Programmed death-ligand 1 (PDL-1) and immune infiltrates are prognostic for better outcome and enriched in the ATM (ataxia telangiectasia mutated)-low segment of gastric cancer (GC)


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Elaine Kilgour1,Helen K. Angell2,Kyoung-Mee Kim3,Soomin Ahn3,Seung Tae Kim3,Alan Sharpe2,Julia Ogden2,Anna Davenport4,J. Carl Barrett5,Darren Hodgson6,Jeeyun Lee3
1AstraZeneca,2AstraZeneca, Cambridge UK,3Samsung Medical Center, Sungyunkwan University Korea,4University Hospital South Manchester UK,5AstraZeneca, Boston USA,6AstraZeneca, Macclesfield UK



 In GC an urgent need exists for effective targeted therapies and predictive markers. In a PhII study, low ATM expression in tumour was associated with greater overall survival (OS) benefit in  patients treated with lynparza/paclitaxel. Antibodies targeting the programmed death-1 checkpoint have reported efficacy in GC, with tumour PD-L1 expression and microsatellite instability (MSI) emerging as predictive markers. We have assessed the prognostic significance of PD-L1 and immune infiltrates in GC and their association with the ATM-low segment.


PD-L1, CD3+ T-lymphocytes, CD8+ cytotoxic T-cells, human epidermal growth factor receptor 2 (HER2) and ATM expression were assessed by immunohistochemistry (IHC) in a cohort of 384 Korean gastric cancers.


PD-L1 positivity (>0%) on tumour cells (TC) and immune infiltrates (IC) was 16% and 90%, respectively and correlated with MSI (p<0.01) and immune infiltrates (CD3 P<0.05; CD8 P<0.01). PD-L1 TC and CD8 were not associated with Lauren subtype. Multivariate analysis showed PD-L1 TC positivity, CD3 and CD8 significantly associated with better OS (p<0.01) and DFS (disease free survival; p<0.01). Prevalence of HER2-high (IHC 3+) was 7% and ATM-low (<10% TC  positive) was 11.5% and  were largely mutually exclusive; only 1/27 HER2-high was also ATM-low. The majority (89%) of HER2-high tumours were microsatellite stable (MSS) with a trend for lower prevalence of PD-L1 (7.4 vs 17%) and CD8 (11.5 vs 21%). The ATM-low segment was significantly enriched for PD-L1 (p<0.01), CD8 (p<0.05) and MSI (p<0.01), but heterogenous with 46% ATM-low tumours being MSS and 65% PD-L1 TC negative.


In GC PD-L1, CD3/CD8 are prognostic for better outcome. Mutually exclusive ATM-low and HER2-high segments differ in their immune profile, with the “immunologically hot” ATM-low segment enriched for MSI, PD-L1 and CD3/8. This illustrates the opportunity to employ different strategies for maximising the benefit from immune therapies in HER2 vs ATM segments.