T Cell Transcriptional Profiling and Immunophenotyping Uncover LAG3 as a Potential Significant Target of Immune Modulation in Multiple Myeloma

• Published in: Biology of blood and marrow transplantation 2020-01, Vol.26 (1), p.7-15
• Main Authors: Lucas, Fabienne, Pennell, Michael, Huang, Ying, Benson, Don M., Efebera, Yvonne A., Chaudhry, Maria, Hughes, Tiffany, Woyach, Jennifer A., Byrd, John C., Zhang, Suohui, Jones, Desiree, Guan, Xiangnan, Burd, Christin E., Rosko, Ashley E.
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antigens, CD - blood; Antigens, CD - immunology; Autografts; Autologous stem cell transplant; Biomarkers, Tumor - blood; Biomarkers, Tumor - immunology; CD4-CD8 Ratio; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - pathology; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - pathology; Exhaustion; Female; Gene Expression Profiling; Hematopoietic Stem Cell Transplantation; Humans; Immunophenotyping; LAG3; Lymphocyte Activation; Male; Middle Aged; Multiple myeloma; Multiple Myeloma - blood; Multiple Myeloma - immunology; Multiple Myeloma - therapy; Neoplasm Proteins - blood; Neoplasm Proteins - immunology; Prospective Studies; Senescence
• ISSN: 1083-8791; 1523-6536
• DOI: 10.1016/j.bbmt.2019.08.009

•Autologous stem cell transplant (ASCT) induces global transcriptional T cell changes and altered molecular levels of markers of T cell subtypes, T cell activation, and exhaustion in patients with multiple myeloma.•High LAG3 transcript expression in T cells detectable as early as 3 months post-transplant is associated with inferior clinical outcomes in patients with myeloma.•ASCT affected soluble levels of molecules with immunomodulatory function by increasing plasma HVEM and TIM3.•ASCT promotes an exhausted immunophenotype in CD4+ cells and a senescent/anergic immunophenotype in CD8+ subsets.•Future work targeting immune defects in multiple myeloma is warranted to augment or restore T cell responses using the next generation of immune checkpoint inhibitors. Autologous stem cell transplant (ASCT) is the standard of care for patients with multiple myeloma (MM). The clinical significance of peripheral blood T lymphocyte (PBTL) immunologic changes associated with ASCT is poorly understood. Here we evaluated T cell transcriptional messenger RNA profiles and immunophenotypes to correlate immunologic senescence, exhaustion, and anergy with clinical endpoints in a cohort of patients with MM undergoing ASCT. ASCT induced global transcriptional T cell changes and altered molecular levels of markers of T cell subtypes, T cell activation, and exhaustion. These included reduced CD4/CD8 ratio, skewing toward the Th1 subset, reduced expression of costimulatory receptors CD27 and CD28, heightened T cell activation, and increased expression of immune modulatory molecules LAG3 and PD1. Multicolor flow cytometry experiments confirmed altered circulating CD4 and CD8 subsets and skewing toward differentiated effector cells. Moreover, ASCT promoted an exhausted immunophenotype in CD3+CD4+ subsets and a senescent immunophenotype in CD3+CD8+ subsets. Subset-specific altered expression was also seen for surface molecules with immunomodulatory function. ASCT affected soluble levels of molecules with immunomodulatory function by increasing plasma HVEM and TIM3. High molecular LAG3 level was associated with inferior event-free survival post-ASCT (hazard ratio = 5.44; confidence interval, 1.92 to 15.46; P = .001; adjusted P [controlling for false discovery rate] = .038). Using a comprehensive evaluation of PBTLs on a molecular and phenotypic level, we have identified that ASCT induces global T cell alterations with CD4 and CD8 subset-specific changes. Moreover, LAG3 emerged as an ear