Immune Checkpoint
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2021 ◽  
Vol 157 ◽  
pp. 225-237
André Manuel Da Silva Lopes ◽  
Sara Colomer-Lahiguera ◽  
Nuria Mederos Alfonso ◽  
Veronica Aedo-Lopez ◽  
Gilliosa Spurrier-Bernard ◽  

2021 ◽  
Sheng Han ◽  
Ziyi Wang ◽  
Wenjie Yu ◽  
Chenyang Jia ◽  
Chenyu Jiao ◽  

Abstract BackgroudsTrem2 is a core member of the Triggering recptor expressed on myeloid cell family, and its role in response to pathological damagewas first discovered in Alzheimer’s disease. Recently, the role of Trem2 played in tumor progression has been highlighted. However, the specific role and related mechanisms of trem2 in HCC (hepatocellular carcinoma) are still ambiguous.MethodsThe 371 HCC data sets in the TCGA cohort combined with the TIMER2.0 online database were used to verify the potential role and prognostic value of trem2 in HCC.TIMER2.0 online database,immunohistology, immunofluorescence, Western Blot and other methods are applied to identify the correlation between Trem2 and HCC patient samples.Animal models of bile duct ligation, intraperitoneal injection of CCL4 and feeding of CDAHFD60 were used to verify the potential mechanism of trem2 to regulate HCC.ResultsTrem2 is significantly overexpressed in HCC and is an independent risk factor predicts the poor prognosis of HCC patients. Trem2 mainly regulates the progression of HCC in response to the mutations of TP53 and CTNNB1, which also suggests that Trem2 plays an important role in tumor pathological metabolism. Since HCC patients often accompanied by different degrees of liver fibrosis, we suspect that Trem2 may promotes the progression of HCC by regulating liver fibrosis.ConclusionOur research highlights the status of trem2 in the tandem or independent events of HCC's pathological metabolism, immune checkpoint coordination, and liver fibrosis. We predict that targeting Trem2 combined with immune checkpoint inhibitors may be an effective treatment for HCC with rich immune and metabolic microenvironment.

2021 ◽  
Yiheng Du ◽  
Jin Cao ◽  
Xiang Jiang ◽  
Xiaowei Cai ◽  
Bo Wang ◽  

Abstract Background Bladder cancer (BLCA) is the most common genitourinary tumor but lacks specific diagnostic biomarkers. Recent years have seen significant advances in the use and approval of immune checkpoint blockade (ICB) therapy to manage bladder cancer at advanced stages when platinum-based therapy has failed. The tumor microenvironment (TME) in bladder cancer is an essential player in patient's responsiveness to ICB therapy. Therefore, this manuscript explored the TME and identified CXCL12, a specific marker for inflammatory cancer associated fibroblasts(iCAFs), as potential molecular markers and therapeutic targets for bladder cancer. Methods We examined the gene expression profiles in the TCGA and GEO datasets to reveal the potential association of CXCL12 with the carcinogenesis and prognosis of bladder cancer. Methylation analysis of CXCL12 was performed using the UALCAN and MethSurv databases. The MCP-COUNTER, ESTIMATE, and TIDE algorithms were applied to estimate the TME components and predict immunotherapy responsiveness. An iCAFs signature was constructed using the ssGSEA algorithm. Bioinformatics analysis results were validated through immunohistochemistry of clinical samples. IMvigor210 cohort was used to validate bioinformatic predictions of therapeutic responsiveness to immune checkpoint inhibitors Results Our analysis revealed the potential association between aberrant promoter methylation of CXCL12 and bladder cancer carcinogenesis. CpG sites methylation of the CXCL12 gene body was associated with bladder cancer prognosis. Moreover, the expression level of CXCL12 exhibited a significant correlation with patients' pathological features and prognosis. Through gene enrichment analysis, CXCL12 was demonstrated to be associated with immune modulation and tumor microenvironment remodeling. The MCP-COUNTER and ESTIMATE algorithms verified significant correlations between CXCL12 and TME components, particularly CAFs, macrophages, and T cells. The TIDE algorithm provided evidence that T-cell clearance and dysfunction were more pronounced in bladder cancers characterized by high CXCL12 expression and high iCAFs scores, contributing to inferior responsiveness to ICB therapy. Patients who expressed high CXCL12 levels and had high iCAFs scores were likely to have less frequent FGFR3 mutation and a stromal-rich molecular subtype. Immunohistochemistry revealed that the close association of CXCL12 with iCAFs in bladder cancer potentially influenced the intratumoral infiltration of CD8 + T cells. CXCL12 expression in MIBC was increased significantly in NMIBC, which supports the bioinformatics analysis results. The IMvigor210 cohort confirmed the iCAFs score to be significantly associated with the responsiveness to immune checkpoint blockade therapy. Conclusions This work explores carcinogenesis and cancer-promoting roles of CXCL12 in bladder cancer. As a specific marker gene of iCAFs, CXCL12 potentially promotes bladder cancer progression by regulating the tumor microenvironment. Further exploration of the association between CXCL12 and iCAFs may unravel potential therapeutic targets for bladder precision medicine and improve the responsiveness of immune checkpoint blockade therapy.

2021 ◽  
Vol 12 ◽  
Anqi Lin ◽  
Hongman Zhang ◽  
Hui Meng ◽  
Ze Deng ◽  
Tianqi Gu ◽  

Translational research on immune checkpoint inhibitors (ICIs) has been underway. However, in the unselected population, only a few patients benefit from ICIs. Therefore, screening predictive markers of ICI efficacy has become the current focus of attention. We collected mutation and clinical data from an ICI-treated non-small cell lung cancer (NSCLC) cohort. Then, a univariate Cox regression model was used to analyze the relationship between tumor necrosis factor α signaling mutated (TNFα-MT) and the prognosis of immunotherapy for NSCLC. We retrospectively collected 36 NSCLC patients (local-cohort) from the Zhujiang Hospital of Southern Medical University and performed whole-exome sequencing (WES). The expression and mutation data of The Cancer Genome Atlas (TCGA)-NSCLC cohort were used to explore the association between TNFα-MT and the immune microenvironment. A local cohort was used to validate the association between TNFα-MT and immunogenicity. TNFα-MT was associated with significantly prolonged overall survival (OS) in NSCLC patients after receiving immunotherapy. Additionally, TNFα-MT is related to high immunogenicity (tumor mutational burden, neoantigen load, and DNA damage response signaling mutations) and enrichment of infiltrating immune cells. These results suggest that TNFα-MT may serve as a potential clinical biomarker for NSCLC patients receiving ICIs.

2021 ◽  
Vol 13 (611) ◽  
Marcel André Schneider ◽  
Laura Heeb ◽  
Michal Mateusz Beffinger ◽  
Stanislav Pantelyushin ◽  
Michael Linecker ◽  

2021 ◽  
Vol 14 (1) ◽  
Wenjing Qian ◽  
Mingfang Zhao ◽  
Ruoyu Wang ◽  
Heming Li

AbstractImmune checkpoint therapy has achieved significant efficacy by blocking inhibitory pathways to release the function of T lymphocytes. In the clinic, anti-programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) monoclonal antibodies (mAbs) have progressed to first-line monotherapies in certain tumor types. However, the efficacy of anti-PD-1/PD-L1 mAbs is still limited due to toxic side effects and de novo or adaptive resistance. Moreover, other immune checkpoint target and biomarkers for therapeutic response prediction are still lacking; as a biomarker, the PD-L1 (CD274, B7-H1) expression level is not as accurate as required. Hence, it is necessary to seek more representative predictive molecules and potential target molecules for immune checkpoint therapy. Fibrinogen-like protein 1 (FGL1) is a proliferation- and metabolism-related protein secreted by the liver. Multiple studies have confirmed that FGL1 is a newly emerging checkpoint ligand of lymphocyte activation gene 3 (LAG3), emphasizing the potential of targeting FGL1/LAG3 as the next generation of immune checkpoint therapy. In this review, we summarize the substantial regulation mechanisms of FGL1 in physiological and pathological conditions, especially tumor epithelial to mesenchymal transition, immune escape and immune checkpoint blockade resistance, to provide insights for targeting FGL1 in cancer treatment.

Cancers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 4616
Yasuhiro Kanda ◽  
Taku Okazaki ◽  
Tomoya Katakai

The migration status of T cells within the densely packed tissue environment of lymph nodes reflects the ongoing activation state of adaptive immune responses. Upon encountering antigen-presenting dendritic cells, actively migrating T cells that are specific to cognate antigens slow down and are eventually arrested on dendritic cells to form immunological synapses. This dynamic transition of T cell motility is a fundamental strategy for the efficient scanning of antigens, followed by obtaining the adequate activation signals. After receiving antigenic stimuli, T cells begin to proliferate, and the expression of immunoregulatory receptors (such as CTLA-4 and PD-1) is induced on their surface. Recent findings have revealed that these ‘immune checkpoint’ molecules control the activation as well as motility of T cells in various situations. Therefore, the outcome of tumor immunotherapy using checkpoint inhibitors is assumed to be closely related to the alteration of T cell motility, particularly in tumor-draining lymph nodes (TDLNs). In this review, we discuss the migration dynamics of T cells during their activation in TDLNs, and the roles of checkpoint molecules in T cell motility, to provide some insight into the effect of tumor immunotherapy via checkpoint blockade, in terms of T cell dynamics and the importance of TDLNs.

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