Spatial relationships in the urothelial and head and neck tumor microenvironment predict response to combination immune checkpoint inhibitors
Alberto Gil-Jimenez (Oncode Institute, Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis)
Nick van Dijk (Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis)
Joris L. Vos (Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis)
Yoni Lubeck (Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis)
Maurits L.van Montfoort (Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis)
Dennis Peters (Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis)
Erik Hooijberg (Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis)
Annegien Broeks (Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis)
L.F.A. Wessels (Oncode Institute, Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis, TU Delft - Pattern Recognition and Bioinformatics)
G.B. More Authors (External organisation)
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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.
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