Journal Article

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

Nederlof, Iris, Foekens, Renée, Timmermans, Mieke, Wijers, Rebecca, Isaeva, Olga I., Smid, Marcel, Kok, Marleen, Salgado, Roberto, Debets, Reno, Horlings, Hugo, Trapman-Jansen, Anita M., Balcioglu, Hayri E., Martens, John W. M., Voorwerk, Leonie, Hammerl, Dora

2021

Overview

Only a subgroup of triple-negative breast cancer (TNBC) responds to immune checkpoint inhibitors (ICI). To better understand lack of response to ICI, we analyze 681 TNBCs for spatial immune cell contextures in relation to clinical outcomes and pathways of T cell evasion. Excluded, ignored and inflamed phenotypes can be 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 is associated with resistance to anti-PD1, demonstrates deposits of collagen-10, enhanced glycolysis, and activation of TGFβ/VEGF pathways; the ignored phenotype, also associated with resistance to anti-PD1, shows either high density of CD163+ myeloid cells or activation of WNT/PPARγ pathways; whereas the inflamed phenotype, which is 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. Only a subset of triple negative breast cancer patients respond to immunotherapy. Here, the authors analysed spatial immune contextures, which can be captured by a gene classifier, in relation to genomic alterations, mechanisms of T cell evasion and response to anti-PD1 treatment.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 14 / 14/1 / 14/63 / 38 / 38/39 / 45 / 45/23 / 631/250 / 631/67 / 692/308 / 692/53 / 692/699 / Adult / Antigens / Antigens, CD - metabolism / Antigens, Differentiation, Myelomonocytic - metabolism / Breast - immunology / Breast - pathology / Breast - surgery / Breast cancer / CD163 antigen / Cell activation / Classifiers / Cohort Studies / Collagen / Datasets as Topic / Dendritic cells / Density / Drug Resistance, Neoplasm - immunology / Female / Genotype & phenotype / Glycolysis / Humanities and Social Sciences / Humans / Immune checkpoint inhibitors / Immune Checkpoint Inhibitors - pharmacology / Immune Checkpoint Inhibitors - therapeutic use / Immune system / Immunophenotyping / Immunotherapy / Inflammation / Lymphocytes / Lymphocytes T / Lymphocytes, Tumor-Infiltrating - immunology / Lymphocytes, Tumor-Infiltrating - metabolism / Mastectomy / Metastases / multidisciplinary / Myeloid cells / Necrosis / Neoadjuvant Therapy - methods / Patients / PD-1 protein / Peroxisome proliferator-activated receptors / Phenotypes / Prognosis / Programmed Cell Death 1 Receptor - antagonists & inhibitors / Receptors, Cell Surface - metabolism / RNA-Seq / Science / Science (multidisciplinary) / Spatial Analysis / Subgroups / T cell receptors / T-Lymphocytes - immunology / T-Lymphocytes - metabolism / Triple Negative Breast Neoplasms - immunology / Triple Negative Breast Neoplasms - pathology / Triple Negative Breast Neoplasms - therapy / Tumor Escape / Tumor Microenvironment - drug effects / Tumor Microenvironment - immunology / Vascular endothelial growth factor / Wnt protein / Wnt Signaling Pathway - immunology