FSTL1
Follistatin-related protein 1 precursor (Follistatin-like protein 1) [FRP]
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Immune dysfunction is a strong factor in the resistance of cancer to treatment. Blocking immune checkpoint pathways is a promising approach to improve anti-tumor immunity, but the clinical efficacies are still limited. We previously identified follistatin-like 1 (FSTL1) as a determinant of immune dysfunction mediated by mesenchymal stromal/stem cells (MSCs) and immunoregulatory cells. Here, we demonstrate that blocking FSTL1 but not immune checkpoint pathways significantly suppresses cancer progression and metastasis in several mouse tumor models with increased MSCs. Expression of DIP2A (the receptor of FSTL1) in tumor cells is critical for FSTL1-induced immunoresistance. FSTL1/DIP2A co-positivity in tumor tissues correlates with poor prognosis in NSCLC patients. Thus, breaking the FSTL1-DIP2A axis may be a useful strategy for successfully inducing anti-tumor immunity.
MeSH Terms
- Animals
- Carcinoma, Non-Small-Cell Lung
- Carrier Proteins
- Case-Control Studies
- Cell Line, Tumor
- Cell Movement
- Cell Proliferation
- Disease Progression
- Female
- Follistatin-Related Proteins
- Gene Expression Regulation, Neoplastic
- Humans
- Immunity, Innate
- Lung Neoplasms
- Male
- Mesenchymal Stem Cells
- Mice
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Nuclear Proteins
- Prognosis
- RNA, Small Interfering
- Signal Transduction
- Survival Analysis
- Tumor Burden
- Xenograft Model Antitumor Assays
Keywords
- FSTL1
- aging
- antibody
- cancer metastasis
- immune checkpoint
- immune exhaustion
- immunosuppression
- lung cancer
- mesenchymal stromal/stem cells
Vitamin D is associated with lung health in epidemiologic studies, but mechanisms mediating observed associations are poorly understood. This study explores mechanisms for an effect of vitamin D in lung through an in vivo gene expression study, an expression quantitative trait loci (eQTL) analysis in lung tissue, and a population-based cohort study of sequence variants. Microarray analysis investigated the association of gene expression in small airway epithelial cells with serum 25(OH)D in adult non-smokers. Sequence variants in candidate genes identified by the microarray were investigated in a lung tissue eQTL database, and also in relation to cross-sectional pulmonary function in the Health, Aging, and Body Composition (Health ABC) study, stratified by race, with replication in the Framingham Heart Study (FHS). 13 candidate genes had significant differences in expression by serum 25(OH)D (nominal p < 0.05), and a genome-wide significant eQTL association was detected for SGPP2. In Health ABC, SGPP2 SNPs were associated with FEV1 in both European- and African-Americans, and the gene-level association was replicated in European-American FHS participants. SNPs in 5 additional candidate genes (DAPK1, FSTL1, KAL1, KCNS3, and RSAD2) were associated with FEV1 in Health ABC participants. SGPP2, a sphingosine-1-phosphate phosphatase, is a novel vitamin D-responsive gene associated with lung function. The identified associations will need to be followed up in further studies.
MeSH Terms
- African Americans
- Aged
- Aging
- Body Composition
- Cohort Studies
- Epithelial Cells
- European Continental Ancestry Group
- Female
- Forced Expiratory Volume
- Humans
- Lung
- Male
- Membrane Proteins
- Oligonucleotide Array Sequence Analysis
- Phenotype
- Phosphoric Monoester Hydrolases
- Polymorphism, Single Nucleotide
- Quantitative Trait Loci
- Respiratory Function Tests
- Vitamin D