Increased interleukin-6/C-reactive protein levels are associated with the upregulation of the adenosine pathway and serve as potential markers of therapeutic resistance to immune checkpoint inhibitor-based therapies in non-small cell lung cancer
© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ..
BACKGROUND: Systemic immune activation, hallmarked by C-reactive protein (CRP) and interleukin-6 (IL-6), can modulate antitumor immune responses. In this study, we evaluated the role of IL-6 and CRP in the stratification of patients with non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs). We also interrogated the underlying immunosuppressive mechanisms driven by the IL-6/CRP axis.
METHODS: In cohort A (n=308), we estimated the association of baseline CRP with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) in patients with NSCLC treated with ICIs alone or with chemo-immunotherapy (Chemo-ICI). Baseline tumor bulk RNA sequencing (RNA-seq) of lung adenocarcinomas (LUADs) treated with pembrolizumab (cohort B, n=59) was used to evaluate differential expression of purine metabolism, as well as correlate IL-6 expression with PFS. CODEFACS approach was applied to deconvolve cohort B to characterize the tumor microenvironment by reconstructing the cell-type-specific transcriptome from bulk expression. Using the LUAD cohort from The Cancer Genome Atlas (TCGA) we explored the correlation between IL-6 expression and adenosine gene signatures. In a third cohort (cohort C, n=18), plasma concentrations of CRP, adenosine 2a receptor (A2aR), and IL-6 were measured using ELISA.
RESULTS: In cohort A, 67.2% of patients had a baseline CRP≥10 mg/L (CRP-H). Patients with CRP-H achieved shorter OS (8.6 vs 14.8 months; p=0.006), shorter PFS (3.3 vs 6.6 months; p=0.013), and lower ORR (24.7% vs 46.3%; p=0.015). After adjusting for relevant clinical variables, CRP-H was confirmed as an independent predictor of increased risk of death (HR 1.51, 95% CI: 1.09 to 2.11) and lower probability of achieving disease response (OR 0.34, 95% CI: 0.13 to 0.89). In cohort B, RNA-seq analysis demonstrated higher IL-6 expression on tumor cells of non-responders, along with a shorter PFS (p<0.05) and enrichment of the purinergic pathway. Within the TCGA LUAD cohort, tumor IL-6 expression strongly correlated with the adenosine signature (R=0.65; p<2.2e-16). Plasma analysis in cohort C demonstrated that CRP-H patients had a greater median baseline level of A2aR (6.0 ng/mL vs 1.3 ng/mL; p=0.01).
CONCLUSIONS: This study demonstrates CRP as a readily available blood-based prognostic biomarker in ICI-treated NSCLC. Additionally, we elucidate a potential link of the CRP/IL-6 axis with the immunosuppressive adenosine signature pathway that could drive inferior outcomes to ICIs in NSCLC and also offer novel therapeutic avenues.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:11 |
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| Enthalten in: |
Journal for immunotherapy of cancer - 11(2023), 10 vom: 10. Okt. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Naqash, Abdul Rafeh [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 30.10.2023 Date Revised 10.02.2024 published: Print Citation Status MEDLINE |
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| doi: |
10.1136/jitc-2023-007310 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM363452397 |
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| 100 | 1 | |a Naqash, Abdul Rafeh |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Increased interleukin-6/C-reactive protein levels are associated with the upregulation of the adenosine pathway and serve as potential markers of therapeutic resistance to immune checkpoint inhibitor-based therapies in non-small cell lung cancer |
| 264 | 1 | |c 2023 | |
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| 500 | |a Date Revised 10.02.2024 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ. | ||
| 520 | |a BACKGROUND: Systemic immune activation, hallmarked by C-reactive protein (CRP) and interleukin-6 (IL-6), can modulate antitumor immune responses. In this study, we evaluated the role of IL-6 and CRP in the stratification of patients with non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs). We also interrogated the underlying immunosuppressive mechanisms driven by the IL-6/CRP axis | ||
| 520 | |a METHODS: In cohort A (n=308), we estimated the association of baseline CRP with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) in patients with NSCLC treated with ICIs alone or with chemo-immunotherapy (Chemo-ICI). Baseline tumor bulk RNA sequencing (RNA-seq) of lung adenocarcinomas (LUADs) treated with pembrolizumab (cohort B, n=59) was used to evaluate differential expression of purine metabolism, as well as correlate IL-6 expression with PFS. CODEFACS approach was applied to deconvolve cohort B to characterize the tumor microenvironment by reconstructing the cell-type-specific transcriptome from bulk expression. Using the LUAD cohort from The Cancer Genome Atlas (TCGA) we explored the correlation between IL-6 expression and adenosine gene signatures. In a third cohort (cohort C, n=18), plasma concentrations of CRP, adenosine 2a receptor (A2aR), and IL-6 were measured using ELISA | ||
| 520 | |a RESULTS: In cohort A, 67.2% of patients had a baseline CRP≥10 mg/L (CRP-H). Patients with CRP-H achieved shorter OS (8.6 vs 14.8 months; p=0.006), shorter PFS (3.3 vs 6.6 months; p=0.013), and lower ORR (24.7% vs 46.3%; p=0.015). After adjusting for relevant clinical variables, CRP-H was confirmed as an independent predictor of increased risk of death (HR 1.51, 95% CI: 1.09 to 2.11) and lower probability of achieving disease response (OR 0.34, 95% CI: 0.13 to 0.89). In cohort B, RNA-seq analysis demonstrated higher IL-6 expression on tumor cells of non-responders, along with a shorter PFS (p<0.05) and enrichment of the purinergic pathway. Within the TCGA LUAD cohort, tumor IL-6 expression strongly correlated with the adenosine signature (R=0.65; p<2.2e-16). Plasma analysis in cohort C demonstrated that CRP-H patients had a greater median baseline level of A2aR (6.0 ng/mL vs 1.3 ng/mL; p=0.01) | ||
| 520 | |a CONCLUSIONS: This study demonstrates CRP as a readily available blood-based prognostic biomarker in ICI-treated NSCLC. Additionally, we elucidate a potential link of the CRP/IL-6 axis with the immunosuppressive adenosine signature pathway that could drive inferior outcomes to ICIs in NSCLC and also offer novel therapeutic avenues | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Adenosine | |
| 650 | 4 | |a Immune Checkpoint Inhibitors | |
| 650 | 4 | |a Inflammation | |
| 650 | 4 | |a Lung Neoplasms | |
| 650 | 4 | |a Tumor Microenvironment | |
| 650 | 7 | |a Adenosine |2 NLM | |
| 650 | 7 | |a K72T3FS567 |2 NLM | |
| 650 | 7 | |a C-Reactive Protein |2 NLM | |
| 650 | 7 | |a 9007-41-4 |2 NLM | |
| 650 | 7 | |a Immune Checkpoint Inhibitors |2 NLM | |
| 650 | 7 | |a Interleukin-6 |2 NLM | |
| 650 | 7 | |a CRP protein, human |2 NLM | |
| 650 | 7 | |a IL6 protein, human |2 NLM | |
| 700 | 1 | |a McCallen, Justin D |e verfasserin |4 aut | |
| 700 | 1 | |a Mi, Emma |e verfasserin |4 aut | |
| 700 | 1 | |a Iivanainen, Sanna |e verfasserin |4 aut | |
| 700 | 1 | |a Marie, Mona A |e verfasserin |4 aut | |
| 700 | 1 | |a Gramenitskaya, Daria |e verfasserin |4 aut | |
| 700 | 1 | |a Clark, James |e verfasserin |4 aut | |
| 700 | 1 | |a Koivunen, Jussi Pekka |e verfasserin |4 aut | |
| 700 | 1 | |a Macherla, Shravanti |e verfasserin |4 aut | |
| 700 | 1 | |a Jonnalagadda, Sweta |e verfasserin |4 aut | |
| 700 | 1 | |a Polsani, Shanker |e verfasserin |4 aut | |
| 700 | 1 | |a Jiwani, Rahim Ali |e verfasserin |4 aut | |
| 700 | 1 | |a Hafiz, Maida |e verfasserin |4 aut | |
| 700 | 1 | |a Muzaffar, Mahvish |e verfasserin |4 aut | |
| 700 | 1 | |a Brunetti, Leonardo |e verfasserin |4 aut | |
| 700 | 1 | |a Stroud, Chipman R G |e verfasserin |4 aut | |
| 700 | 1 | |a Walker, Paul R |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Kun |e verfasserin |4 aut | |
| 700 | 1 | |a Chung, Youngmin |e verfasserin |4 aut | |
| 700 | 1 | |a Ruppin, Eytan |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Se-Hoon |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Li V |e verfasserin |4 aut | |
| 700 | 1 | |a Pinato, David J |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Joo Sang |e verfasserin |4 aut | |
| 700 | 1 | |a Cortellini, Alessio |e verfasserin |4 aut | |
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