A single-cell map of intratumoral changes during anti-PD1 treatment of patients with breast cancer
(1) Bassez A (2) Vos H (3) Van Dyck L (4) Floris G (5) Arijs I (6) Desmedt C (7) Boeckx B (8) Vanden Bempt M (9) Nevelsteen I (10) Lambein K (11) Punie K (12) Neven P (13) Garg AD (14) Wildiers H (15) Qian J (16) Smeets A (17) Lambrechts D
(1) Bassez A (2) Vos H (3) Van Dyck L (4) Floris G (5) Arijs I (6) Desmedt C (7) Boeckx B (8) Vanden Bempt M (9) Nevelsteen I (10) Lambein K (11) Punie K (12) Neven P (13) Garg AD (14) Wildiers H (15) Qian J (16) Smeets A (17) Lambrechts D
Immune-checkpoint blockade (ICB) combined with neoadjuvant chemotherapy improves pathological complete response in breast cancer. To understand why only a subset of tumors respond to ICB, patients with hormone receptor-positive or triple-negative breast cancer were treated with anti-PD1 before surgery. Paired pre- versus on-treatment biopsies from treatment-naive patients receiving anti-PD1 (n_=_29) or patients receiving neoadjuvant chemotherapy before anti-PD1 (n_=_11) were subjected to single-cell transcriptome, T cell receptor and proteome profiling. One-third of tumors contained PD1-expressing T cells, which clonally expanded upon anti-PD1 treatment, irrespective of tumor subtype. Expansion mainly involved CD8(+) T cells with pronounced expression of cytotoxic-activity (PRF1, GZMB), immune-cell homing (CXCL13) and exhaustion markers (HAVCR2, LAG3), and CD4(+) T cells characterized by expression of T-helper-1 (IFNG) and follicular-helper (BCL6, CXCR5) markers. In pre-treatment biopsies, the relative frequency of immunoregulatory dendritic cells (PD-L1(+)), specific macrophage phenotypes (CCR2(+) or MMP9(+)) and cancer cells exhibiting major histocompatibility complex class I/II expression correlated positively with T cell expansion. Conversely, undifferentiated pre-effector/memory T cells (TCF7(+), GZMK(+)) or inhibitory macrophages (CX3CR1(+), C3(+)) were inversely correlated with T cell expansion. Collectively, our data identify various immunophenotypes and associated gene sets that are positively or negatively correlated with T cell expansion following anti-PD1 treatment. We shed light on the heterogeneity in treatment response to anti-PD1 in breast cancer.
Author Info:
(1) Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium. VIB Center for Cancer Biology, Leuven, Belgium. (2) Department of Surgical Onco
logy, University Hospitals Leuven, KU Leuven, Leuven, Belgium. (3) Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium. VIB Center for Cancer Biology, Leuven, Belgium. (4) Department of Imaging & Pathology, Laboratory of Translational Cell & Tissue Research and Department of Pathology, University Hospitals Leuven, KU Leuven, Leuven, Belgium. (5) Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium. VIB Center for Cancer Biology, Leuven, Belgium. (6) Laboratory for Translational Breast Cancer Research, Department of Oncology, KU Leuven, Leuven, Belgium. (7) Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium. VIB Center for Cancer Biology, Leuven, Belgium. (8) VIB Center for Cancer Biology, Leuven, Belgium. (9) Department of Surgical Oncology, University Hospitals Leuven, KU Leuven, Leuven, Belgium. (10) Department of Surgical Oncology, University Hospitals Leuven, KU Leuven, Leuven, Belgium. (11) Department of General Medical Oncology, University Hospitals Leuven, KU Leuven, Leuven, Belgium. (12) Department of Gynaecology and Obstetrics, University Hospitals Leuven, KU Leuven, Leuven, Belgium. (13) Laboratory of Cell Stress & Immunity, Department of Cellular & Molecular Medicine, KU Leuven, Leuven, Belgium. (14) Department of General Medical Oncology, University Hospitals Leuven, KU Leuven, Leuven, Belgium. (15) Department of Gynecologic Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China. dr_qian@zju.edu.cn. (16) Department of Surgical Oncology, University Hospitals Leuven, KU Leuven, Leuven, Belgium. Ann.Smeets@uzleuven.be. (17) Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium. Diether.Lambrechts@vib-kuleuven.be. VIB Center for Cancer Biology, Leuven, Belgium. Diether.Lambrechts@vib-kuleuven.be.
