Spatial immunophenotypes predict response to anti-PD1 treatment and capture distinct paths of T-cell evasion in triple negative breast cancer

Only a subgroup of triple-negative breast cancer (TNBC) responds to immune checkpoint inhibitors (ICI). To better understand lack of response to ICI, we analyzed 681 TNBCs for spatial immune cell contextures in relation to clinical outcomes as well as pathways of T-cell evasion. Excluded, ignored and inflamed phenotypes were captured by a gene classifier that predicts prognosis of various cancers as well as anti-PD1 response of metastatic TNBC patients in a phase II trial. The excluded phenotype, which was associated with resistance to anti-PD1, demonstrated deposits of collagen-10, enhanced glycolysis, and activation of TGFb/VEGF pathways; the ignored phenotype, also associated with resistance to anti-PD1, showed either high density of CD163+ myeloid cells or activation of WNT/PPARg pathways; whereas the inflamed phenotype, which was associated with response to anti-PD1, revealed necrosis, high density of CLEC9A+ dendritic cells, high TCR clonality independent of neo-antigens, and enhanced expression of T-cell co-inhibitory receptors. 43 TNBC specimen with matched clinical data, IHC data and multiplexed immunofluorescence data were sequenced **** Submitter declares that the raw data will be deposited in EGA due to patient privacy concerns. ****