Immune escape in breast cancer during in situ to invasive carcinoma transition

To investigate immune escape during breast tumor progression, we analyzed the composition of leukocytes in normal breast tissues, ductal carcinoma in situ (DCIS), and invasive ductal carcinomas (IDC). We found signifi cant tissue and tumor subtype-specifi c differences in multiple cell types including T cells and neutrophils. Gene expression profi ling of CD45⁺CD3⁺ T cells demonstrated a decrease in CD8⁺ signatures in IDCs. Immunofl uorescence analysis showed fewer activated GZMB⁺CD8⁺ T cells in IDC than in DCIS, including in matched DCIS and recurrent IDC. T-cell receptor clonotype diversity was signifi cantly higher in DCIS than in IDCs. Immune checkpoint protein TIGIT-expressing T cells were more frequent in DCIS, whereas high PD-L1 expression and amplifi cation of CD274 (encoding PD-L1) was only detected in triple-negative IDCs. Coamplifi cation of a 17q12 chemokine cluster with ERBB2 subdivided HER2⁺ breast tumors into immunologically and clinically distinct subtypes. Our results show coevolution of cancer cells and the immune microenvironment during tumor progression. SIGNIFICANCE: The design of effective cancer immunotherapies requires the understanding of mechanisms underlying immune escape during tumor progression. Here we demonstrate a switch to a less active tumor immune environment during the in situ to invasive breast carcinoma transition, and identify immune regulators and genomic alterations that shape tumor evolution.