Pablo Moreno-Ruiz1, Sara Corvigno2, Nienke C Te Grootenhuis3, Linnéa La Fleur4, Max Backman4, Carina Strell1, Artur Mezheyeuski2, Gabriele Hoelzlwimmer5, Christian Klein6, Johan Botling4, Patrick Micke4, Arne Östman7. 1. Karolinska Institutet, Cancer Center Karolinska, Department of Oncology-Pathology, Stockholm, Sweden. 2. Karolinska Institutet, Cancer Center Karolinska, Department of Oncology-Pathology, Stockholm, Sweden; Uppsala University, Genetics and Pathology, Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala, Sweden. 3. University of Groningen, University Medical Center Groningen, Department of Obstetrics and Gynecology, Groningen, The Netherlands. 4. Uppsala University, Genetics and Pathology, Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala, Sweden. 5. Roche Innovation Center Munich Penzberg, Germany. 6. Roche Innovation Center Zurich, Schlieren, Switzerland. 7. Karolinska Institutet, Cancer Center Karolinska, Department of Oncology-Pathology, Stockholm, Sweden. Electronic address: Arne.Ostman@ki.se.
Abstract
OBJECTIVES: Fibroblasts regulate tumor growth and immune surveillance. Here, we study FAP, PDGFβR and α-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, PDGFβR and α-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. α-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 α-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.
OBJECTIVES: Fibroblasts regulate tumor growth and immune surveillance. Here, we study FAP, PDGFβR and α-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, PDGFβR and α-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. α-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 α-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.