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

ABSTRACT: 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 early biomarker of adverse events post-ASCT. These findings will support the development of treatment strategies targeting immune defects in MM to augment or restore T cell responses.

SUBMITTER: Lucas F

PROVIDER: S-EPMC6952061 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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

Lucas Fabienne F Pennell Michael M Huang Ying Y Benson Don M DM Efebera Yvonne A YA Chaudhry Maria M Hughes Tiffany T Woyach Jennifer A JA Byrd John C JC Zhang Suohui S Jones Desiree D Guan Xiangnan X Burd Christin E CE Rosko Ashley E AE

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 20190821 1

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 change ...[more]

PMID: 31445183

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Project description:Plasmablasts represent a specialized class of antibody-secreting effector B cells that transiently appear in blood circulation following infection or vaccination. The expansion of these cells generally tends to be massive in patients with systemic infections such as dengue or Ebola that cause hemorrhagic fever. To gain a detailed understanding of human plasmablast responses beyond antibody expression, here, we performed immunophenotyping and RNA sequencing (RNA-seq) analysis of the plasmablasts from dengue febrile children in India. We found that plasmablasts expressed several adhesion molecules and chemokines or chemokine receptors that are involved in endothelial interactions or homing to inflamed tissues, including skin, mucosa, and intestine, and upregulated the expression of several cytokine genes that are involved in leukocyte extravasation and angiogenesis. These plasmablasts also upregulated the expression of receptors for several B-cell prosurvival cytokines that are known to be induced robustly in systemic viral infections such as dengue, some of which generally tend to be relatively higher in patients manifesting hemorrhage and/or shock than in patients with mild febrile infection. These findings improve our understanding of human plasmablast responses during the acute febrile phase of systemic dengue infection. IMPORTANCE Dengue is globally spreading, with over 100 million clinical cases annually, with symptoms ranging from mild self-limiting febrile illness to more severe and sometimes life-threatening dengue hemorrhagic fever or shock, especially among children. The pathophysiology of dengue is complex and remains poorly understood despite many advances indicating a key role for antibody-dependent enhancement of infection. While serum antibodies have been extensively studied, the characteristics of the early cellular factories responsible for antibody production, i.e., plasmablasts, are only beginning to emerge. This study provides a comprehensive understanding of the transcriptional profiles of human plasmablasts from dengue patients.

Dataset Information

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

Publications

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

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