Introduction: Immunotherapy is firmly established as a treatment regimen in various solid
tumors, driven by its exceptional benefits observed in a select group of patients. Despite
widespread use of immune checkpoint blockade (ICB) across diverse solid tumors, the quest
for a clinically informative biomarker for long-term benefit ...»»»»
Introduction: Immunotherapy is firmly established as a treatment regimen in various solid
tumors, driven by its exceptional benefits observed in a select group of patients. Despite
widespread use of immune checkpoint blockade (ICB) across diverse solid tumors, the quest
for a clinically informative biomarker for long-term benefit remains unmet.
Methods: A total of 49 metastatic NSCLC patients treated with ICB were included. Long-term
(LTR) and Short-term responders (STR) were defined as those with a response to ICB lasting
more than 24 months or less than 6 months, respectively. Longitudinal blood specimens were
collected before treatment initiation and early-on treatment (before cycle 2 – at 3rd week).
Plasma ctDNA NGS panel and serum proteomics were performed. Standard diagnostic
workup included PD-L1 immunohistochemistry and NGS in tumor tissue. Tumor tissue
RNAseq panel focused on immune related genes was performed in a subset of patients.
Results: Our analysis revealed specific characteristics of long-term patients compared with
short term benefit, namely higher PD-L1 in tumor cells (p=0.005) and higher incidence of irAEs
(p=0.001). Genomic features that associated with lack of benefit to ICB included cooccurrence
of mutations in KRAS/STK11, KRAS/KEAP1 and TP53/KMT2D (p<0.05). At a
serum proteomic level, LTR patients exhibited higher abundance of proteins related with
apoptosis (CASP8, PRKRA), chemotaxis, immune proteosome, processing of MHC class I
(S100A4, PSMD9, RNF41) and immunehomeostasis (HAVCR1, ARG1) (p<0.05 for all
proteins). In line with peripheral immunological features, transcriptional analysis of tumor
samples showed that LTR patients displayed higher levels of genes linked with T cell
recruitment/trafficking (CXCL11) and T cell effector functions (GMZB) within the tumor
microenvironment (p<0.05). Finally, a longitudinal analysis identified a set of proteins that
presented opposite dynamics in LTR compared to STR, making them interesting candidates
for treatment efficacy evaluation.
Conclusions: Our comprehensive analysis of metastatic NSCLC patients treated with ICB
has unveiled distinct clinicopathological and immunological features associated with long-term
benefit, highlighting the presence of a pre-existing antitumor immunity as a stronger predictor
of long-term benefit. These findings offer insights into potential biomarkers and therapeutic
strategies for enhancing ICB outcomes in metastatic NSCLC.
Keywords: Lung neoplasms; Immunotherapy; Long-term responders; Serum proteomics;
blood-based biomarkers.^^^^
