TY - JOUR
T1 - Phenotype, Function, and Clinical Significance of CD26+ and CD161+Tregs in Splenic Marginal Zone Lymphoma
AU - Tang, Xinyi
AU - Yang, Zhi Zhang
AU - Kim, Hyo Jin
AU - Anagnostou, Theodora
AU - Yu, Yue
AU - Wu, Xiaosheng
AU - Chen, Jun
AU - Krull, Jordan E.
AU - Wenzl, Kerstin
AU - Mondello, Patrizia
AU - Bhardwaj, Vaishali
AU - Wang, Junwen
AU - Novak, Anne J.
AU - Ansell, Stephen M.
N1 - Funding Information:
This work was supported by grants from the Department of Defense (W81XWH1810650), the Mayo Clinic/Iowa Lymphoma SPORE (P50 CA97274), a SEAFAM Discovery Grant from the Immuno-Oncology Program at Mayo Clinic (91314143), a CCatTS-CBD Pilot Award for Team Science (FP00120421), and the Predolin Foundation (91314145), National Library of Medicine (1R01LM013438). We thank Fariborz Rakhshan Rohakhtar, MS; Vernadette Simon, MS; and other colleagues in Mayo Clinic Medical Genome Facility Genome Analysis Core for performing the CITE-seq assay. We thank Ying Li, PhD, and other colleagues in Mayo
Funding Information:
X. Wu reports grants from NCI outside the submitted work. A.J. Novak reports other support from Bristol Myers Squibb outside the submitted work. S.M. Ansell reports grants from Bristol Myers Squibb, ADC Therapeutics, Pfizer, Affimed, and Regeneron outside the submitted work. No disclosures were reported by the other authors.
Publisher Copyright:
© 2022 American Association for Cancer Research.
PY - 2022/10/1
Y1 - 2022/10/1
N2 - Purpose: Regulatory T-cells (Treg) are essential to Tregs homeostasis and modulate the antitumor immune response in patients with lymphoma. However, the biology and prognostic impact of Tregs in splenic marginal zone lymphoma (SMZL) have not been studied. Experimental Design: Biopsy specimens from 24 patients with SMZL and 12 reactive spleens (rSP) from individuals without lymphoma were analyzed by using CITE-seq (cellular indexing of transcriptomes and epitopes by sequencing), CyTOF (mass cytometry) analysis, and flow cytometry to explore the phenotype, transcriptomic profile, and clinical significance of intratumoral Tregs and their subsets. The biological characteristics and cell signaling pathways of intratumoral Treg subsets were confirmed by in vitro functional assays. Results: We found that Tregs are more abundant in SMZL patients' spleens than rSP, and Tregs from patients with SMZL and rSP can be separated into CD161+Treg and CD26+Treg subsets. CD161+Tregs are increased in SMZL but have dysregulated immune function. We found that CD161+Treg and CD26+Tregs have unique gene expression and phenotypic profiles and are differentially correlated with patient outcomes. Specifically, increased CD161+Tregs are significantly associated with a favorable prognosis in patients with SMZL, whereas CD26+Tregs are associated with a poor prognosis. Furthermore, activation of the IL2/ STAT5 pathway contributes to the induction of CD26+Tregs and can be reversed by STAT5 inhibition. Conclusions: IL2/STAT5-mediated expansion of CD26+Tregs contributes to a poor clinical outcome in SMZL and may represent a therapeutic opportunity in this disease.
AB - Purpose: Regulatory T-cells (Treg) are essential to Tregs homeostasis and modulate the antitumor immune response in patients with lymphoma. However, the biology and prognostic impact of Tregs in splenic marginal zone lymphoma (SMZL) have not been studied. Experimental Design: Biopsy specimens from 24 patients with SMZL and 12 reactive spleens (rSP) from individuals without lymphoma were analyzed by using CITE-seq (cellular indexing of transcriptomes and epitopes by sequencing), CyTOF (mass cytometry) analysis, and flow cytometry to explore the phenotype, transcriptomic profile, and clinical significance of intratumoral Tregs and their subsets. The biological characteristics and cell signaling pathways of intratumoral Treg subsets were confirmed by in vitro functional assays. Results: We found that Tregs are more abundant in SMZL patients' spleens than rSP, and Tregs from patients with SMZL and rSP can be separated into CD161+Treg and CD26+Treg subsets. CD161+Tregs are increased in SMZL but have dysregulated immune function. We found that CD161+Treg and CD26+Tregs have unique gene expression and phenotypic profiles and are differentially correlated with patient outcomes. Specifically, increased CD161+Tregs are significantly associated with a favorable prognosis in patients with SMZL, whereas CD26+Tregs are associated with a poor prognosis. Furthermore, activation of the IL2/ STAT5 pathway contributes to the induction of CD26+Tregs and can be reversed by STAT5 inhibition. Conclusions: IL2/STAT5-mediated expansion of CD26+Tregs contributes to a poor clinical outcome in SMZL and may represent a therapeutic opportunity in this disease.
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U2 - 10.1158/1078-0432.CCR-22-0977
DO - 10.1158/1078-0432.CCR-22-0977
M3 - Article
C2 - 35686915
AN - SCOPUS:85139521792
VL - 28
SP - 4322
EP - 4335
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 19
ER -