The clinical significance of PD-L1 in advanced gastric cancer is dependent on ARID1A mutations and ATM expression

Simonetta Buglioni, Elisa Melucci, Francesca Sperati, Matteo Pallocca, Irene Terrenato, Francesca De Nicola, Frauke Goeman, Beatrice Casini, Carla Azzurra Amoreo, Enzo Gallo, Maria Grazia Diodoro, Edoardo Pescarmona, Patrizia Vici, Domenico Sergi, Laura Pizzuti, Luigi Di Lauro, Marco Mazzotta, Maddalena Barba, Maurizio Fanciulli, Ilio VitaleRuggero De Maria, Gennaro Ciliberto, Marcello Maugeri-Saccà

Research output: Contribution to journalArticlepeer-review

Abstract

Whether PD-L1 expression is associated with survival outcomes in gastric cancer (GC) is controversial. The inhibition of the PD-1/PD-L1 pathway is effective against genomically unstable tumors. Hypothesizing that also the clinical significance of PD-L1 might be dependent on the activation of molecular circuits ensuring genomic stability, we evaluated PD-L1 expression in tissue samples from 72 advanced GC patients treated with first-line chemotherapy. Samples were already characterized for DNA damage repair (DDR) component expression (pATM, pChk1, pWee1, γ-H2AX and pRPA2) along with mutations in DDR-linked genes (TP53 and ARID1A). Overall, PD-L1 expression was not associated with progression-free survival (PFS) and overall survival (OS), independently on whether we considered its expression in tumor cells (PD-L1-TCs) or in the immune infiltrate (PD-L1-TILs). In subgroup analysis, positive PD-L1-TC immunostaining was associated with better PFS in patients whose tumors did not carry DDR activation (multivariate Cox: HR 0.34, 95%CI: 0.15-0.76, p = 0.008). This subset (DDRoff) was characterized by negative pATM expression or the presence of ARID1A mutations. Conversely, the relationship between PD-L1-TC expression and PFS was lost in a molecular scenario denoting DDR activation (DDRon), as defined by concomitant pATM expression and ARID1A wild-type form. Surprisingly, while PD-L1-TC expression was associated with better OS in the DDRoff subset (multivariate Cox: HR 0.41, 95% CI: 0.17-0.96, p = 0.039), in the DDRon subgroup we observed an opposite impact on OS (multivariate Cox: HR 2.56, 95%CI: 1.06-6.16, p = 0.036). Thus, PD-L1-TC expression may impact survival outcomes in GC on the basis of the activation/inactivation of genome-safeguarding pathways.

Original languageEnglish
Pages (from-to)e1457602
JournalOncoImmunology
Volume7
Issue number8
DOIs
Publication statusPublished - 2018

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