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Spatial architecture of myeloid and T cells orchestrates immune evasion and clinical outcome in lung cancer.

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posted on 2024-06-06, 10:38 authored by Katey SS Enfield, Emma Colliver, Claudia Lee, Alastair Magness, David A Moore, Monica Sivakumar, Kristiana Grigoriadis, Oriol Pich, Takahiro Karasaki, Philip S Hobson, Dina Levi, Selvaraju Veeriah, Clare Puttick, Emma L Nye, Mary Green, Krijn K Dijkstra, Masako Shimato, Ayse U Akarca, Teresa Marafioti, Roberto Salgado, Allan Hackshaw, TRACERx Consortium, Mariam Jamal-Hanjani, Febe van Maldegem, Nicholas McGranahan, Benjamin Glass, Hanna Pulaski, Eric Walk, James L Reading, Sergio A Quezada, Crispin T Hiley, Julian Downward, Erik Sahai, Charles Swanton, Mihaela Angelova
Understanding the role of the tumour microenvironment (TME) in lung cancer is critical to improving patient outcome. We identified four histology-independent archetype TMEs in treatment-naive early-stage lung cancer using imaging mass cytometry in the TRACERx study (n=81 patients/198 samples/2.3million cells). In immune-hot adenocarcinomas, spatial niches of T cells and macrophages increased with clonal neoantigen burden, whereas such an increase was observed for niches of plasma and B cells in immune-excluded squamous cell carcinomas (LUSC). Immune-low TMEs were associated with fibroblast barriers to immune infiltration. The fourth archetype, characterised by sparse lymphocytes and high tumour-associated neutrophil (TAN) infiltration, had tumour cells spatially separated from vasculature and exhibited low spatial intratumour heterogeneity. TAN-High LUSC had frequent PIK3CA mutations. TAN-High tumours harboured recently expanded and metastasis-seeding subclones and had a shorter disease-free survival independent of stage. These findings delineate genomic, immune and physical barriers to immune surveillance and implicate neutrophil-rich TMEs in metastasis.

Funding

Crick (Grant ID: CC2041, Grant title: Swanton CC2041) Crick (Grant ID: CC1062, Grant title: STP Flow Cytometry) Crick (Grant ID: CC1061, Grant title: STP Experimental Histopathology) Crick (Grant ID: CC2040, Grant title: Sahai CC2040) Crick (Grant ID: CC2097, Grant title: Downward CC2097) Novo Nordisk UK Research Foundation (Grant ID: NNF15OC0016584, Grant title: NovoNordisk Foundation 16584) European Research Council (Grant ID: 835297 - PROTEUS, Grant title: ERC 835297 - PROTEUS) European Research Council (Grant ID: 101019366 - CAN_ORGANISE, Grant title: ERC 101019366 - CAN_ORGANISE)

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