Journal Article

894 Conserved immune inhibitory receptor-signaling in macrophages limits antitumour chemo-immunotherapy

Naulaerts, Stefan, Schlenner, Susan M, Salvador, Raquel, Cafarello, Sarah Trusso, Daelemans, Dirk, Verelst, Joren, Jacquemyn, Maarten, Pretto, Samantha, Zhao, Shikang, Tejpar, Sabine, Mazzone, Massimiliano, Sprooten, Jenny, Govaerts, Jannes, Trotta, Rosa, Boon, Louis, Vanmeerbeek, Isaure, Pociupany, Martyna, Garg, Abhishek D

2023

Overview

BackgroundDespite the success of PD1 blockade in various cancers, overcoming resistance to cancer immunotherapy remains challenging. Targeting CD8+ T cell-associated alternative immune-checkpoints is anticipated to overcome this issue. However, such immune-checkpoints are also expressed on myeloid cells, but their therapeutic and clinical impact remains enigmatic. Thus, the aim of this study was to reveal underappreciated TAMs-ontology enriching immune-inhibitory receptors, to design biomarker-driven immunotherapy.MethodsWe used reverse translational methodologies starting from human tumour multi-omics bioinformatics to inform pre-clinical experimental research, culminating into human multi-omics prognostic/predictive validationResultsWe identified a unique niche of tumour-associated macrophages (TAMs), preferentially co-expressing the TIM3 and VISTA immune-checkpoints, that dominated the human and mouse tumours resistant to PD(L)1 blockade. Subcutaneous epithelial-origin tumours and orthotopic melanoma in mouse showed that TIM3+VISTA+TAMs were sustained by IL4/IL13-enriching tumours with low (neo)antigenic and non-immunogenic milieu. TIM3/VISTA were instrumental in sustaining a hyper-efferocytotic and anti-inflammatory TAM phenotype, and blunting type I interferon (IFN) sensing, thereby fuelling immune subversion. This was established with cancer cells succumbing to immunogenic cell death (ICD). Herein, while dying cancer cells triggered autocrine type I IFN production, yet they also exposed extracellular HMGB1 and surface VISTA as ligands to engage TIM3 and VISTA on TAMs respectively, to suppress paracrine IFN responses. Consequently, TIM3/VISTA blockade preferentially synergized with paclitaxel, an ICD inducing chemotherapy in vivo, to replace the anti-inflammatory TIM3+VISTA+TAMs with pro-inflammatory TAMs-driven cytotoxicity, thus blunting the immuno-resistant tumours. In vivo macrophage-specific genetic knockout of TIM3/VISTA confirmed this synergism, while immune/genetic ablation of type I IFN sensing, macrophages (but not CD8+T cells), or cancer cell associated HMGB1/VISTA disrupted it. Finally, TIM3+VISTA+TAM signature exhibited pan-cancer negative prognostic impact and predicted resistance to immunotherapy in patients.ConclusionsWe discovered that as-yet-uncharacterized TIM3+VISTA+TAMs, enriched by human and mouse non-immunogenic tumours, mediate chemo-immunotherapy resistance. Thus, targeting TIM3+VISTA+TAMs is a novel and conserved strategy to overcome low neo-antigenic, CD8+T cells independent, tumours.Ethics ApprovalMouse Experiments were approved by the animal ethics committee at KU Leuven (project P114/2019 and p195/2020) following the European directive 2010/63/EU as amended by the Regulation (EU) 2019/1010 and the Flemish government decree of 17 February 2017.

• Publisher: BMJ Publishing Group Ltd,BMJ Publishing Group LTD,BMJ Publishing Group
• Subject: Cancer / Chemotherapy / Immunotherapy / Regular and Young Investigator Award Abstracts / Tumors