Soluble HLA-G expression levels and HLA-G/irinotecan association in metastatic colorectal cancer treated with irinotecan-based strategy

Lucia Scarabel,Sara Fortuna,Marica Garziera,Silvano Geremia,Giuseppe Toffoli,Fioretta Asaro

doi:10.1038/s41598-020-65424-z

Abstract

We here explore the soluble Human Leukocyte Antigen-G (sHLA-G) expression level as clinical biomarker in metastatic colorectal cancer (mCRC). To this aim the sHLA-G protein was measured in plasma samples of 40 patients with mCRC treated with the FOLFIRI (irinotecan (CPT-11) plus 5-fluorouracil (5-FU) and leucovorin (LV)) regimen. The results suggest a link between HLA-G levels and irinotecan (CPT-11) pharmacokinetic, leading to hypothesize a molecular interaction between sHLA-G and CPT-11. This interaction was confirmed experimentally by fluorescence spectroscopy. HLA-G is known to exist in a number of polymorphs that affect both the protein expression levels and its peptide-binding cleft. The interaction between HLA-G polymorphs and CPT-11 was explored by means of computational modelling, confirming the hypothesis that CPT-11 could actually target the peptide binding cleft of the most common HLA-G polymorphs.

Highlights

We here explore the soluble Human Leukocyte Antigen-G expression level as clinical biomarker in metastatic colorectal cancer
Untreated plasma and blood samples collected from 40 patients with metastatic colorectal cancer (mCRC) prior to administration of FOLFIRI (irinotecan (CPT-11) plus 5-fluorouracil (5-FU) and leucovorin (LV)) regimen, were considered for this analysis
Based on the possible role of the soluble Human Leukocyte Antigen-G (sHLA-G) plasmatic level in patients with mCRC treated with first-line FOLFIRI regimen, we further investigated the possible correlation between sHLA-G levels and pharmacokinetic parameters (PK) previously reported by our group[43] CPT-11 AUC, SN38 AUC, SN38 glucuronide (SN38G), GR and BI

Summary

Introduction

We here explore the soluble Human Leukocyte Antigen-G (sHLA-G) expression level as clinical biomarker in metastatic colorectal cancer (mCRC). The clinical relevance of sHLA-G expression has recently suggested that a stratification based on sHLA-G levels could be an independent predictive and prognostic factor for patients with colorectal cancer (CRC) because its presence could alter the TILs interaction and the immune system response[10]. These patients are often administered with irinotecan (CPT-11) as part of their therapy. This exemplifies one of the peculiarities of the non-classical HLA-G functions

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Conclusion