B cell leukemia elicits a suppressive Tr1-CD4+ T cell response that can be reprogrammed with PDL1-blockade.

Abstract

Current therapies induce an initial remission in most patients with B cell acute lymphoblastic leukemia (B-ALL). However, a majority of B-ALL patients experience a subsequent relapse and thus have poor long-term survival. CD4+ T cells expressing inhibitory receptors associated with “dysfunctional” T cells have been strongly correlated with leukemia relapse. However, antibody-mediated blockade of those inhibitory receptors (“checkpoint blockade”) has not been effective by itself. Using a murine model of BCR-ABL+ B-ALL, we showed that combining PDL1 checkpoint blockade with targeted therapy via the tyrosine kinase inhibitor nilotinib prevented leukemia relapse and improved survival. Depletion of CD4+ T cells abrogated the efficacy of the combination therapy, pointing to a key role for CD4s in preventing leukemia relapse. Although inhibitory receptor-expressing (IRhi) T cells are usually associated with impaired effector function, we showed that IRhi CD4+ T cells from leukemic mice upregulated genes associated with immune-suppressive CD4+ T cells. Indeed, IRhi CD4+ T cells from leukemic mice resembled a subset of CD4s that are elicited by hematopoetic stem cells (HSCs) to maintain immune-tolerance within the HSC niche. We showed that B-ALL co-opts this HSC-driven program to induce immune-suppressive “Tr1” CD4+ T cells. The immune-suppressive activity of Tr1s that protects healthy HSCs is utilized by B-ALL to evade T cell surveillance. Unlike exhausted CD8+ T cells, CD4+ Tr1s do not epigenetically silence effector cytokines-indicative of a state distinct from T cell-intrinsic dysfunction. Treatment of leukemic mice with nilotinib alone resulted in an expansion of effector CD8 T cells, but also a significant expansion of immune-suppressive Tr1 CD4+ T cells. In contrast, treatment with nilotinib and PDL1 blockade together resulted in a reduction in Tr1s, and an increase in Th1-memory CD4+ T cells that correlated with prevention of relapse. Mice that were successfully treated with nilotinib and PDL1 blockade were able to resist a leukemia re-challenge in a CD4+ T cell-dependent manner, pointing to the protective ability of anti-leukemia memory CD4+ T cells. We observed a similar population of Tr1-CD4s in human B-ALL patients, which correlated with worse prognosis. Thus, B-ALL induces CD4+ T cells to adopt an immune-suppressive Tr1 state; which can be reprogrammed by treatment with nilotinib and anti-PDL1 blockade, thereby preventing relapse.