Predictive value of CXCL1(+)_FAP(+) phenotype in CAFs for distant metastasis and its correlation with PD-L1 expression in locoregionally advanced nasopharyngeal carcinoma patients.
There is a lack of effective biomarkers for predicting the distant metastasis in nasopharyngeal carcinoma (NPC). We aimed to explore the expression of FAP+Cancer-associated fibroblasts (CAFs) derived CXCL1 in NPC and its predictive values for distant metastasis and correlation with PD-L1 expression.
A total of 345 patients with locoregionally advanced NPC were retrospectively enrolled (the training cohort: the validation cohort = 160:185). Co-expression of CXCL1 and FAP and the expression of PD-L1 were detected by multi-immunofluorescence staining and immunohistochemistry, respectively. The primary end-point was distant metastasis-free survival (DMFS). The Kaplan-Meier method was used to calculate the survival. The Cox proportional hazards model was used to assess prognostic risk factors.
A novel CXCL1+_FAP+ phenotype in CAFs was identified in NPC and then used to divide patients into low and high risk groups. Both in the training cohort and validation cohort, patients in the high risk group had poorer DMFS, overall survival (OS), progression-free survival (PFS) and locoregional relapse-free survival (LRFS) than patients in the low risk group. Multivariate analysis revealed CXCL1+_FAP+ phenotype was an independent prognostic factor for DMFS, OS, PFS and LRFS. Further results showed patients in the high risk group had higher PD-L1 expression than those in the low risk group.
Our study showed CXCL1+_FAP+ phenotype in CAFs could effectively classified locoregionally advanced NPC patients into different risk groups for distant metastasis and might be a potential biomarker for anti-PD-1/PD-L1 immunotherapy.
Wen YF
，Huang WJ
，Chen XL
，Cai HT
，Zhang YB
，Song XL
，Xie CB
，Peng HH
，Yu HW
，Chen CC
，Wei LQ
，Zhou TC
，Cai S
，Wang F
，Lin XD
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Fibroblast Activation Protein-α Expression in Cancer-Associated Fibroblasts Shows the Poor Survival of Colorectal Cancer via Immune-Mediated Pathways : Implications of FAP in Cancer-Associated Fibroblasts Link Immune Dysregulation to Adverse Survival in C
Cancer-associated fibroblasts (CAFs) and immune cells, the key components of the tumor microenvironment (TME), play critical roles in oncogenesis. Despite the recognized function of fibroblast activation protein-α (FAP), a specific biomarker of CAFs in cancer progression, its role in the survival of patients with colorectal cancer (CRC) and tumor immune microenvironment (TIME) remains unclear.
We investigated 180 pathological sections obtained from 178 consecutive patients with CRC who underwent surgical resection at Shiga University of Medical Science Hospital between January 2013 and December 2015. FAP expression levels and CD3 and CD8 densities at the invasive margin and center of tumor were assessed using immunohistochemical (IHC) staining. Furthermore, we used single-cell RNA sequencing (scRNA-seq) of CAFs in a separate cohort of 10 untreated patients with CRC derived from the Gene Expression Omnibus database.
According to IHC evaluation, high FAP expression in patients with CRC showed a correlation with reduced tumor-infiltrating lymphocyte (TIL) distribution and poor survival. Based on the FAP transcription levels obtained through scRNA-seq analysis, CAFs were grouped into high and low FAP expression groups. Elevated FAP expression was correlated with decreased expression of T- and B-cell biomarkers, suggesting an association with an immunosuppressive TME promotion. Several genes associated with cancer-related immune-mediated pathways (CXCL12, COL11A1, CCL11, and COL10A1) were significantly upregulated in FAP-positive CAFs.
This study highlights the effects of FAP expression on survival of patients with CRC, its interaction with TILs, and relevant signaling pathways, and underscores potential immunotherapeutic targets for future investigation.
Qin Y
，Miyake T
，Muramoto K
，Maekawa T
，Nishina Y
，Wang Y
，Shimizu T
，Tani M
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Comparison of efficacy and safety of PD-1/PD-L1 combination therapy in first-line treatment of advanced NSCLC: an updated systematic review and network meta-analysis.
The use of immune checkpoint inhibitors has led to an increase in randomized controlled trials exploring various first-line combination treatment regimens. With the introduction of new PD-1/PD-L1 inhibitors, there are now more clinical options available. For the first time, the AK105 monoclonal antibody Penpulimab, developed in China, was included. The AK105-302 Phase III trial studied the efficacy and safety of Penpulimab combined with chemotherapy in patients with advanced or metastatic squamous NSCLC. To determine the optimal treatment options, we conducted an updated network meta-analysis to compare the effectiveness and safety of these regimens.
The system retrieves data from Chinese and English electronic databases, Clinical Trials, and the gov Clinical Trial Registration website up to September 6, 2023. The study indirectly compared the efficacy and safety of PD-1/PD-L1 combination regimens, including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), all-grade adverse events, and above-grade III adverse events. Subgroup analyses were conducted based on programmed death ligand 1 (PD-L1) level, histological type, ECOG score, sex, and smoking history.
Nineteen RCTS were included, with a total of ten thousand eight hundred patients. Penpulimab plus chemotherapy (Pen + CT) provided the best OS (HR = 0.55, 95% CI 0.38-0.81) for PD-L1 patients with non-selective advanced NSCLC. Except Nivolumab plus Ipilimumab (Niv + Ipi), other PD-1/PD-L1 combination therapies significantly extended PFS compared with CT, and Nivolumab plus Bevacizumab combined with chemotherapy (Niv + Bev + CT) (HR = 0.43, 95% CI 0.26-0.74) provided the best PFS benefit and was comparable to Pen + CT (HR = 1.0) for PFS prolongation. For ORR, except Niv + Ipi, all the other regimens significantly improved ORR compared with CT. In terms of safety, except Tor + CT, the incidence of any-grade AEs or grade ≥ 3 adverse events may be higher than those of chemotherapy. The subgroup analysis revealed that for patients with PD-L1 levels below 1%, treatment with Tor + CT resulted in the best progression-free survival (HR = 0.47, 95% CI 0.25-0.86). For patients with PD-L1 levels of 1% or higher, Sintilimab plus chemotherapy (Sin + CT) (HR = 0.56, 95% CI 0.31-0.99) and Camrelizumab plus chemotherapy (Cam + CT) (HR = 0.43, 95% CI 0.28-0.64) were associated with the best overall survival and progression-free survival, respectively. For patients with SqNSCLC, combined immunotherapy may provide greater survival benefits. For patients with Non-sqNSCLC, Niv + Bev + CT and Tor + CT were associated with optimal PFS and OS, respectively. Cam + CT provided the best PFS in male patients with a history of smoking and an ECOG score of 0. In both female and non-smoking patient subgroups, Pem + CT was associated with the best PFS and OS benefits.
For patients with advanced non-selective PD-L1 NSCLC, two effective regimens are Pen + CT and Niv + Bev + CT, which rank first in OS and PFS among all patients. Cam + CT and Tor + CT have advantages for OS in patients with SqNSCLC and Non-sqNSCLC, respectively. Niv + Ipi + CT provided the best OS benefit for patients with an ECOG score of 0, while Pem + CT may be the most effective treatment for patients with an ECOG score of 1. Pem + CT has a better effect on female patients and non-smokers. Sin + CT was found to be the most effective treatment for male patients and the smoking subgroup, while Cam + CT was found to be the most effective for PFS. In addition, Tor + CT was associated with the best PFS for patients with negative PD-L1 expression. Pem + CT was found to significantly improve both PFS and OS compared to CT alone. For patients with positive PD-L1 expression, Sin + CT and Cam + CT were found to be optimal for OS and PFS, respectively. It is important to note that, with the exception of Tor + CT, the toxicity of the other combinations was higher than that of CT alone.
Yang Y
，Chen W
，Dong L
，Duan L
，Gao P
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ResearchGate
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