Combination therapy with nilotinib and PDL1 blockade reverses CD4 T cell dysfunction and prevents relapse in acute B cell leukemia

ABSTRACT: Patients with acute lymphoblastic leukemia have experienced significantly improved outcomes due to the advent of chimeric antigen receptor T-cells and bispecific T-cell engagers, although a proportion of patients still relapse despite these advances. T cell exhaustion has been recently suggested to be an important driver of relapse in these patients. Indeed, phenotypic exhaustion of CD4+ T-cells are predictive of relapse and poor overall survival in B-ALL. Thus, therapies that counter T cell exhaustion, such as immune checkpoint blockade, may improve leukemia immunosurveillance and prevent relapse. Here, we used a murine model of Ph+ B-ALL as well as human bone marrow biopsy samples to assess the fundamental nature of CD4+ T-cell exhaustion and the preclinical therapeutic potential for combining anti-PDL1 based checkpoint blockade with tyrosine kinase inhibitors targeting the BCR-ABL oncoprotein. scRNA-seq analysis revealed that B-ALL induces a unique subset of CD4+ T-cells with both cytotoxic and helper functions. Combination treatment with the tyrosine kinase inhibitor nilotinib and anti-PDL1 dramatically improves long-term survival of leukemic mice. Depletion of CD4 T cells prior to therapy completely abrogates the survival benefit, implicating CD4 T cells as key drivers of the protective anti-leukemia immune response. Indeed, treatment with anti-PDL1 leads to clonal expansion of leukemia-specific CD4 T cells with the afore-mentioned cytotoxic/helper phenotype, as well as reduced expression of exhaustion markers. These findings support efforts to utilize PD1/PD-L1 checkpoint blockade in clinical trials and highlight the importance of CD4+ T-cell dysfunction in limiting the endogenous anti-leukemia response.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE195964 | GEO | 2022/07/15

REPOSITORIES: GEO