129O Resistance to immunotherapy is associated with high parenchymal PD1+CD8+/CD8+ T cells (PD1tR) driven by tumour CD155. (15th December 2019)

• Record Type: Journal Article
• Authors: de Oliveira, A Lepletier; Madore, J; O'donnell, J S; Johnston, R L; Eastgate, M; Mallardo, D; Ascierto, P A; Massi, D; Merelli, B; Mandala, M; Wilmott, J S; Bald, T; Stagg, J; Routy, B; Long, G V; Scolyer, R A; Waddell, N; Dougall, W C; Teng, M W L; Smyth, M
• Is Part Of: Annals of oncology. Volume 30(2019)Supplement 11
• Publication Date: 2019-12-15
• Subjects: Oncology -- Periodicals; 616.992
• DOI: 10.1093/annonc/mdz452
• Languages: English
• ISSNs: 0923-7534

Abstract

Abstract: Background: We have previously shown that a possible complementary target to PD1-based immune-checkpoint blockade (ICB) is the adhesion molecule CD155, which promotes tumor growth and metastasis in mouse models. To date, it is unclear to what extent tumor CD155 expression impacts the immune infiltrate contexture or if expression of CD155 by human tumors affects sensitivity to ICB. Methods: We assessed pretreatment tumor FFPE specimens from 146 metastatic melanomas patients treated with immune checkpoint blockade (ICB) and 41 patients that have received 1st line BRAF/MEK targeted therapy and no ICB. CD155 expression was defined by immunohistochemistry (IHC) H-score. The immune infiltrate was separately analysed in stroma and parenchymal (intratumor) regions using multiplex immunohistofluorescence (IHF) for CD8, PD1 and SOX10. Associations were made between IHC analyses, bulk tumor RNA-seq results, and immunotherapeutic response (RECIST, PFS, and disease specific OS). Key findings were functionally validated in a relevant mouse melanoma model. Results: Melanoma patients with high levels of tumor CD155 (score 3+) frequently had progressive disease or shorter PFS through promotion of dysfunctional PD1 + CD8 + T cells. Further, the intratumor ratio of PD1 + CD8 + to total CD8 + T cells (PD1 tR ) is a strong predictor of ICB refractory patients. Importantly, outcome correlations appeared specific to ICB therapy and were not present in melanoma patients treated with BRAF/MEK targeted therapy. In humans, CD155 high tumors show reduced Interferon-gamma and cytotoxic gene signatures. In PD1 resistant mouse tumor models, deletion of CD155 prevented accumulation of intratumor PD1 hi CD8 + T cells. Additionally, therapeutic blockade of the CD155 cognate receptors TIGIT and CD96 restored IFNγ production and improved anti-PD1 tumor control. Conclusion: Our findings are the first to demonstrate that tumor CD155 underpins the accumulation of dysfunctional PD1 hi CD8 + T cells in human tumors and propose pretreatment PD1 tR as a potential biomarker of response to ICB. Legal entity responsible for the study: The Council of the Queensland Institute of Medical Research. Funding: Bristol-Myers Squibb. Disclosure: P.A. Ascierto: Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (self): Roche-Genentech; Advisory / Consultancy, Research grant / Funding (self): Array; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy: Novartis; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Incyte; Advisory / Consultancy: Genmab; Advisory / Consultancy: Newlink Genetics; Advisory / Consultancy: Medimmune; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Syndax; Advisory / Consultancy: Sun Pharma; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Idera; Advisory / Consultancy: Ultimovacs; Advisory / Consultancy: Sandoz; Advisory / Consultancy: Immunocore. G. V. Long: Advisory / Consultancy: Aduro; Advisory / Consultancy: Amgen; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Merck MSD; Advisory / Consultancy: Novartis; Advisory / Consultancy: Roche. R. A. Scolyer: Advisory / Consultancy: Merck Sharp Dohme; Advisory / Consultancy: Novartis; Advisory / Consultancy: Myriad; Advisory / Consultancy: NeraCare. W. C. Dougall: Research grant / Funding (self): Bristol-Myers Squibb; Advisory / Consultancy: Omeros Corporation ; Advisory / Consultancy: Cascadia Drug Development Group. M. W. L. Teng: Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert testimony: MSD; Speaker Bureau / Expert testimony: Bristol-Myers Squibb. M. Smyth: Research grant / Funding (self): Bristol-Myers Squibb; Research grant / Funding (self): Aduro Biotech; Research grant / Funding (self): Tizona Pharmaceuticals. All other authors have declared no conflicts of interest.