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Psychological distress has long been suspected to influence cancer incidence and mortality. It remains largely unknown whether and how stress affects the efficacy of anticancer therapies. We observed that social defeat caused anxiety-like behaviors in mice and dampened therapeutic responses against carcinogen-induced neoplasias and transplantable tumors. Stress elevated plasma corticosterone and upregulated the expression of glucocorticoid-inducible factor Tsc22d3, which blocked type I interferon (IFN) responses in dendritic cell (DC) and IFN-γ+ T cell activation. Similarly, close correlations were discovered among plasma cortisol levels, TSC22D3 expression in circulating leukocytes and negative mood in patients with cancer. In murine models, exogenous glucocorticoid injection, or enforced expression of Tsc22d3 in DC was sufficient to abolish therapeutic control of tumors. Administration of a glucocorticoid receptor antagonist or DC-specific Tsc22d3 deletion reversed the negative impact of stress or glucocorticoid supplementation on therapeutic outcomes. Altogether, these results indicate that stress-induced glucocorticoid surge and Tsc22d3 upregulation can subvert therapy-induced anticancer immunosurveillance.

Single cell RNAseq analyses were performed on T cells from MC38 and CT26 tumor models. PCA-based sub-clustering and STARTRAC analyses revealed fine-tuned T cell subsets and dynamic in tumor. CCR8 was identified as a novel target on Tregs to synergize with anti–PD-1 for cancer immunotherapy., Single-cell RNA sequencing is a powerful tool to examine cellular heterogeneity, novel markers and target genes, and therapeutic mechanisms in human cancers and animal models. Here, we analyzed single-cell RNA sequencing data of T cells obtained from multiple mouse tumor models by PCA-based subclustering coupled with TCR tracking using the STARTRAC algorithm. This approach revealed various differentiated T cell subsets and activation states, and a correspondence of T cell subsets between human and mouse tumors. STARTRAC analyses demonstrated peripheral T cell subsets that were developmentally connected with tumor-infiltrating CD8+ cells, CD4+ Th1 cells, and T reg cells. In addition, large amounts of paired TCRα/β sequences enabled us to identify a specific enrichment of paired public TCR clones in tumor. Finally, we identified CCR8 as a tumor-associated T reg cell marker that could preferentially deplete tumor-associated T reg cells. We showed that CCR8-depleting antibody treatment provided therapeutic benefit in CT26 tumors and synergized with anti–PD-1 treatment in MC38 and B16F10 tumor models., Graphical Abstract

Cancer immunotherapies have shown sustained clinical responses in treating non-small-cell lung cancer1–3, but efficacy varies and depends in part on the amount and properties of tumor infiltrating lymphocytes4–6. To depict the baseline landscape of the composition, lineage and functional states of tumor infiltrating lymphocytes, here we performed deep single-cell RNA sequencing for 12,346 T cells from 14 treatment-naive non-small-cell lung cancer patients. Combined expression and T cell antigen receptor based lineage tracking revealed a significant proportion of inter-tissue effector T cells with a highly migratory nature. As well as tumor-infiltrating CD8+ T cells undergoing exhaustion, we observed two clusters of cells exhibiting states preceding exhaustion, and a high ratio of “pre-exhausted” to exhausted T cells was associated with better prognosis of lung adenocarcinoma. Additionally, we observed further heterogeneity within the tumor regulatory T cells (Tregs), characterized by the bimodal distribution of TNFRSF9, an activation marker for antigen-specific Tregs. The gene signature of those activated tumor Tregs, which included IL1R2, correlated with poor prognosis in lung adenocarcinoma. Our study provides a new approach for patient stratification and will help further understand the functional states and dynamics of T cells in lung cancer. Deep single-cell RNA sequencing of tumor-infiltrating T cells in non-small-cell lung cancer identifies features associated with functional states and clinical outcome

Additional file 2. Review history.

Objective Currently, no satisfactory targets for colorectal cancer or markers for immunotherapy and diagnosis and prognosis are available. Immunoglobulin G (IgG) is widely expressed in many cancers, and it promotes cancer progression. This study explored the role of cancer-derived IgG (CIgG) in colorectal cancer. Methods First, using a monoclonal antibody to CIgG, we examined the expression levels of CIgG in colorectal cancer cell lines by western blot and immunofluorescence analyses and in tissue specimens by immunohistochemistry. Second, the variable region gene was amplified by nested polymerase chain reaction (PCR), and PCR products were sequenced and analyzed. Third, we investigated the effect of CIgG on colorectal cancer cells by cell proliferation, wound healing, migration and invasion assays, and colony formation assay. Fourth, we performed in vivo tumorigenicity experiments to explore the effect of CIgG on tumorigenicity. Finally, we used RNA-seq analysis and co-immunoprecipitation experiments to further clarify possible mechanisms of CIgG. Results We found that CIgG is widely expressed in colorectal cancer cells, and the overexpression of CIgG indicates significantly poor colorectal cancer prognosis. Furthermore, CIgG knockdown significantly inhibits the proliferation, migration and invasion ability of cells, and tumor growth in vivo. RNA-seq analysis indicated that CIgG knockdown results primarily in changes in expression of apical junction and epithelial-mesenchymal transition-related genes. CIgG may be involved in colorectal cancer invasion and metastasis through interacting with E-cadherin. Conclusions CIgG is a potential human oncogene in colorectal cancer and that it has potential for application as a novel target in targeted therapy and a marker for prognostic evaluation.

Fast, robust and technology-independent computational methods are needed for supervised cell type annotation of single-cell RNA sequencing data. We present SciBet, a Bayesian classifier that accurately predicts cell identity for newly sequenced cells or cell clusters. We enable web client deployment of SciBet for rapid local computation without uploading local data to the server. This user-friendly and cross-platform tool can be widely useful for single cell type identification.

Protein modification by ubiquitin and ubiquitin-like proteins (UBLs) regulates numerous biological functions. The UFM1 system, a novel UBL conjugation system, is implicated in mouse development and hematopoiesis. However, its broad biological functions and working mechanisms remain largely elusive. CDK5RAP3, a possible ufmylation substrate, is essential for epiboly and gastrulation in zebrafish. Herein, we report a critical role of CDK5RAP3 in liver development and hepatic functions. Cdk5rap3 knockout mice displayed prenatal lethality with severe liver hypoplasia, as characterized by delayed proliferation and compromised differentiation. Hepatocyte-specific Cdk5rap3 knockout mice suffered post-weaning lethality, due to serious hypoglycemia and impaired lipid metabolism. Depletion of CDK5RAP3 triggered endoplasmic reticulum stress and activated unfolded protein responses in hepatocytes. We detected the in vivo interaction of CDK5RAP3 with UFL1, the defined E3 ligase in ufmylation. Notably, loss of CDK5RAP3 altered the ufmylation profile in liver cells, suggesting that CDK5RAP3 serves as a novel substrate adaptor for this UBL modification. Collectively, our study identifies CDK5RAP3 as an important regulator of ufmylation and suggests the involvement of ufmylation in mammalian development.

Psychological distress has long been suspected to influence cancer incidence and mortality. It remains largely unknown whether and how stress affects the efficacy of anticancer therapies. We observed that social defeat caused anxiety-like behaviors in mice and dampened therapeutic responses against carcinogen-induced neoplasias and transplantable tumors. Stress elevated plasma corticosterone and upregulated the expression of glucocorticoid-inducible factor Tsc22d3, which blocked type I interferon (IFN) responses in dendritic cell (DC) and IFN-γ

In the version of this article originally published, the P statistic described in Fig. 3d was incorrect. It was described as "P < 22 × 10-16". It should have been "P < 2.2 × 10-16". Also, the "CD8+ Treg" label in Fig. 4f was incorrect. It should have been "CD4+ Treg". The errors have been corrected in the HTML and PDF versions of this article.

Systematic interrogation of tumor-infiltrating lymphocytes is key to the development of immunotherapies and the prediction of their clinical responses in cancers. Here, we perform deep single-cell RNA sequencing on 5,063 single T cells isolated from peripheral blood, tumor, and adjacent normal tissues from six hepatocellular carcinoma patients. The transcriptional profiles of these individual cells, coupled with assembled T cell receptor (TCR) sequences, enable us to identify 11 T cell subsets based on their molecular and functional properties and delineate their developmental trajectory. Specific subsets such as exhausted CD8+ T cells and Tregs are preferentially enriched and potentially clonally expanded in hepatocellular carcinoma (HCC), and we identified signature genes for each subset. One of the genes, layilin, is upregulated on activated CD8+ T cells and Tregs and represses the CD8+ T cell functions in vitro. This compendium of transcriptome data provides valuable insights and a rich resource for understanding the immune landscape in cancers.