Peripheral cytokine as a pan-cancer predictor for immunotherapy with anti-PD-1/PD-L1 antibody.

Abstract

e15044 Background: Currently, only a small proportion of cancer patients may benefit from anti-PD-1/PD-L1 immune checkpoint inhibition (ICI), suggesting an urgent need for effective biomarkers. Due to the limited accessibility and heterogeneity of the tissue samples in advanced cancer, predictors as cytokines in the peripheral immune system revealed distinct advantages. Methods: Plasma samples were collected before anti-PD-L1/PD-L1 treatment in two subsets of patients, which comprises 21 esophageal squamous cell cancer (ESCC) patients in the discovery cohort and 61 pan-cancer cases in the validation cohort. A total of 59 immunological factors including cytokines, chemokines, and checkpoints were measured by using a Luminex immunoassay kit. Moreover, tumor infiltrating lymphocytes (TILs) were analyzed using multiplex immunohistochemistry (mIHC) in a subset of tissue samples from the combined cohort. Results: In the discovery cohort of ESCC patients, multiplex Luminex profiling data revealed that soluble PD-L1 and C-C motif chemokine 5 (CCL5/RANTES) were significantly upregulated in patients with clinic benefit at baseline. We therefore tested the predictive and prognostic value of the two peripheral factors, along with their combined signature, “the 2-cytokine signature”. In specific, the signature-high subgroups displayed remarkably increased disease control rate (DCR) and prolonged survival, versus that of the lower subgroups (p < 0.05 for all comparison). More importantly, in the pan-cancer validation cohort, the three signatures exhibited a strong predictive value as well (PD-L1, AUC = 0.71; CCL5/RANTES, AUC = 0.71; the 2-cytokine signature, AUC = 0.72; p < 0.05 for all comparison). Notably, the 2-cytokine signature revealed significant stratification power for overall survival (HR = 0.431, p < 0.05) and progression free survival (HR = 0.423, p < 0.01). Intriguingly, further quantitative analysis of the local tumor microenvironment by mIHC assays revealed a positive correlation between the levels of the 2-cytokine signature and NK cell infiltration. Conclusions: A combined peripheral signature comprising CCL5/RANTES and soluble PD-L1 appears to be an effective pan-cancer biomarker to identify patients who may benefit from anti-PD-1/PD-L1 monotherapy. Further analysis indicated a link between higher peripheral signature and enrichment of NK cells in the local microenvironment. Therefore, peripheral immunological features may play an essential role in guiding patient selection for ICI immunotherapy.