TY - JOUR
T1 - Immune infiltrate diversity confers a good prognosis in follicular lymphoma
AU - Tsakiroglou, Anna-Maria
AU - Astley, Susan
AU - Dave, Manàs
AU - Fergie, Martin
AU - Harkness, Elaine
AU - Rosenberg, Adeline
AU - Sperrin, Matthew
AU - West, Catharine
AU - Byers, Richard
AU - Linton, Kim
N1 - Funding Information:
We thank Uwe Schmidt and Martin Weigert for the training on the implementation of “StarDist” cell detection algorithm. We also thank the histology and microscopy core facility staff of CRUK Manchester Centre and acknowledge the support of the Christie NHS Foundation Trust Leukaemia and Lymphoma team in patient recruitment and sample collection. The work was funded by the Manchester Cancer Research UK (CRUK) Manchester Centre. CW and EH are supported by the NIHR Manchester Biomedical Research Centre (IS-BRC-1215–20007).
Funding Information:
The work was funded by the Manchester Cancer Research UK (CRUK) Manchester Centre. CW and EH are supported by the NIHR Manchester Biomedical Research Centre (IS-BRC-1215–20007).
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/4/30
Y1 - 2021/4/30
N2 - BACKGROUND: Follicular lymphoma (FL) prognosis is influenced by the composition of the tumour microenvironment. We tested an automated approach to quantitatively assess the phenotypic and spatial immune infiltrate diversity as a prognostic biomarker for FL patients.METHODS: Diagnostic biopsies were collected from 127 FL patients initially treated with rituximab-based therapy (52%), radiotherapy (28%), or active surveillance (20%). Tissue microarrays were constructed and stained using multiplex immunofluorescence (CD4, CD8, FOXP3, CD21, PD-1, CD68, and DAPI). Subsequently, sections underwent automated cell scoring and analysis of spatial interactions, defined as cells co-occurring within 30 μm. Shannon's entropy, a metric describing species biodiversity in ecological habitats, was applied to quantify immune infiltrate diversity of cell types and spatial interactions. Immune infiltrate diversity indices were tested in multivariable Cox regression and Kaplan-Meier analysis for overall (OS) and progression-free survival (PFS).RESULTS: Increased diversity of cell types (HR = 0.19 95% CI 0.06-0.65, p = 0.008) and cell spatial interactions (HR = 0.39, 95% CI 0.20-0.75, p = 0.005) was associated with favourable OS, independent of the Follicular Lymphoma International Prognostic Index. In the rituximab-treated subset, the favourable trend between diversity and PFS did not reach statistical significance.CONCLUSION: Multiplex immunofluorescence and Shannon's entropy can objectively quantify immune infiltrate diversity and generate prognostic information in FL. This automated approach warrants validation in additional FL cohorts, and its applicability as a pre-treatment biomarker to identify high-risk patients should be further explored. The multiplex image dataset generated by this study is shared publicly to encourage further research on the FL microenvironment.
AB - BACKGROUND: Follicular lymphoma (FL) prognosis is influenced by the composition of the tumour microenvironment. We tested an automated approach to quantitatively assess the phenotypic and spatial immune infiltrate diversity as a prognostic biomarker for FL patients.METHODS: Diagnostic biopsies were collected from 127 FL patients initially treated with rituximab-based therapy (52%), radiotherapy (28%), or active surveillance (20%). Tissue microarrays were constructed and stained using multiplex immunofluorescence (CD4, CD8, FOXP3, CD21, PD-1, CD68, and DAPI). Subsequently, sections underwent automated cell scoring and analysis of spatial interactions, defined as cells co-occurring within 30 μm. Shannon's entropy, a metric describing species biodiversity in ecological habitats, was applied to quantify immune infiltrate diversity of cell types and spatial interactions. Immune infiltrate diversity indices were tested in multivariable Cox regression and Kaplan-Meier analysis for overall (OS) and progression-free survival (PFS).RESULTS: Increased diversity of cell types (HR = 0.19 95% CI 0.06-0.65, p = 0.008) and cell spatial interactions (HR = 0.39, 95% CI 0.20-0.75, p = 0.005) was associated with favourable OS, independent of the Follicular Lymphoma International Prognostic Index. In the rituximab-treated subset, the favourable trend between diversity and PFS did not reach statistical significance.CONCLUSION: Multiplex immunofluorescence and Shannon's entropy can objectively quantify immune infiltrate diversity and generate prognostic information in FL. This automated approach warrants validation in additional FL cohorts, and its applicability as a pre-treatment biomarker to identify high-risk patients should be further explored. The multiplex image dataset generated by this study is shared publicly to encourage further research on the FL microenvironment.
KW - Diversity
KW - Follicular lymphoma
KW - Multiplex
KW - Prognosis
KW - Spatial heterogeneity
KW - Tumour microenvironment
U2 - 10.1007/s00262-021-02945-0
DO - 10.1007/s00262-021-02945-0
M3 - Article
C2 - 33929583
JO - Cancer Immunology, Immunotherapy
JF - Cancer Immunology, Immunotherapy
SN - 0340-7004
ER -
