Development and validation of a novel prognostic lncRNA signature based on the APOBEC3 family genes in gastric cancer.

Introduction: Gastric Cancer (GC) refers to a prevalent malignant cancer accompanied by a weak prognosis. The APOBEC3 family genes and lncRNAs are linked with cancer progression. Nevertheless, there is still a scarcity of data concerning the prognostic value of APOBEC3-related lncRNAs in GC. Methods: We extracted the data from GC samples, including transcriptome as well as clinical data, obtained from the TCGA database. Then, we screened for lncRNAs that were correlated with the APOBEC3 family genes and constructed an APOBEC3-related lncRNA prognostic signature (LPS) by utilizing univariate Cox and lasso regression analysis. Furthermore, we validated our constructed signature and evaluated it thoroughly, including analysis of its function, immunity, mutations, and clinical applications via multiple methods, including Metascape, GSEA, and analyses including TIC and TME, immune checkpoints, CNV and SNPs, Kaplan-Meier survival curves, nomogram, decision tree and drug prediction analysis. Finally, we overexpressed LINC01094 to evaluate the impacts on the proliferation as well as migration with regards to KATO-2 cells. Results: We selected eight lncRNAs for our APOBEC3-related LPS, which is demonstrated as a valuable tool in predicting the individual GC patients' prognosis. Subsequently, we segregated the samples into subgroups of high-as well as low-risk relying on the risk score with regards to APOBEC3-related LPS. By performing functional analysis, we have shown that immune-as well as tumor-related pathways were enriched in high- and low-risk GC patients. Furthermore, immune analysis revealed a robust correlation between the APOBEC3-related LPS and immunity. We found that immune checkpoints were significantly associated with the APOBEC3-related LPS and were greatly exhibited in GC tumor and high-risk samples. Mutational analysis suggested that the mutational rate was greater in low-risk samples. Furthermore, we predicted small molecular drugs displayed greater sensitivity in patients categorized as high-risk. Moreover, the immune response was also better in high-risk patients. Of these drugs, dasatinib was significant in both methods and might be considered a potential novel drug for treating high-risk GC patients. Finally, we found that LINC01094 has the potential to enhance the migration, proliferation as well as inhibit apoptosis of KATO-2 in GC cells. And Dasatinib has an inhibitory effect on the migration as well as proliferation in GC cells. Conclusion: We created a novel APOBEC3-related LPS in predicting the prognosis with regards to individual GC patients. Importantly, this APOBEC3-related LPS was closely associated with immunity and might guide clinical treatment.

JAML promotes the antitumor role of tumor-resident CD8+ T cells by facilitating their innate-like function in human lung cancer.

Tissue-resident memory CD8+T cells (CD8+TRMs) are thought to play a crucial role in cancer immunosurveillance. However, the characteristics of CD8+TRMs in the tumor microenvironment (TME) of human non-small cell lung cancer (NSCLC) remain unclear. Here, we report that CD8+TRMs accumulate explicitly and exhibit a unique gene expression profile in the TME of NSCLC. Interestingly, these tumor-associated CD8+TRMs uniquely exhibit an innate-like phenotype. Importantly, we found that junction adhesion molecule-like (JAML) provides an alternative costimulatory signal to activate tumor-associated CD8+TRMs via combination with cancer cell-derived CXADR (CXADR Ig-like cell adhesion molecule). Furthermore, we demonstrated that activating JAML could promote the expression of TLR1/2 on CD8+TRMs, inhibit tumor progression and prolong the survival of tumor-bearing mice. Finally, we found that higher CD8+TRMs and JAML expression in the TME could predict favorable clinical outcomes in NSCLC patients. Our study reveals an intrinsic bias of CD8+TRMs for receiving the tumor-derived costimulatory signal in the TME, which sustains their innate-like function and antitumor role. These findings will shed more light on the biology of CD8+TRMs and aid in the development of potential targeted treatment strategies for NSCLC.

Inflammatory dendritic cells restrain CD11b+CD4+ CTLs via CD200R in human NSCLC.

CD4+ cytotoxic T lymphocytes (CD4+ CTLs) are suggested to play a crucial role in inflammatory diseases, including cancer, but their characteristics in human non-small cell lung cancer (NSCLC) remain unknown. Here, using the cell surface marker CD11b, we identify CD11b+CD4+ CTLs as a cytotoxic subset of CD4+ T cells in multiple tissues of NSCLC patients. In addition, tumor-infiltrating CD11b+CD4+ CTLs show a dysfunctional phenotype with elevated expression of CD200 receptor (CD200R), a negatively immunomodulatory receptor. CD4+ regulatory T (Treg) cells restrain the anti-tumor role of CD11b+CD4+ CTLs via CD200. Mechanistically, inflammatory dendritic cells promote the CD200R expression of CD11b+CD4+ CTLs by secreting interleukin-1ß (IL-1ß). Finally, we demonstrate that CD200 blockade can revive the tumor-killing role of CD11b+CD4+ CTLs and prolong the survival of tumor-bearing mice. Taken together, our study identifies CD11b+CD4+ CTLs in NSCLC with decreased cytotoxicity that can be reinvigorated by CD200 blockade, suggesting that targeting CD200 is a promising immunotherapy strategy in NSCLC.

NMI: a potential biomarker for tumor prognosis and immunotherapy.

N-Myc and STAT Interactor protein (NMI) is an interferon inducible protein participating in various cellular activities, and is widely involved in the process of tumorigenesis and progression. Studies have shown that the loss of NMI expression in breast cancer can promote its progression by inducing epithelial-mesenchymal transition (EMT). However, the expression level of NMI in other tumors and its impact on immune cell infiltration, patient prognosis, and drug treatment are still unclear. Here, we analyzed the role of NMI in pan-cancer through multiple omics data. We found that NMI was abnormally expressed in a variety of tumor tissues. The expression of NMI was closely related to the unique molecular and immunotyping, diagnosis and prognosis of various tumor tissues. In addition, we identified the main proteins that interact with NMI, and focused on the relationship between the clinical parameters of lower grade glioma (LGG) and NMI expression. Subsequently, we found that the expression of NMI was correlated with the infiltration of multiple immune cells and the expression of immune checkpoints. Finally, we also found that the expression of NMI was correlated with the sensitivity to multiple antitumor drugs. In conclusion, our comprehensive pan-cancer analysis of NMI revealed that it is a potential molecular marker for tumor diagnosis and treatment, plays an important role in tumor immunity, and is a promising molecular target for cancer treatment.

Tissue-resident CD69+ CXCR6+ Natural Killer cells with exhausted phenotype accumulate in human non-small cell lung cancer.

Natural killer (NK) cells with tissue-residency features (trNK cells) are a new subpopulation of NK cells, which plays an important role in tissue homeostasis. However, the characteristics of trNK cells in the tumor microenvironment (TME) of human cancers remain unclear. Using multicolor flow cytometry, we investigated the quantity, phenotype, and function of trNK cells in biospecimens freshly resected from 60 non-small cell lung cancer (NSCLC) patients. We successfully identified a new CD69+ CXCR6+ trNK subset with an immunomodulatory-like and exhausted phenotype, specifically accumulated in the TME of NSCLC. In vitro experiments showed that CD69+ CXCR6+ trNK cells more readily secreted IFN-γ and TNF-α spontaneously. Furthermore, the production of IFN-γ and TNF-α by tumor-infiltrating CD69+ CXCR6+ trNK cells was not induced by their reactivation in vitro, which is analogous to T-cell exhaustion. Finally, we demonstrated that the dysfunction of CD69+ CXCR6+ trNK cells could be partly ameliorated by PD-1 and CTLA-4 blockade. In summary, we identified a new dysfunctional CD69+ CXCR6+ trNK cell subset that specifically accumulates in the TME of NSCLC. Our findings suggest that CD69+ CXCR6+ trNK cells are a promising target for immune checkpoint inhibitors in the treatment of NSCLC.

The immune landscape of human thymic epithelial tumors.

Human thymic epithelial tumors (TET) are common malignancies in the anterior mediastinum with limited biological understanding. Here we show, by single cell analysis of the immune landscape, that the developmental pattern of intra-tumoral T-cells identify three types within TETs. We characterize the developmental alterations and TCR repertoires of tumor-infiltrating T cells in the context of the distinguishing epithelial tumor cell types. We demonstrate that a subset of tumor cells, featuring medullary thymic epithelial cell (TEC) phenotype and marked by KRT14/GNB3 expression, accumulate in type 1 TETs, while T-cell positive selection is inhibited. Type 2 TETs are dominated by CCL25+ cortical TEC-like cells that appear to promote T-cell positive selection. Interestingly, the CHI3L1+ medullary TEC-like cells that are the characteristic feature of type 3 TETs don't seem to support T-cell development, however, they may induce a tissue-resident CD8+ T cell response. In summary, our work suggests that the molecular subtype of epithelial tumour cells in TETs determine their tumour immune microenvironment, thus GNB3 and CHI3L1 might predict the immunological behavior and hence prognosis of these tumours.

Oncolytic adenovirus promotes vascular normalization and nonclassical tertiary lymphoid structure formation through STING-mediated DC activation.

Inducing a full antitumor immune response in the tumor microenvironment (TME) is essential for successful cancer immunotherapy. Here, we report that an oncolytic adenovirus carrying mIL-15 (Ad-IL15) can effectively induce antitumor immune response and inhibit tumor growth in a mouse model of cancer. We found that Ad-IL15 facilitated the activation and infiltration of immune cells, including dendritic cells (DCs), T cells and natural killer (NK) cells, in the TME. Unexpectedly, we observed that Ad-IL15 also induced vascular normalization and tertiary lymphoid structure formation in the TME. Moreover, we demonstrated these Ad-IL15-induced changes in the TME were depended on the Ad-IL15-induced activation of the STING-TBK1-IRF3 pathway in DCs. Taken together, our findings suggest that Ad-IL15 is a candidate for cancer immunotherapy that promotes immune cell activation and infiltration, tumor vascular normalization and tertiary lymphoid structure formation in the TME.

CD38 identifies pre-activated CD8+ T cells which can be reinvigorated by anti-PD-1 blockade in human lung cancer.

BACKGROUND: CD38 has been observed expressing in activated T cells, while the features and functions of CD38+ T cells in human NSCLC are still unclear. METHODS: Here we uncovered the correlation between CD38 expression and survival and immune infiltration levels in tumor of NSCLC. Then, we collected samples from 51 NSCLC patients to study the biological feature and response to anti-PD-1 of tumor-infiltrating CD38+ CD8+ T cells in vitro. RESULTS: We found CD38 expression correlated with the survival and immune infiltration levels of NSCLC. It is interesting that CD38+ CD8+ T cells enriched in the tumors expressed higher level of cytotoxic molecule, cytokines and PD-1 than CD38- CD8+ T cells. Moreover, PD-1+ subset in tumor-infiltrating CD38+ CD8+ T cells expressed higher level of activated markers than PD-1+ CD38- CD8+ T cells. Next, we found tumor-infiltrating CD38+ CD8+ T cells expressed higher level of CD103, IFN-γ, TNF-α and perforin than CD38- CD8+ T cells when were reactivated in vitro. Finally, we observed that CD38+ CD8+ T cells isolated from tumors could be reinvigorated by anti-PD-1 in vitro. CONCLUSIONS: Our findings demonstrate that CD38 expression defines a subset of CD8+ T cells enriched in tumors of NSCLC which have paradoxical phenotypes and response to anti-PD-1. Our results suggest a pre-priming of these cells is may exist in tumor and consequentially facilitate it acquiring both anti-tumor potency and exhausted phenotype which can be reinvigorated by PD-1 blockade.

Systemic Immune Dysregulation Correlates With Clinical Features of Early Non-Small Cell Lung Cancer.

Background: Systemic immune dysregulation correlates with cancer progression. However, the clinical implications of systemic immune dysregulation in early non-small cell lung cancer (NSCLC) remain unclear. Methods: Using a panel of 9 markers to identify 12 parameters in the peripheral blood of 326 patients (34 in the discovery group and 292 in the validation group), we investigated systemic immune dysregulation in early NSCLC. Then, we analyzed the impact of surgery on the systemic immune state of these patients. Finally, we analyzed correlations between systemic immune dysregulation and the clinical features of early NSCLC. Results: We found striking systemic immune dysregulation in the peripheral blood of early NSCLC patients. This dysregulation was characterized by a significant decrease in total lymphocytes, T cells, quiescent T cells, CD4+ T cells, and NKT cells. We also observed increased proportions of activated lymphocytes and activated T cells. Systemic immune dysregulation was increased after surgery. Furthermore, systemic immune dysregulation was correlated with multiple clinical features, such as sex, age, smoking history, pathological type, tumor stage, surgical approach, tumor differentiation, and epidermal growth factor receptor (EGFR) mutation. Finally, we observed that systemic immune dysregulation was correlated with complications and systemic inflammatory response syndrome (SIRS) in early NSCLC patients. Conclusions: Our results reveal systemic immune dysregulation occurring in early NSCLC and demonstrate the correlation between these dysregulations and clinical features. Our findings suggest that systemic immune dysregulation is involved in cancer development and may be a promising candidate for high-risk screening and treatment strategies for early NSCLC.