Spatial relationships in the urothelial and head and neck tumor microenvironment predict response to combination immune checkpoint inhibitors

Alberto Gil-Jimenez, Nick Dijk, Joris L. Vos, Yoni Lubeck, Maurits L. Montfoort, Dennis Peters, Erik Hooijberg, Annegien Broeks, Charlotte L. Zuur, Bas W. G. Rhijn, Daniel J. Vis, Michiel S. Heijden and Lodewyk F. A. Wessels ()
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Alberto Gil-Jimenez: The Netherlands Cancer Institute
Nick Dijk: The Netherlands Cancer Institute
Joris L. Vos: The Netherlands Cancer Institute
Yoni Lubeck: The Netherlands Cancer Institute
Maurits L. Montfoort: The Netherlands Cancer Institute
Dennis Peters: Netherlands Cancer Institute
Erik Hooijberg: The Netherlands Cancer Institute
Annegien Broeks: Netherlands Cancer Institute
Charlotte L. Zuur: The Netherlands Cancer Institute
Bas W. G. Rhijn: The Netherlands Cancer Institute
Daniel J. Vis: The Netherlands Cancer Institute
Michiel S. Heijden: The Netherlands Cancer Institute
Lodewyk F. A. Wessels: The Netherlands Cancer Institute

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract Immune checkpoint inhibitors (ICI) can achieve remarkable responses in urothelial cancer (UC), which may depend on tumor microenvironment (TME) characteristics. However, the relationship between the TME, usually characterized by immune cell density, and response to ICI is unclear. Here, we quantify the TME immune cell densities and spatial relationships (SRs) of 24 baseline UC samples, obtained before pre-operative combination ICI treatment, using multiplex immunofluorescence. We describe SRs by approximating the first nearest-neighbor distance distribution with a Weibull distribution and evaluate the association between TME metrics and ipilimumab+nivolumab response. Immune cell density does not discriminate between response groups. However, the Weibull SR metrics of CD8+ T cells or macrophages to their closest cancer cell positively associate with response. CD8+ T cells close to B cells are characteristic of non-response. We validate our SR response associations in a combination ICI cohort of head and neck tumors. Our data confirm that SRs, in contrast to density metrics, are strong biomarkers of response to pre-operative combination ICIs.

Date: 2024
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DOI: 10.1038/s41467-024-46450-1

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