Fibroblast activation protein in the tumor microenvironment predicts outcomes of PD-1 blockade therapy in advanced non-small cell lung cancer

Abstract

Purpose The identification of robust predictive biomarkers of the response to programmed cell death-1 (PD-1) blockade remains a critical concern. Here, we investigated on fibroblast activation protein (FAP) as a microenvironment-derived biomarker of clinical outcomes of PD-1 blockade therapy, and the correlation between FAP expression and T cell infiltration in advanced non-small cell lung cancer (NSCLC). Methods A total of 135 patients with advanced NSCLC who received PD-1 blockade therapy were retrospectively analyzed. The potential associations among FAP expression, CD3 + T cell and CD8 + T cell infiltration, and clinical outcomes of immunotherapy were validated by immunohistochemistry, bioinformatic analyses, and statistical measurements. Results FAP was widely expressed in advanced NSCLC tissues. FAP was correlated with decreased density of CD8 + T cells (Spearman’s rho – 0.32, p < 0.001) and immunosuppressive tumor microenvironment (TME) status. No correlations were detected between FAP and PD-L1 expression or with the density of CD3 + T cells. The patients with higher expression of FAP showed worse response rate (16.4% vs. 38.7%, p < 0.001) and worse progression-free survival (HR = 2.56, 95% CI 1.69–3.87, p < 0.001). In addition, FAP contributed to shortened overall survival in subgroups of the patients with squamous cell lung cancer (p = 0.020), PD-1 blockade monotherapy (p = 0.017), and first-line therapy (p = 0.028). Conclusion FAP is a potential predictive biomarker of resistance to PD-1 blockade. Further investigation is warranted to identify a strategy for targeting FAP to alleviate the immunosuppressive TME and broaden the clinical effectiveness of PD-1 blockade therapy.

Fibroblast Activation Protein (FAP)-Mediated Cleavage of Type III Collagen Reveals Serum Biomarker Potential in Non-Small Cell Lung Cancer and Spondyloarthritis

“…As such, the biomarker could be a useful tool in other diseases, as FAP has been shown to be upregulated and influential in multiple types of cancer as well as non-cancerous diseases including acute coronary syndrome, fibrosis, and arthritis [ 54 , 55 , 56 , 57 ]. For future studies, it would be interesting to investigate if C3F could show other biomarker properties like those of FAP protein quantification as multiple studies have shown an indication of its prognostic or predictive potential in multiple cancer types including renal, colorectal, hepatic, and lung cancer [ 25 , 58 , 59 , 60 ]. It is also of great interest to investigate the value of C3F as a predictive or pharmacodynamic biomarker for various FAP-targeting treatment procedures as this could be where the use of C3F will be applied in the future.…”

FAP, CD10, and GPR77-labeled CAFs cause neoadjuvant chemotherapy resistance by inducing EMT and CSC in gastric cancer

“…This may be caused by the malignant biological behavior due to CAF-induced EMT pathway. In colorectal cancer [ 20 , 46 ], ovarian cancer [ 21 ], non-small cell lung cancer [ 17 ], high-grade invasive uroepithelial carcinoma of the bladder [ 22 ], pancreatic cancer [ 47 ], and melanoma [ 48 ], FAP + CAFs also predict a poorer prognosis for patients. Applying multiplex immunofluorescence, Sun et al found that low FAP protein expression in CAFs was associatied with a significantly better OS and DFS than high FAP protein expression in patients with GC [ 49 ].…”

“…It exhibits dipeptidyl peptidases and collagenase activities [ 15 ]. FAP + CAFs promote the progression of various cancers, including gastric cancer [ 16 ], non-small cell lung cancer [ 17 ], prostate cancer [ 18 ], esophageal adenocarcinoma [ 19 ], clear cell renal cell carcinomas [ 20 ], ovarian cancer [ 21 ], and high-grade invasive urothelial carcinoma of the bladder [ 22 ]. CD10 and GPR77 have also been found to be CAF markers.…”

FAP, CD10, GPR77-labeled CAFs cause neoadjuvant chemotherapy resistance by inducing EMT and CSC in gastric cancer

“…This may be caused by the malignant biological behavior due to CAF-induced EMT pathway. In colorectal cancer [38], ovarian cancer [44], non-small cell lung cancer [45],…”