categories, such as words, tools, and animals. The formation of these areas is driven by bottom-up visual and top-down nonvisual experiences. However, the specific mechanisms through which top-down nonvisual experiences modulate category-specific regions in the VOTC are still unknown. To address this question, we conducted a study in which participants were trained for approximately 13 h to associate three sets of novel meaningless figures with different top-down nonvisual features: the wordlike category with word features, the non-wordlike category with nonword features, and the visual familiarity condition with no nonvisual features. Pre- and post-training functional MRI (fMRI) experiments were used to measure brain activity during stimulus presentation. Our results revealed that training induced a categorical preference for the two training categories within the VOTC. Moreover, the locations of two training category-specific regions exhibited a notable overlap. Remarkably, within the overlapping category-specific region, training resulted in a dissociation in activation intensity and pattern between the two training categories. These findings provide important insights into how different nonvisual categorical information is encoded in the human VOTC.

Abstract Mixed lineage kinase domain-like (MLKL) is widely accepted as an executioner of necroptosis, in which MLKL mediates necroptotic signaling and triggers cell death in a receptor-interacting protein kinase 3 (RIPK3)-dependent manner. Recently, it is increasingly noted that RIPK3 is intrinsically silenced in hepatocytes, raising a question about the role of MLKL in hepatocellular carcinoma (HCC). This study reports a previously unrecognized role of MLKL in regulating parthanatos, a programmed cell death distinct from necroptosis. In HCC cells with intrinsic RIPK3 deficiency, knockout of MLKL impedes the orthotopic tumor growth, activates the anti-tumor immune response and enhances the therapeutic effect of immune checkpoint blockade in syngeneic HCC tumor models. Mechanistically, MLKL is required for maintaining the endoplasmic reticulum (ER)-mitochondrial Mg2+ dynamics in HCC cells. MLKL deficiency restricts ER Mg2+ release and mitochondrial Mg2+ uptake, leading to ER dysfunction and mitochondrial oxidative stress, which together confer increased susceptibility to metabolic stress-induced parthanatos. Importantly, pharmacological inhibition of poly(ADP-ribose) polymerase to block parthanatos restores the tumor growth and immune evasion in MLKL-knockout HCC tumors. Together, our data demonstrate a new RIPK3-independent role of MLKL in regulating parthanatos and highlight the role of MLKL in facilitating immune evasion in HCC.

Desmoplasia is a hallmark of intrahepatic cholangiocarcinoma (ICC), which constitutes a barrier to infiltration of lymphocyte, but not myeloid cells. Given that dense desmoplastic stroma has been reported to be a barrier to infiltration of lymphocyte, but not myeloid cells. We here investigated whether fibroblastic FAP influenced ICC progression via non-T cell-related immune mechanisms. We demonstrated fibroblastic FAP expression was critical for STAT3 activation and CCL2 production, and ICC-CAFs were the primary source of CCL2 in human ICC microenvironment by using ICC-Fbs from six ICC patients. Fibroblastic knockdown of FAP significantly impaired the ability of ICC-CAFs to promote ICC growth, MDSCs infiltration and angiogenesis, which was restored by adding exogenous CCL2. Furthermore, interestingly, the tumor-promoting effect of fibroblastic FAP is dependent on MDSCs via secretion of CCL2, as depletion of Gr-1+ cells reversed the restoring effects of exogenous CCL2 on tumor growth and angiogenesis. In vitro migration assay confirmed that exogenous CCL2 could rescue the impaired ability of ICC-Fbs to attract Gr-1+ cells caused by fibroblastic FAP knockdown. In contrast, fibroblastic FAP knockdown had no effect on ICC cell proliferation and apoptotic resistance. Depletion MDSCs by anti-Gr-1 monoclonal antibody in subcutaneous transplanted tumor model abrogated tumor promotion by ICC-CAFs suggested that the pro-tumor function of Fibroblastic FAP relied on MDSCs. Mechanical, flow cytometry and chamber migration assay were conducted to find Fibroblastic FAP was required by the ability of ICC-CAFs to promote MDSC migration directly. Moreover, fibroblastic FAP knockdown had no effect on cell proliferation and apoptotic resistance. Here, we revealed the T-cell independent mechanisms underlying the ICC-promoting effect of fibroblastic FAP by attracting MDSCs via CCL2, which was mainly attributed to the ability of FAP to attract MDSCs and suggests that specific targeting fibroblastic FAP may represent a promising therapeutic strategy against ICC.

Background Regulating T-cell metabolism is crucial for their anticancer activity. Therefore, understanding the function and metabolism of human tumor-infiltrating T cells is of broad interest and clinical importance.Methods CD3+CD45+ T cells were sorted from adjacent area or tumor core of human hepatocellular carcinoma (HCC), then the clusters and heterogeneity of T cells were further interrogated by single-cell transcriptomic profiling. 118 surgical samples from patients with HCC were histologically examined for infiltration of CD8+ T cells in tumor and adjacent tissue.Results Single-cell transcriptomic profiling indicated that several exhausted T-cell (Tex) populations differentially coexisted in the tumor and adjacent tissue. CD137 identifies and enriches Tex with superior effector functions and proliferation capacity. Furthermore, enhanced fatty acid-binding protein 5 (FABP5) expression along with increased mitochondrial oxidative metabolism were evident in these CD137-enriched Tex. Inhibiting FABP5 expression and mitochondrial fatty acid oxidation impaired the anti-apoptosis and proliferation of CD137-enriched Tex. These observations have been verified by generating CD137 CART. Immunohistochemistry staining on the tissue microarray of 118 patients with HCC showed intra-tumoral FABP5 high CD8+ T-cell infiltration was linked to overall and recurrence-free survival.Conclusions The tumor microenvironment can impose metabolic restrictions on T-cell function. CD137, a costimulatory molecule highly expressed on some Tex, uses exogenous fatty acids and oxidative metabolism to mediate antitumor immunity. The immunometabolic marker FABP5 should be investigated in larger, longitudinal studies to determine their potential as prognostic biomarkers for HCC.

Despite the success of monotherapies based on blockade of programmed cell death 1 (PD-1) in human melanoma, most patients do not experience durable clinical benefit. T-cell infiltration and/or the presence of PD-L1 in tumors may be used as indicators of clinical response; However, recent studies reported that preexisting tumor-specific T cells may have limited reinvigoration capacity. Therefore, evaluating status of T cells of tumor-adjacent area and its impact on the prognosis are very important. Here, we examined 117 surgical samples from HCC patients for infiltration of exhausted T cell (Tex) including CD4+-Tex, CD8+-Tex and regulatory T cell (FOXP3+-Treg) in tumor and adjacent tissue. CD3+CD45RO+T cells were sorted from adjacent area or tumor core, then the clusters and heterogeneity of T cells were further interrogated by single-cell RNA sequencing. As a result, we suggested that abundance or location of T cell subsets is differentially correlate with long-term clinical outcome of HCC. In contrast with CD4+T or CD4+-Tex, the infiltration of CD8+T or CD8+-Tex cells was closely linked to overall or recurrence-free survival. FOXP3+-Treg is more predictive of early recurrence. Single-cell transcriptional analysis demonstrates the composition of CD4+-Tex, CD8+-Tex, and FOXP3+-Treg is shifted in tumor and adjacent tissue. Molecular profiles including genes coding checkpoint receptors, effector molecules are distinct between CD4+-Tex, CD8+-Tex, though some common features of CD4+ and CD8+ T cell exhaustion are revealed. In conclusion, we underline the heterogeneity and clinical relevance of Tex cells in HCC patients. A better understanding of Tex is critical for HCC monitoring and treatment.

As a rare type of liver cancer, intrahepatic cholangiocarcinoma (ICC) has become an increasingly important malignancy and continues to present significant therapeutic challenges. Since coagulopathy is associated with poor prognosis in hepatocellular carcinoma (HCC), and prognostic factors of ICC after curative resection were still not clear, we aim to analyze the characteristics of ICC patients with coagulopathy and its correlation to prognosis. From January 2000 to June 2011, 541 ICC patients, after curative resection, were enrolled in our study. Survival curves were depicted by the Kaplan-Meier method and analyzed by the log-rank test. The Cox proportional hazard regression was adopted for multivariate survival analysis. Student's t test was performed to analyze the difference between the coagulopathy group and the normal group. The correlation between coagulation parameters and prognosis was also evaluated. The incidence rate of at least one coagulation parameter abnormality was 22.6% (122/541) while PT was the most common factor (8.87%, 48/541). The one-year survival rate of patients with coagulopathy was significantly lower than that of patients with normal coagulation (p < 0.01). In a univariate analysis, patients with prolonged PT was associated with shortened DFS (p < 0.05). Meanwhile, PT was negatively correlated with prealbumin level. TNM stage, CA19-9, GGT, and pre-albumin level were independent prognostic factors of DFS in the multivariate analysis. In conclusion, the incidence rate of coagulopathy of ICC patients is lower than HCC patients. Prolonged PT, advanced TNM stage, low prealbumin level, and high CA19-9 and GGT level were correlated with high recurrence rate and poor prognosis. [ABSTRACT FROM AUTHOR]