BACKGROUND: Adjuvant immune checkpoint blockade (ICB) following chemoradiotherapy and adding ICB to chemotherapy have been key advances for stages III-IV non-small cell lung cancer (NSCLC) treatment. However, known biomarkers like PD-L1 are not consistently indicative of ICB response. Other markers within the tumor immune microenvironment (TIME) may better reflect ICB response and/or resistance mechanisms, but an understanding of how TIMEs differ between stage III and IV NSCLC has not been explored. METHODS: Real-world data from unresectable, stage III-IV, non-squamous, pretreatment NSCLCs (stage III n = 106, stage IV n = 285) were retrospectively analyzed. PD-L1 immunohistochemistry (IHC) was compared to CD274 gene expression. Then, differential gene expression levels, pathway enrichment, and immune infiltrate between stages were calculated from whole-transcriptome RNA-seq. Analyses were stratified by EGFR status. RESULTS: PD-L1 IHC and CD274 expression in tumor cells were highly correlated (n = 295, P < 2.2e-16, ⍴ = 0.74). CTLA4 expression was significantly increased in stage III tumors (P = 1.32e-04), while no differences were observed for other ICB-related genes. Metabolic pathway activity was significantly enriched in stage IV tumors (P = 0.004), whereas several immune-related KEGG pathways were enriched in stage III. Stage IV tumors had significantly increased macrophage infiltration (P = 0.0214), and stage III tumors had a significantly higher proportion of CD4 + T cells (P = 0.017). CD4 + T cells were also relatively more abundant in EGFR-mutant tumors vs. wild-type (P = 0.0081). CONCLUSION: Directly comparing the TIMEs of stage III and IV NSCLC, these results carry implications for further studies of ICB response in non-resectable stage III NSCLC and guide further research of prognostic biomarkers and therapeutic targets.
BACKGROUND: Adjuvant immune checkpoint blockade (ICB) following chemoradiotherapy and adding ICB to chemotherapy have been key advances for stages III-IV non-small cell lung cancer (NSCLC) treatment. However, known biomarkers like PD-L1 are not consistently indicative of ICB response. Other markers within the tumor immune microenvironment (TIME) may better reflect ICB response and/or resistance mechanisms, but an understanding of how TIMEs differ between stage III and IV NSCLC has not been explored. METHODS: Real-world data from unresectable, stage III-IV, non-squamous, pretreatment NSCLCs (stage III n = 106, stage IV n = 285) were retrospectively analyzed. PD-L1 immunohistochemistry (IHC) was compared to CD274 gene expression. Then, differential gene expression levels, pathway enrichment, and immune infiltrate between stages were calculated from whole-transcriptome RNA-seq. Analyses were stratified by EGFR status. RESULTS: PD-L1 IHC and CD274 expression in tumor cells were highly correlated (n = 295, P < 2.2e-16, ⍴ = 0.74). CTLA4 expression was significantly increased in stage III tumors (P = 1.32e-04), while no differences were observed for other ICB-related genes. Metabolic pathway activity was significantly enriched in stage IV tumors (P = 0.004), whereas several immune-related KEGG pathways were enriched in stage III. Stage IV tumors had significantly increased macrophage infiltration (P = 0.0214), and stage III tumors had a significantly higher proportion of CD4 + T cells (P = 0.017). CD4 + T cells were also relatively more abundant in EGFR-mutant tumors vs. wild-type (P = 0.0081). CONCLUSION: Directly comparing the TIMEs of stage III and IV NSCLC, these results carry implications for further studies of ICB response in non-resectable stage III NSCLC and guide further research of prognostic biomarkers and therapeutic targets.
Authors: Jhanelle E Gray; Augusto Villegas; Davey Daniel; David Vicente; Shuji Murakami; Rina Hui; Takayasu Kurata; Alberto Chiappori; Ki Hyeong Lee; Byoung Chul Cho; David Planchard; Luis Paz-Ares; Corinne Faivre-Finn; Johan F Vansteenkiste; David R Spigel; Catherine Wadsworth; Maria Taboada; Phillip A Dennis; Mustafa Özgüroğlu; Scott J Antonia Journal: J Thorac Oncol Date: 2019-10-14 Impact factor: 15.609
Authors: David E Gerber; James J Urbanic; Corey Langer; Chen Hu; I-Fen Chang; Bo Lu; Benjamin Movsas; Robert Jeraj; Walter J Curran; Jeffrey D Bradley Journal: Clin Lung Cancer Date: 2016-10-26 Impact factor: 4.785
Authors: S Peters; E Felip; U Dafni; C Belka; M Guckenberger; A Irigoyen; E Nadal; A Becker; H Vees; M Pless; A Martinez-Marti; A Tufman; M Lambrecht; N Andratschke; A C Piguet; M Kassapian; H Roschitzki-Voser; M Rabaglio-Poretti; R A Stahel; J Vansteenkiste; D De Ruysscher Journal: Lung Cancer Date: 2019-05-03 Impact factor: 5.705
Authors: Patrick M Forde; Jonathan Spicer; Shun Lu; Mariano Provencio; Tetsuya Mitsudomi; Mark M Awad; Enriqueta Felip; Stephen R Broderick; Julie R Brahmer; Scott J Swanson; Keith Kerr; Changli Wang; Tudor-Eliade Ciuleanu; Gene B Saylors; Fumihiro Tanaka; Hiroyuki Ito; Ke-Neng Chen; Moishe Liberman; Everett E Vokes; Janis M Taube; Cecile Dorange; Junliang Cai; Joseph Fiore; Anthony Jarkowski; David Balli; Mark Sausen; Dimple Pandya; Christophe Y Calvet; Nicolas Girard Journal: N Engl J Med Date: 2022-04-11 Impact factor: 176.079