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T cell exhaustion and a failure in antigen presentation drive resistance to the graft-versus-leukemia effect
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T cell exhaustion and a failure in antigen presentation drive resistance to the graft-versus-leukemia effect
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Journal Article
T cell exhaustion and a failure in antigen presentation drive resistance to the graft-versus-leukemia effect
2020
Overview
In hematopoietic cell transplants, alloreactive T cells mediate the graft-versus-leukemia (GVL) effect. However, leukemia relapse accounts for nearly half of deaths. Understanding GVL failure requires a system in which GVL-inducing T cells can be tracked. We used such a model wherein GVL is exclusively mediated by T cells that recognize the minor histocompatibility antigen H60. Here we report that GVL fails due to insufficient H60 presentation and T cell exhaustion. Leukemia-derived H60 is inefficiently cross-presented whereas direct T cell recognition of leukemia cells intensifies exhaustion. The anti-H60 response is augmented by H60-vaccination, an agonist αCD40 antibody (FGK45), and leukemia apoptosis. T cell exhaustion is marked by inhibitory molecule upregulation and the development of TOX
+
and CD39
−
TCF-1
+
cells. PD-1 blockade diminishes exhaustion and improves GVL, while blockade of Tim-3, TIGIT or LAG3 is ineffective. Of all interventions, FGK45 administration at the time of transplant is the most effective at improving memory and naïve T cell anti-H60 responses and GVL. Our studies define important causes of GVL failure and suggest strategies to overcome them.
In hematopoietic stem cell transplants, T cells mediate graft-versus-leukemia (GVL), but GVL can fail leading to leukemia relapse. Here the authors use a mouse model in which T cells target the minor histocompatibility antigen H60 to show how this can occur, characterize the CD8
+
T cell response and demonstrate how anti-CD40 antibody therapy improves GVL.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 64/60
/ Animals
/ Antigen Presentation - immunology
/ Antigens
/ Failure
/ Graft vs Leukemia Effect - immunology
/ Graft-versus-leukemia reaction
/ Grafting
/ Hematopoietic Stem Cell Transplantation - methods
/ Humanities and Social Sciences
/ Humans
/ Leukemia
/ Minor histocompatibility antigens
/ Minor Histocompatibility Antigens - genetics
/ Minor Histocompatibility Antigens - immunology
/ Minor Histocompatibility Antigens - metabolism
/ Science
