Chromogenic Multiplex Immunohistochemistry Reveals Modulation of the Immune Microenvironment Associated with Survival in Elderly Patients with Lung Adenocarcinoma.

Marius Ilié,Emmanuel Chamorey,Renaud Schiappa,Olivier Guérin,Charlotte Cohen,Jean-François Pomerol,Charles-Hugo Marquette,Véronique Hofman,Mélanie Beaulande,Saima Ben Hadj,Elodie Long-Mira,Paul Hofman,Catherine Butori,Sylvie Leroy,Gilles Erb,Jérôme Mouroux,Sandra Lassalle

doi:10.3390/cancers10090326

Abstract

With underrepresentation of elderly patients with lung adenocarcinoma (LADC) in anti-PD-1/PD-L1 clinical trials, better understanding of the interplay of PD-L1 and tumor-associated immune cells (TAICs) could assist clinicians in stratifying these patients for immunotherapy. One hundred and one patients with LADCs, stratified by age, were included for analysis of PD-L1 expression and density of TAICs expressing CD4, CD8, and CD33, by using multiplex chromogenic immunohistochemistry (IHC) assays and automated digital quantification. The CD4+/CD8+ ratio was significantly higher in elderly patients. In patients <75 years, the density of CD4+, CD8+, and PD-L1 in TAICs showed a positive significant correlation with PD-L1 expression in tumor cells (TCs), while a lower correlation was observed in the elderly population. In the latter, a high CD4+/CD8+ ratio, and combined PD-L1 expression ≥1% TCs with a low CD8+ density, low CD33+ density, and a high CD4+ density correlated to worse overall survival. We identified differences according to age in the CD4+/CD8+ ratio and in correlation between PD-L1 expression and the density of TAICs in LADC patients. Distinct groups of tumor microenvironments had an impact on the OS of elderly patients with LADC.

Highlights

Therapies targeting programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) have demonstrated clinical improvement for some patients with immunogenic cancer types, including advanced lung adenocarcinoma (LADC) [1]
A comparative evaluation of the PD-L1 expression on tumor cells (TCs) and tumor-associated immune cells (TAICs) assessed by standard IHC
Upper panel: strong PD-L1 expression observed in the same LADC case adenocarcinoma (LADC)

Summary

Introduction

Therapies targeting programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) have demonstrated clinical improvement for some patients with immunogenic cancer types, including advanced lung adenocarcinoma (LADC) [1]. PD-L1 expression in tumors or tumor-associated immune cells (TAICs) assessed by immunohistochemistry (IHC) is the predictive biomarker evaluated in clinical trials, and is currently used in the clinical setting to select patients who may benefit from these therapies [2]. LADC, some patients do not benefit from this therapy, and the majority of those who respond develop resistance [3]. In this context, intense research is focusing on improving patient stratification for PD-1/PD-L1 immune-based therapy by optimizing the assessment of PD-L1 expression, and by identifying multiparametric, integrated immune-based biomarkers on formalin-fixed paraffin-embedded (FFPE) tissue sections [4,5,6]. No randomized phase III trials on the efficacy of PD-1/PD-L1 inhibitors in elderly patients with advanced non-small cell lung carcinoma (NSCLC) are available

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