Using immunostaining, transcriptomics, and proteomics, Cabrita and Lauss et al. correlated improved patient survival with metastatic melanoma infiltration by TCF7+IL7R+ naive/memory-like CD8+ and/or CD4+ T cells. BCL-2+CD4+ T cells clustered with mature, proliferating Ki67hiCD40+CXCL13hiCXCR5hiDC-LAMPhiCD20+ B cells in tertiary lymphoid structures (TLS). Maturity of TLS varied, independent of location within a tumor. CD4+ T cells in tumors lacking TLS had an exhausted PD1hiTIM3hiGZMBhiBCL-2lo profile. A TLS+ melanoma gene signature was derived that predicted clinical outcomes of immune checkpoint blockade-treated patients.
Contributed by Paula Hochman
ABSTRACT: Checkpoint blockade therapies that reactivate tumour-associated T cells can induce durable tumour control and result in the long-term survival of patients with advanced cancers(1). Current predictive biomarkers for therapy response include high levels of intratumour immunological activity, a high tumour mutational burden and specific characteristics of the gut microbiota(2,3). Although the role of T cells in antitumour responses has thoroughly been studied, other immune cells remain insufficiently explored. Here we use clinical samples of metastatic melanomas to investigate the role of B cells in antitumour responses, and find that the co-occurrence of tumour-associated CD8(+) T cells and CD20(+) B cells is associated with improved survival, independently of other clinical variables. Immunofluorescence staining of CXCR5 and CXCL13 in combination with CD20 reveals the formation of tertiary lymphoid structures in these CD8(+)CD20(+) tumours. We derived a gene signature associated with tertiary lymphoid structures, which predicted clinical outcomes in cohorts of patients treated with immune checkpoint blockade. Furthermore, B-cell-rich tumours were accompanied by increased levels of TCF7(+) naive and/or memory T cells. This was corroborated by digital spatial-profiling data, in which T cells in tumours without tertiary lymphoid structures had a dysfunctional molecular phenotype. Our results indicate that tertiary lymphoid structures have a key role in the immune microenvironment in melanoma, by conferring distinct T cell phenotypes. Therapeutic strategies to induce the formation of tertiary lymphoid structures should be explored to improve responses to cancer immunotherapy.
Author Info: (1) Department of Clinical Sciences, Division of Oncology and Pathology, Lund University Cancer Center, Lund University, Lund, Sweden. (2) Department of Clinical Sciences, Division
Author Info: (1) Department of Clinical Sciences, Division of Oncology and Pathology, Lund University Cancer Center, Lund University, Lund, Sweden. (2) Department of Clinical Sciences, Division of Oncology and Pathology, Lund University Cancer Center, Lund University, Lund, Sweden. (3) Department of Clinical Sciences, Division of Oncology and Pathology, Lund University Cancer Center, Lund University, Lund, Sweden. (4) National Center for Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital, Herlev, Denmark. (5) Department of Clinical Pathology, Herlev University Hospital, Herlev, Denmark. (6) Department of Clinical Sciences, Division of Oncology and Pathology, Lund University Cancer Center, Lund University, Lund, Sweden. (7) Department of Clinical Sciences, Division of Oncology and Pathology, Lund University Cancer Center, Lund University, Lund, Sweden. (8) Department of Clinical Sciences, Division of Oncology and Pathology, Lund University Cancer Center, Lund University, Lund, Sweden. (9) Department of Clinical Sciences, Division of Oncology and Pathology, Lund University Cancer Center, Lund University, Lund, Sweden. (10) Department of Clinical Sciences, Division of Oncology and Pathology, Lund University Cancer Center, Lund University, Lund, Sweden. (11) NanoString Technologies, Seattle, WA, USA. (12) Department of Clinical Sciences, Division of Oncology and Pathology, Lund University Cancer Center, Lund University, Lund, Sweden. (13) NanoString Technologies, Seattle, WA, USA. (14) Department of Clinical Sciences, Division of Oncology and Pathology, Lund University Cancer Center, Lund University, Lund, Sweden. (15) Department of Clinical Sciences, Division of Oncology and Pathology, Lund University Cancer Center, Lund University, Lund, Sweden. (16) Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University Cancer Center, Lund University, Lund, Sweden. (17) Department of Surgery, Skane University Hospital, Lund, Sweden. (18) Department of Surgery, Skane University Hospital, Lund, Sweden. (19) Department of Dermatology, University Hospital of Essen, Essen, Germany. (20) Department of Oncology, Arhus University Hospital, Aarhus, Denmark. (21) Department of Oncology, Odense University Hospital, Odense, Denmark. (22) Department of Clinical Sciences, Division of Oncology and Pathology, Lund University Cancer Center, Lund University, Lund, Sweden. Department of Oncology, Skane University Hospital, Lund, Sweden. (23) Department of Surgical Oncology, MD Anderson Cancer Center, Houston, TX, USA. (24) National Center for Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital, Herlev, Denmark. (25) Department of Clinical Sciences, Division of Oncology and Pathology, Lund University Cancer Center, Lund University, Lund, Sweden. goran_b.jonsson@med.lu.se.
