Paper - Review

DOI: 10.1136/jitc-2020-001458

Abstract

Background

❗: Some sarcomas
→ respond → to immune checkpoint inhibition
❓: Predictive biomarkers
→ are unknown

Analyzed
→ tumor DNA methylation profiles
→ 1⃣ in relation → to immunological parameters 2⃣ in response → to anti-PD-1 immune check inhibitor (ICI) therapy
← in patients with sarcoma

Patients and methods

Retrospectively identified adult patients
← who had received anti-PD-1 ICI therapy
→ for recurrent sarcoma ← in two independent centers

Performed
→ 1⃣ blinded radiological response evaluation ← according to iRECIST
→ 2⃣ tumor DNA methylation profiling of > 850K probes ← using Infinium MethylationEPIC microarrays
→ 3⃣ analysis of tumor-infiltrating immune cell subset & intra-tumoral expression of (immune checkpoint molecules) ← using immuno-histochemistry
→ 4⃣ evaluation of blood-based systemic inflammation scores

Response → to anti-PD-1 therapy
→ was (1⃣ bioinformatically 2⃣ statistically) correlated
← with 1⃣ DNA methylation profiles 2⃣ immunological data

Results

35 patients
→ were included ← in this study

The objective response rate
→ to anti-PD-1 ICI therapy
→ was 22.9% ← with complete responses ← in 3 / 35
← with partial responses ← in 5 / 35

2,435 differentially methylated CpG sites
→ were identified

Clustering of sarcoma samples
← based on these DMPs
→ revealed two main clusters
→ 1⃣ methylation cluster 1 ← consisted of 73% responders
→ 2⃣ methylation cluster 2 ← contained only non-responders → to anti-PD-1 ICI

Median progression-free survival
← from anti-PD-1 therapy
→ start of 1⃣ MC1 2⃣ MC2 patients
→ was 16.5 & 1.9 months

Median overall survival
← of these patients
→ was 34.4 month & 8.0 months

The most prominent DNA methylation differences
→ were found ← in pathways implicated
← in 1⃣ Rap1 signaling 2⃣ focal adhesion 3⃣ adherens junction PI3K-Akt signaling 4⃣ ECM-receptor interactions

Conclusions

Tumor DNA methylation profiles
→ may serves ← as a predictive marker
→ for response to anti-PD-1 ICI therapy ← in sarcoma

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