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Cd58 Alterations Govern Antitumor Immune Responses by Inducing Pdl1 and Ido in Diffuse Large B-Cell Lymphoma Publisher Pubmed



Xu X1 ; Zhang Y1 ; Lu Y1 ; Zhang X2 ; Zhao C3 ; Wang J1, 4 ; Guan Q1, 5 ; Feng Y1 ; Gao M1 ; Yu J1 ; Song Z1 ; Liu X1 ; Golchehre Z6 ; Li L1 Show All Authors
Authors
  1. Xu X1
  2. Zhang Y1
  3. Lu Y1
  4. Zhang X2
  5. Zhao C3
  6. Wang J1, 4
  7. Guan Q1, 5
  8. Feng Y1
  9. Gao M1
  10. Yu J1
  11. Song Z1
  12. Liu X1
  13. Golchehre Z6
  14. Li L1
  15. Ren W7
  16. Panhammarstrom Q7
  17. Zhang H1, 8
  18. Wang X1, 8
Show Affiliations
Authors Affiliations
  1. 1. National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Department of Lymphoma, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
  2. 2. State Key Laboratory of Experimental Hematology, Division of Pediatric Blood Diseases Center, Institute of Hematology and Blood Diseases Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Tianjin, China
  3. 3. National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Department of VIP Ward, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
  4. 4. Department of Lymphoma and Head and Neck Oncology, College of Clinical Medicine for Oncology, Fujian Medical University, Fuzhou, China
  5. 5. Department of Critical Care Medicine, Tianjin Cancer Hospital Airport Hospital, Tianjin, China
  6. 6. De-partment of Medical Genetics, Tehran University of Medical Sciences, Tehran, Iran
  7. 7. Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
  8. 8. Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin, 300060, China

Source: Cancer Research Published:2024


Abstract

Recurrent abnormalities in immune surveillance–related genes affect the progression of diffuse large B-cell lymphoma (DLBCL) and modulate the response to therapeutic interventions. CD58 interacts with the CD2 receptor on T cells and NK cells and is recurrently mutated and deleted in DLBCL, suggesting that it may play a role in regulating antitumor immunity. In this study, we comprehensively analyzed the genomic characteristics of CD58 through targeted next-generation sequencing, RNA sequencing (RNA-seq), whole-exome sequencing, and single-cell RNA-seq in patients with newly diagnosed DLBCL. The CD58 mutation rate was 9.1%, and the copy number loss rate was 44.7% among all enrolled patients with DLBCL. Notably, CD58 genetic alterations, along with low CD58 expression, significantly correlated with reduced rates of response to R-CHOP therapy and inferior progression-free survival and overall survival. Single-cell RNA-seq revealed that CD58 expression in tumor cells was negatively correlated with CD8+ T-cell exhaustion/dysfunction status. Insufficient T-cell activation resulting from CD58 alterations could not be attributed solely to CD2 signaling. CD58 inhibited the activity of the JAK2/STAT1 pathway by activating the LYN/CD22/SH2 domain–containing phosphatase 1 (SHP1) axis, thereby limiting PDL1 and IDO expression. Elevated PDL1 and IDO expression in CD58-deficient DLBCL cells led to immune evasion and tumor-intrinsic resistance to chimeric antigen receptor T-cell therapy. Direct activation of CD58–CD2 costimulatory signaling in combination with anti-PDL1 blockade or IDO inhibitor sensitized CD58-deficient DLBCL to chimeric antigen receptor T-cell therapy. Collectively, this work identified the multiple roles of CD58 in regulating antitumor immune responses in DLBCL. ©2024 American Association for Cancer Research.
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