Τίτλος:
Germinal centers determine the prognostic relevance of tertiary lymphoid structures and are impaired by corticosteroids in lung squamous cell carcinoma
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
In solid tumors, the presence of lymph node-like structures called tertiary lymphoid structures (TLS) is associated with improved patient survival. However, little is known about how TLS develop in cancer, how their function affects survival, and whether they are affected by cancer therapy. In this study, we used multispectral microscopy, quantitative pathology, and gene expression profiling to analyze TLS formation in human lung squamous cell carcinoma (LSCC) and in an experimental model of lung TLS induction. We identified a niche of CXCL13+ perivascular and CXCL12+LTB+ and PD-L1+ epithelial cells supporting TLS formation. We also characterized sequential stages of TLS maturation in LSCC culminating in the formation of germinal centers (GC). In untreated patients, TLS density was the strongest independent prognostic marker. Furthermore, TLS density correlated with GC formation and expression of adaptive immune response-related genes. In patients treated with neoadjuvant chemotherapy, TLS density was similar, but GC formation was impaired and the prognostic value of TLS density was lost. Corticosteroids are coadministered with chemotherapy to manage side effects in LSCC patients, so we evaluated whether they impaired TLS development independently of chemotherapy. TLS density and GC formation were each reduced in chemotherapy-naïve LSCC patients treated with corticosteroids before surgery, compared with untreated patients, a finding that we confirmed in the experimental model of lung TLS induction. Overall, our results highlight the importance of GC formation in TLS during tumor development and treatment. ©2017 American Association for Cancer Research.
Συγγραφείς:
Silina, K.
Soltermann, A.
Attar, F.M.
Casanova, R.
Uckeley, Z.M.
Thut, H.
Wandres, M.
Isajevs, S.
Cheng, P.
Curioni-Fontecedro, A.
Foukas, P.
Levesque, M.P.
Moch, H.
Line, A.
Van Den Broek, M.
Περιοδικό:
Clinical Cancer Research
Εκδότης:
American Association for Cancer Research Inc.
Λέξεις-κλειδιά:
corticosteroid; CXCL13 chemokine; dexamethasone; lymphotoxin beta receptor; programmed death 1 ligand 1; stromal cell derived factor 1; tumor marker; antineoplastic agent; corticosteroid, adaptive immunity; adult; animal experiment; animal model; Article; C57BL/6N mouse; cancer growth; cancer prognosis; cancer staging; cancer survival; cancer therapy; clinical article; cohort analysis; comorbidity; controlled study; epithelium cell; female; follow up; gene expression; gene expression profiling; germinal center; HBEC cell line (bronchial); histopathology; human; human tissue; immune response gene; low drug dose; lung alveolus epithelium cell; male; mouse; neoadjuvant chemotherapy; nonhuman; perivascular epithelioid cell tumor; priority journal; quantitative analysis; squamous cell lung carcinoma; structure analysis; tertiary lymphoid structure; treatment outcome; aged; animal; apoptosis; C57BL mouse; cell proliferation; chemically induced; drug effect; drug screening; germinal center; immunology; lung tumor; middle aged; non small cell lung cancer; pathology; prognosis; squamous cell carcinoma; survival rate; tertiary lymphoid structure; tumor associated leukocyte; tumor cell culture; tumor microenvironment, Adrenal Cortex Hormones; Aged; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cell Proliferation; Female; Follow-Up Studies; Gene Expression Profiling; Germinal Center; Humans; Lung Neoplasms; Lymphocytes, Tumor-Infiltrating; Male; Mice; Mice, Inbred C57BL; Middle Aged; Prognosis; Survival Rate; Tertiary Lymphoid Structures; Tumor Cells, Cultured; Tumor Microenvironment; Xenograft Model Antitumor Assays
DOI:
10.1158/0008-5472.CAN-17-1987
