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Characterization of immune exhaustion and suppression in the tumor microenvironment of splenic marginal zone lymphoma

Leukemia volume 37, pages 1485–1498 (2023)Cite this article

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Abstract

The role of the tumor microenvironment (TME) and intratumoral T cells in splenic marginal zone lymphoma (sMZL) is largely unknown. In the present study, we evaluated 36 sMZL spleen specimens by single cell analysis to gain a better understanding of the TME in sMZL. Using mass cytometry (CyTOF), we observed that the TME in sMZL is distinct from that of control non-malignant reactive spleen (rSP). We found that the number of TFH cells varied greatly in sMZL, ICOS+ TFH cells were more abundant in sMZL than rSP, and TFH cells positively correlated with increased numbers of memory B cells. Treg cell analysis revealed that TIGIT+ Treg cells are enriched in sMZL and correlate with suppression of TH17 and TH22 cells. Intratumoral CD8+ T cells were comprised of subsets of short-lived, exhausted and late-stage differentiated cells, thereby functionally impaired. We observed that T-cell exhaustion was present in sMZL and TIM-3 expression on PD-1low cells identified cells with severe immune dysfunction. Gene expression profiling by CITE-seq analysis validated this finding. Taken together, our data suggest that the TME as a whole, and T-cell population specifically, are heterogenous in sMZL and immune exhaustion is one of the major factors impairing T-cell function.

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Fig. 1: The overall immune content of spleens in patients with sMZL differs from rSP.
Fig. 2: ICOS+ TFH cells are expanded and positively correlate with memory B cells in sMZL.
Fig. 3: TIGIT+ Treg cells enrich in MZL and correlate with a suppression of TH17 and TH22 cells.
Fig. 4: CD8+ T cells in sMZL display a phenotype of late-stage differentiation.
Fig. 5: Coexpression of TIM-3 and PD-1 results in severe exhaustion in T cells.
Fig. 6: PD-1/TIM-3-defined subsets are transcriptomically different and DP cells exhibit gene expression profiling of more exhaustion in sMZL.
Fig. 7: Spatial profiling identifies different T cell subsets residing in various areas in sMZL tissue.

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Data availability

All CyTOF files were deposited at the FlowRepository website (http://flowrepository.org/).

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Acknowledgements

We thank Dr. Kevin D. Pavelko and Mr. Michael A. Strausbauch from the Mayo Clinic (MC) Immune Monitoring Core, Vernadette Simon and Rakhshan Rohakhtar from the MC Advanced Genomic Technology Center, Vivian Negron and Karla J. Kopp from the MC Pathology Research Core for the technical assistance.

Funding

This work was supported by grants from the Department of Defense (W81XWH1810650), a Research Training Award for Fellows by the American Society of Hematology, a Developmental Research Award by the Mayo Clinic/Iowa Lymphoma SPORE (P50 CA97274), a Research Grant by the Immune Monitoring Core at Mayo Clinic and the Predolin Foundation.

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  1. These authors contributed equally: Theodora Anagnostou, Zhi-Zhang Yang.

Authors and Affiliations

  1. Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, MN, USA

    Theodora Anagnostou, Zhi-Zhang Yang, Shahrzad Jalali, Hyo Jin Kim, Xinyi Tang, Joshua C. Pritchett, Jose Villasboas Bisneto, Tammy L. Price-Troska, Patrizia Mondello, Anne J. Novak & Stephen M. Ansell

  2. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Theodora Anagnostou

  3. Department of Pathology, Mayo Clinic, Rochester, MN, USA

    Daniel P. Larson

  4. Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA

    Yue Yu

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Contributions

TA, ZZY, and SMA designed and performed experiments, analyzed and interpreted data, and wrote the manuscript. SJ, HJK, XT, and DPL performed experiments and analyzed data. YY, JCP, JVB, TLP, PM, and AJN analyzed data. All authors revised the manuscript and approved its final version.

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Correspondence to Zhi-Zhang Yang or Stephen M. Ansell.

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Anagnostou, T., Yang, ZZ., Jalali, S. et al. Characterization of immune exhaustion and suppression in the tumor microenvironment of splenic marginal zone lymphoma. Leukemia 37, 1485–1498 (2023). https://doi.org/10.1038/s41375-023-01911-2

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