Tumor-Infiltrating Normal B Cells Revealed by Immunoglobulin Repertoire Clonotype Analysis Are Highly Prognostic and Crucial for Antitumor Immune Responses in DLBCL

Author:

Xu-Monette Zijun Y.1ORCID,Li Yong2ORCID,Snyder Thomas3ORCID,Yu Tiantian1ORCID,Lu Tingxun1ORCID,Tzankov Alexandar4ORCID,Visco Carlo5ORCID,Bhagat Govind6ORCID,Qian Wenbin7ORCID,Dybkaer Karen8ORCID,Chiu April9ORCID,Tam Wayne10ORCID,Zu Youli11ORCID,Hsi Eric D.12ORCID,Hagemeister Fredrick B.13ORCID,Wang Yingjun14ORCID,Go Heounjeong15ORCID,Ponzoni Maurilio16ORCID,Ferreri Andrés J.M.16ORCID,Møller Michael B.17ORCID,Parsons Benjamin M.18ORCID,Fan Xiangshan19ORCID,van Krieken J. Han20ORCID,Piris Miguel A.21ORCID,Winter Jane N.22ORCID,Au Qingyan23ORCID,Kirsch Ilan3ORCID,Zhang Mingzhi14ORCID,Shaughnessy John24ORCID,Xu Bing25ORCID,Young Ken H.126ORCID

Affiliation:

1. 1Hematopathology Division and Department of Pathology, Duke University Medical Center, Durham, North Carolina.

2. 2Department of Medicine, Baylor College of Medicine, Houston, Texas.

3. 3Adaptive Biotechnologies, Seattle, Washington.

4. 4Institute of Pathology, University Hospital Basel, Basel, Switzerland.

5. 5Department of Hematology, University of Verona, Verona, Italy.

6. 6Columbia University Irving Medical Center and New York Presbyterian Hospital, New York, New York.

7. 7Department of Hematology, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.

8. 8Aalborg University Hospital, Aalborg, Denmark.

9. 9Mayo Clinic, Rochester, Minnesota.

10. 10Weill Medical College of Cornell University, New York, New York.

11. 11The Methodist Hospital, Houston, Texas.

12. 12Wake Forest University, Winston-Salem, North Carolina.

13. 13Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.

14. 14The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

15. 15Asan Medical Center, Ulsan University College of Medicine, Seoul, Korea.

16. 16San Raffaele H. Scientific Institute, Milan, Italy.

17. 17Odense University Hospital, Odense, Denmark.

18. 18Gundersen Lutheran Health System, La Crosse, Wisconsin.

19. 19Pathology Center, Anhui Medical University and the first Affiliated Hospital, Hefei, China.

20. 20Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.

21. 21Hospital Universitario Marqués de Valdecilla, Santander, Spain.

22. 22Feinberg School of Medicine, Northwestern University, Chicago, Illinois.

23. 23NeoGenomics Laboratories, Aliso Viejo, California.

24. 24Myeloma Center, Winthrop P. Rockefeller Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas.

25. 25The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China.

26. 26Duke Cancer Institute, Durham, North Carolina.

Abstract

Abstract Purpose: Tumor-infiltrating B lymphocytes (TIL-B) have demonstrated prognostic and predictive significance in solid cancers. In this study, we aimed to distinguish TIL-Bs from malignant B-cells in diffuse large B-cell lymphoma (DLBCL) and determine the clinical and biological significance. Experimental Design: A total of 269 patients with de novo DLBCL from the International DLBCL R-CHOP Consortium Program were studied. Ultra-deep sequencing of the immunoglobulin genes was performed to determine B-cell clonotypes. The frequencies and numbers of TIL-B clonotypes in individual repertoires were correlated with patient survival, gene expression profiling (GEP) data, and frequencies of DLBCL-infiltrating immune cells quantified by fluorescent multiplex IHC at single-cell resolution. Results: TIL-B abundance, evaluated by frequencies of normal B-cell clonotypes in the immunoglobulin repertoires, remarkably showed positive associations with significantly better survival of patients in our sequenced cohorts. DLBCLs with high versus low TIL-B abundance displayed distinct GEP signatures, increased pre-memory B-cell state and naïve CD4 T-cell state fractions, and higher CD4+ T-cell infiltration. TIL-B frequency, as a new biomarker in DLBCL, outperformed the germinal center (GC) B-cell–like/activated B-cell–like classification and TIL-T frequency. The identified TIL-B–high GEP signature, including genes upregulated during T-dependent B-cell activation and those highly expressed in normal GC B cells and T cells, showed significant favorable prognostic effects in several external validation cohorts. Conclusions: TIL-B frequency is a significant prognostic factor in DLBCL and plays a crucial role in antitumor immune responses. This study provides novel insights into the prognostic determinants in DLBCL and TIL-B functions with important therapeutic implications.

Funder

National Center for Advancing Translational Sciences

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

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