The Francis Crick Institute
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Spatial positioning of immune hotspots reflects the interplay between B and T cells in lung squamous cell carcinoma.

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journal contribution
posted on 2023-05-04, 09:49 authored by Hanyun Zhang, Khalid AbdulJabbar, David A Moore, Ayse Akarca, Katey SS Enfield, Mariam Jamal-Hanjani, Shan E Ahmed Raza, Selvaraju Veeriah, Roberto Salgado, Nicholas McGranahan, John Le Quesne, Charles Swanton, Teresa Marafioti, Yinyin Yuan
Beyond tertiary lymphoid structures, a significant number of immune rich areas without germinal center-like structures are observed in non-small cell lung cancer. Here, we integrated transcriptomic data and digital pathology images to study the prognostic implications, spatial locations, and constitution of immune rich areas (immune hotspots) in a cohort of 935 lung cancer patients from the TCGA. A high intratumoral immune hotspot score, which measures the proportion of immune hotspots interfacing with tumor islands, was correlated with poor overall survival in lung squamous cell carcinoma but not in lung adenocarcinoma. Lung squamous cell carcinomas with high intratumoral immune hotspot scores were characterized by consistent upregulation of B cell signatures. Spatial statistical analyses conducted on serial multiplex immunohistochemistry slides further revealed that only 4.87% of peritumoral immune hotspots and 0.26% of intratumoral immune hotspots were tertiary lymphoid structures. Significantly lower densities of CD20+CXCR5+ and CD79b+ B cells and less diverse immune cell interactions were found in intratumoral immune hotspots compared to peritumoral immune hotspots. Furthermore, there was a negative correlation between the percentages of CD8+ T cells and T regulatory cells in intratumoral but not in peritumoral immune hotspots, with tertiary lymphoid structures excluded. These findings suggest that the intratumoral immune hotspots reflect an immunosuppressive niche compared to peritumoral immune hotspots, independent of the distribution of tertiary lymphoid structures. A balance towards increased intratumoral immune hotspots is indicative of a compromised anti-tumor immune response and poor outcome in lung squamous cell carcinoma.


Crick (Grant ID: 10169, Grant title: Swanton FC001169) 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 Commission (Grant ID: 838540 - TRACERxTIME, Grant title: EC 838540 - TRACERxTIME)