Poor clinical outcomes and immunoevasive contexture in gastric cancer patients bearing p16 high phenotype.

Abstract

The aberrant p16^INK4a expression has been identified in gastric cancer (GC). However, the staining pattern of p16^INK4a and its associations with clinical outcomes and immune contexture remains obscure. This study involved two patient cohorts, the Zhongshan Hospital (ZSHS, n = 443) and Samsung Medical Center (SMC, n = 43) cohort. Patients were divided into p16^INK4a loss, wild-type (WT), and overexpression (OE) subgroups. The patient characteristics, overall survival (OS), response to adjuvant chemotherapy (ACT) and immune checkpoint inhibitor (ICI) treatment, as well as tumor immune contexture were investigated in each subgroup. In ZSHS cohort, 90 of 443 (20.3%) patients with p16^INK4a OE gastric cancer, who were characterized by advanced pT stage (p = .011), higher Ki-67 (p < .001), Rb loss (p < .001), and CCNE1 OE incidence (p < .001). Patients with p16^INK4a OE tumors presented with poor OS (ZSHS: OE vs. WT, p = .004; specific in MSI tumors, p = .019), inferior responsiveness to ACT (OE vs. WT, p = .011; specific in MSI tumors, p = .024) and ICI (OE vs. WT, p = .045; specific in programmed death-ligand 1 CPS ≥1 and CIN tumors, p = .027 and p = .032, respectively), whereas patients with p16^INK4a loss and WT gastric cancer exhibited comparable clinical outcomes (loss vs. WT: OS, p = .424; ACT, p = .834; ICI, p = .223). Moreover, p16^INK4a OE gastric cancer was associated with lower antitumor M1, neutrophils, and CD8⁺T cells infiltration and higher pro-tumor TGF-β, CD73, and IDO expression. This study identified a specific triple classification staining pattern of p16^INK4a expression in GC, and demonstrated that p16^INK4a OE was associated with poor clinical outcomes and evasive immune contexture.