Spatial analyses implicate high stromal tumour-infiltrating CD8+ lymphocytes as a negative predictive marker for chemotherapy in estrogen receptor-positive breast cancer

Abstract

Abstract Female patients with ER + HER2 - breast cancer have a favourable prognosis for 5-10 years. Later relapses are, however, common, yet predictions of late recurrence risk are suboptimal, particularly for patients with intermediate risk determined by the Oncotype Dx Recurrence Score (RS, 16-25). Here, we analyse tissue samples from patients with ER + HER2 - breast cancer using spatial proteomics (multiplex immunofluorescence with 5 markers, n  = 440) and spatial transcriptomics ( n  = 359), and find decoupled immune states between stroma and epithelia. Moreover, inflamed stroma express genes linked to tissue remodelling, immune exhaustion, and inhibitory/checkpoint receptors ( CTLA4, TIGIT, CD96 ); inflamed epithelia similarly express genes associated with checkpoints ( CTLA4 ) and exhaustion ( CXCL13 ), but also genes attributed to antigen presentation. In our randomised, Intermediate RS cohort treated with chemotherapy we observe an association between higher stromal tumour-infiltrating CD8 + lymphocyte (sTIL CD8 + ) density and poor outcome (ΔLR-χ 2 : 6.79, p  = 0.009), which we validate using data from whole-resection specimens (ΔLR-χ 2 : 8.90, p  = 0.003). Our data thus provide insights into the immune states in ER + HER2 - breast cancer, and propose sTIL CD8 + density as candidate biomarker for treatment decisions.