Stromal FAP is an independent poor prognosis marker in non-small cell lung adenocarcinoma and associated with p53 mutation

Pablo Moreno-Ruiz; Sara Corvigno; Nienke C. te Grootenhuis; Linnea La Fleur; Max Backman; Carina Strell; Artur Mezheyeuski; Gabriele Hoelzlwimmer; Christian Klein; Johan Botling; Patrick Micke; Arne Ostman

doi:10.1016/j.lungcan.2021.02.028

Stromal FAP is an independent poor prognosis marker in non-small cell lung adenocarcinoma and associated with p53 mutation

Pablo Moreno-Ruiz, Sara Corvigno, Nienke C. te Grootenhuis, Linnea La Fleur, Max Backman, Carina Strell, Artur Mezheyeuski, Gabriele Hoelzlwimmer, Christian Klein, Johan Botling, Patrick Micke, Arne Ostman^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Objectives: Fibroblasts regulate tumor growth and immune surveillance. Here, we study FAP, PDGF?R and ?-SMA fibroblast markers in a well-annotated clinical cohort of non?small-cell lung cancer (NSCLC) for analyses of associations with immune cell infiltration, mutation status and survival. Materials and Methods: A well-annotated NSCLC cohort was subjected to IHC analyses of stromal expression of FAP, PDGF?R and ?-SMA and of stromal CD8 density. Fibroblast markers-related measurements were analyzed with regard to potential associations with CD8 density, cancer genetic driver mutations, survival and PD-L1 expression in the whole NSCLC cohort and in subsets of patients. Results: High stromal FAP expression was identified as an independent poor prognostic marker in the whole study population (HR 1.481; 95 % CI, 1.012?2.167, p = 0.023) and in the histological subset of adenocarcinoma (HR 1.720; 95 % CI, 1.126?2.627, p = 0.012). Among patients with adenocarcinoma, a particularly strong association of FAP with poor survival was detected in patients with low stromal CD8 infiltration, and in other subpopulations identified by specific clinical characteristics; elderly patients, females, non-smokers and patients with normal ECOG performance status. ?-SMA expression was negatively associated with CD8 infiltration in non-smokers, but none of the fibroblast markers expression was associated with CD8 density in the whole study population. Significant associations were detected between presence of p53 mutations and high ?-SMA (p = 0.003) and FAP expression (p < 0.001). Conclusion: The study identifies FAP intensity as a candidate independent NSCLC prognostic biomarker. The study also suggests continued analyses of the relationships between genetic driver mutations and the composition of tumor stroma, as well as continued probing of marker-defined fibroblasts as NSCLC subset-specific modifiers of immune surveillance and outcome.

Original language	English
Pages (from-to)	10-19
Number of pages	10
Journal	Lung Cancer
Volume	155
DOIs	https://doi.org/10.1016/j.lungcan.2021.02.028
Publication status	Published - May-2021

Keywords

FAP
Fibroblast
Stroma
PDGF?R
?-SMA
Biomarkers
CD8
Non?small-cell lung cancer
CANCER-ASSOCIATED FIBROBLASTS
IMPACT
CLASSIFICATION
SURVIVAL
TUMORS
ROS

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Stromal FAP is an independent poor prognosis marker in non-small cell lung adenocarcinoma and associated with p53 mutationFinal publisher's version, 4.89 MBLicence: CC BY

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Moreno-Ruiz, P., Corvigno, S., te Grootenhuis, N. C., La Fleur, L., Backman, M., Strell, C., Mezheyeuski, A., Hoelzlwimmer, G., Klein, C., Botling, J., Micke, P., & Ostman, A. (2021). Stromal FAP is an independent poor prognosis marker in non-small cell lung adenocarcinoma and associated with p53 mutation. Lung Cancer, 155, 10-19. https://doi.org/10.1016/j.lungcan.2021.02.028

@article{300f9f258fb3432a91b9e8c2c0375939,

title = "Stromal FAP is an independent poor prognosis marker in non-small cell lung adenocarcinoma and associated with p53 mutation",

abstract = "Objectives: Fibroblasts regulate tumor growth and immune surveillance. Here, we study FAP, PDGF?R and ?-SMA fibroblast markers in a well-annotated clinical cohort of non?small-cell lung cancer (NSCLC) for analyses of associations with immune cell infiltration, mutation status and survival. Materials and Methods: A well-annotated NSCLC cohort was subjected to IHC analyses of stromal expression of FAP, PDGF?R and ?-SMA and of stromal CD8 density. Fibroblast markers-related measurements were analyzed with regard to potential associations with CD8 density, cancer genetic driver mutations, survival and PD-L1 expression in the whole NSCLC cohort and in subsets of patients. Results: High stromal FAP expression was identified as an independent poor prognostic marker in the whole study population (HR 1.481; 95 % CI, 1.012?2.167, p = 0.023) and in the histological subset of adenocarcinoma (HR 1.720; 95 % CI, 1.126?2.627, p = 0.012). Among patients with adenocarcinoma, a particularly strong association of FAP with poor survival was detected in patients with low stromal CD8 infiltration, and in other subpopulations identified by specific clinical characteristics; elderly patients, females, non-smokers and patients with normal ECOG performance status. ?-SMA expression was negatively associated with CD8 infiltration in non-smokers, but none of the fibroblast markers expression was associated with CD8 density in the whole study population. Significant associations were detected between presence of p53 mutations and high ?-SMA (p = 0.003) and FAP expression (p < 0.001). Conclusion: The study identifies FAP intensity as a candidate independent NSCLC prognostic biomarker. The study also suggests continued analyses of the relationships between genetic driver mutations and the composition of tumor stroma, as well as continued probing of marker-defined fibroblasts as NSCLC subset-specific modifiers of immune surveillance and outcome.",

keywords = "FAP, Fibroblast, Stroma, PDGF?R, ?-SMA, Biomarkers, CD8, Non?small-cell lung cancer, CANCER-ASSOCIATED FIBROBLASTS, IMPACT, CLASSIFICATION, SURVIVAL, TUMORS, ROS",

author = "Pablo Moreno-Ruiz and Sara Corvigno and {te Grootenhuis}, {Nienke C.} and {La Fleur}, Linnea and Max Backman and Carina Strell and Artur Mezheyeuski and Gabriele Hoelzlwimmer and Christian Klein and Johan Botling and Patrick Micke and Arne Ostman",

year = "2021",

month = may,

doi = "10.1016/j.lungcan.2021.02.028",

language = "English",

volume = "155",

pages = "10--19",

journal = "Lung Cancer",

issn = "0169-5002",

publisher = "ELSEVIER IRELAND LTD",

}

Moreno-Ruiz, P, Corvigno, S, te Grootenhuis, NC, La Fleur, L, Backman, M, Strell, C, Mezheyeuski, A, Hoelzlwimmer, G, Klein, C, Botling, J, Micke, P & Ostman, A 2021, 'Stromal FAP is an independent poor prognosis marker in non-small cell lung adenocarcinoma and associated with p53 mutation', Lung Cancer, vol. 155, pp. 10-19. https://doi.org/10.1016/j.lungcan.2021.02.028

TY - JOUR

T1 - Stromal FAP is an independent poor prognosis marker in non-small cell lung adenocarcinoma and associated with p53 mutation

AU - Moreno-Ruiz, Pablo

AU - Corvigno, Sara

AU - te Grootenhuis, Nienke C.

AU - La Fleur, Linnea

AU - Backman, Max

AU - Strell, Carina

AU - Mezheyeuski, Artur

AU - Hoelzlwimmer, Gabriele

AU - Klein, Christian

AU - Botling, Johan

AU - Micke, Patrick

AU - Ostman, Arne

PY - 2021/5

Y1 - 2021/5

N2 - Objectives: Fibroblasts regulate tumor growth and immune surveillance. Here, we study FAP, PDGF?R and ?-SMA fibroblast markers in a well-annotated clinical cohort of non?small-cell lung cancer (NSCLC) for analyses of associations with immune cell infiltration, mutation status and survival. Materials and Methods: A well-annotated NSCLC cohort was subjected to IHC analyses of stromal expression of FAP, PDGF?R and ?-SMA and of stromal CD8 density. Fibroblast markers-related measurements were analyzed with regard to potential associations with CD8 density, cancer genetic driver mutations, survival and PD-L1 expression in the whole NSCLC cohort and in subsets of patients. Results: High stromal FAP expression was identified as an independent poor prognostic marker in the whole study population (HR 1.481; 95 % CI, 1.012?2.167, p = 0.023) and in the histological subset of adenocarcinoma (HR 1.720; 95 % CI, 1.126?2.627, p = 0.012). Among patients with adenocarcinoma, a particularly strong association of FAP with poor survival was detected in patients with low stromal CD8 infiltration, and in other subpopulations identified by specific clinical characteristics; elderly patients, females, non-smokers and patients with normal ECOG performance status. ?-SMA expression was negatively associated with CD8 infiltration in non-smokers, but none of the fibroblast markers expression was associated with CD8 density in the whole study population. Significant associations were detected between presence of p53 mutations and high ?-SMA (p = 0.003) and FAP expression (p < 0.001). Conclusion: The study identifies FAP intensity as a candidate independent NSCLC prognostic biomarker. The study also suggests continued analyses of the relationships between genetic driver mutations and the composition of tumor stroma, as well as continued probing of marker-defined fibroblasts as NSCLC subset-specific modifiers of immune surveillance and outcome.

AB - Objectives: Fibroblasts regulate tumor growth and immune surveillance. Here, we study FAP, PDGF?R and ?-SMA fibroblast markers in a well-annotated clinical cohort of non?small-cell lung cancer (NSCLC) for analyses of associations with immune cell infiltration, mutation status and survival. Materials and Methods: A well-annotated NSCLC cohort was subjected to IHC analyses of stromal expression of FAP, PDGF?R and ?-SMA and of stromal CD8 density. Fibroblast markers-related measurements were analyzed with regard to potential associations with CD8 density, cancer genetic driver mutations, survival and PD-L1 expression in the whole NSCLC cohort and in subsets of patients. Results: High stromal FAP expression was identified as an independent poor prognostic marker in the whole study population (HR 1.481; 95 % CI, 1.012?2.167, p = 0.023) and in the histological subset of adenocarcinoma (HR 1.720; 95 % CI, 1.126?2.627, p = 0.012). Among patients with adenocarcinoma, a particularly strong association of FAP with poor survival was detected in patients with low stromal CD8 infiltration, and in other subpopulations identified by specific clinical characteristics; elderly patients, females, non-smokers and patients with normal ECOG performance status. ?-SMA expression was negatively associated with CD8 infiltration in non-smokers, but none of the fibroblast markers expression was associated with CD8 density in the whole study population. Significant associations were detected between presence of p53 mutations and high ?-SMA (p = 0.003) and FAP expression (p < 0.001). Conclusion: The study identifies FAP intensity as a candidate independent NSCLC prognostic biomarker. The study also suggests continued analyses of the relationships between genetic driver mutations and the composition of tumor stroma, as well as continued probing of marker-defined fibroblasts as NSCLC subset-specific modifiers of immune surveillance and outcome.

KW - FAP

KW - Fibroblast

KW - Stroma

KW - PDGF?R

KW - ?-SMA

KW - Biomarkers

KW - CD8

KW - Non?small-cell lung cancer

KW - CANCER-ASSOCIATED FIBROBLASTS

KW - IMPACT

KW - CLASSIFICATION

KW - SURVIVAL

KW - TUMORS

KW - ROS

U2 - 10.1016/j.lungcan.2021.02.028

DO - 10.1016/j.lungcan.2021.02.028

M3 - Article

SN - 0169-5002

VL - 155

SP - 10

EP - 19

JO - Lung Cancer

JF - Lung Cancer

ER -

Stromal FAP is an independent poor prognosis marker in non-small cell lung adenocarcinoma and associated with p53 mutation

Abstract

Keywords

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