T cell exhaustion and a failure in antigen presentation drive resistance to the graft-versus-leukemia effect

Meng Zhou, Faruk Sacirbegovic, Kai Zhao, Sarah Rosenberger and Warren D. Shlomchik ()
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Meng Zhou: University of Pittsburgh School of Medicine
Faruk Sacirbegovic: University of Pittsburgh School of Medicine
Kai Zhao: University of Pittsburgh School of Medicine
Sarah Rosenberger: University of Pittsburgh School of Medicine
Warren D. Shlomchik: University of Pittsburgh School of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-18

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-17991-y

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