Functional Engagement of the PD-1/PD-L1 Complex But Not PD-L1 Expression Is Highly Predictive of Patient Response to Immunotherapy in Non–Small-Cell Lung Cancer

Abstract

PURPOSE In many cancers, the expression of immunomodulatory ligands leads to immunoevasion, as exemplified by the interaction of PD-L1 with PD-1 on tumor-infiltrating lymphocytes. Profound advances in cancer treatments have come with the advent of immunotherapies directed at blocking these immuno-suppressive ligand-receptor interactions. However, although there has been success in the use of these immune checkpoint interventions, correct patient stratification for these therapies has been challenging. MATERIALS AND METHODS To address this issue of patient stratification, we have quantified the intercellular PD-1/PD-L1 interaction in formalin-fixed paraffin-embedded tumor samples from patients with non–small cell lung carcinoma, using a high-throughput automated quantitative imaging platform (quantitative functional proteomics [QF-Pro]). RESULTS The multisite blinded analysis across a cohort of 188 immune checkpoint inhibitor-treated patients demonstrated the intra- and intertumoral heterogeneity of PD-1/PD-L1 immune checkpoint engagement and notably showed no correlation between the extent of PD-1/PD-L1 interaction and PD-L1 expression. Importantly, PD-L1 expression scores used clinically to stratify patients correlated poorly with overall survival; by contrast, patients showing a high PD-1/PD-L1 interaction had significantly better responses to anti–PD-1/PD-L1 treatments, as evidenced by increased overall survival. This relationship was particularly strong in the setting of first-line treatments. CONCLUSION The functional readout of PD-1/PD-L1 interaction as a predictive biomarker for the stratification of patients with non–small-cell lung carcinoma, combined with PD-L1 expression, should significantly improve the response rates to immunotherapy. This would both capture patients excluded from checkpoint immunotherapy (high PD-1/PD-L1 interaction but low PD-L1 expression, 24% of patients) and additionally avoid treating patients who despite their high PD-L1 expression do not respond and suffer from side effects.

Anti-metabolic agent pegaspargase plus PD-1 antibody sintilimab for first-line treatment in advanced natural killer T cell lymphoma

“…The interaction between tumoral PD-L1 and PD-1 on TILs contributes to immune evasion in multiple cancers and is the key therapeutic target of anti-PD1 antibody. 18 The likelihood of response was not associated with clinical parameters and oncogenic mutations but was associated with the expression of PD-L1 and PD-1. Tumoral PD-L1 expression linked to favorable response to pegaspargase plus sintilimab treatment.…”

“…Although clinical studies report promising efficacy of PD-1 antibody in treating multiple cancers, such as lymphoma, melanoma, lung cancer, gastric cancer, breast cancer, etc, not all patients respond to treatment, encouraging further investigation on the therapeutic mechanisms and prognostic biomarkers. Tumor infiltrating lymphocytes (TIL) and tumoral PD-1 expression are potential predictors, 18 but their efficacy in NKTCL remains to be clarified. Besides, clonal expansion of T cells upon treatment indicates therapeutic response to PD-1 antibody.…”

The Tumor Immune Microenvironment Is Associated With Recurrence in Early-Stage Lung Adenocarcinoma

“…It has recently become possible to assess functional PD-1–PD-L1 interaction (reflecting the interaction between TILs and tumor cells) and to analyze spatial information, with such data being potentially more useful than IHC findings as a biomarker. 35 Fifth, our study was conducted with an Asian population treated with S-1, and its findings cannot, therefore, be generalized to white populations.…”

Differential predictive value of resident memory CD8+T cell subpopulations in non-small-cell lung cancer patients treated by immunotherapy

“…One of the limitations of this study analyzing and comparing the predictive value of subpopulations of T RM as a parameter of response to immunotherapy is that it was performed against total CD8, TCF-1 + progenitor T cells, and PD-L1, but not against markers of spatial interactions between PD-1 and PD-L1 or PD-L1 and CD8. These emerging biomarkers have also been reported to predict response to immunotherapy in NSCLC (Ghiringhelli, Bibeau et al, 2023, Sanchez-Magraner, Gumuzio et al, 2023).…”