Patients with acute lymphoblastic leukemia have experienced significantly improved outcomes due to the advent of chimeric antigen receptor (CAR) 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 is predictive of relapse and poor overall survival in B-cell acute lymphoblastic leukemia (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–PD-L1 based checkpoint blockade with tyrosine kinase inhibitors targeting the BCR-ABL oncoprotein. Single-cell RNA-sequence 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–PD-L1 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–PD-L1 leads to clonal expansion of leukemia-specific CD4+ T cells with the aforementioned helper/cytotoxic phenotype as well as reduced expression of exhaustion markers. These findings support efforts to use PD1/PD-L1 checkpoint blockade in clinical trials and highlight the importance of CD4+ T-cell dysfunction in limiting the endogenous anti-leukemia response.
Bibliographical noteFunding Information:
This work was supported by a hematology training grant (T32HL007062) (S.I.T.). Funding was provided by the Masonic Cancer Center and an R01 grant (R01 CA232317), a grant from Merck (M.A.F.), and a grant from the Children's Cancer Research Fund (M.A.F. and S.I.T.).
The authors thank G. Hubbard for assistance with mouse procedures; T. Martin, J. Motl, and P. Champoux for cell sorting and maintenance of the Flow Cytometry Core Facility at the University of Minnesota (5P01AI035296); and E. Stanley and UMGC core for assistance with scRNAseq. The authors also acknowledge the Minnesota Supercomputing Institute (MSI) at the University of Minnesota for providing computational resources. This work was supported by a hematology training grant (T32HL007062) (S.I.T.). Funding was provided by the Masonic Cancer Center and an R01 grant (R01 CA232317), a grant from Merck (M.A.F.), and a grant from the Children's Cancer Research Fund (M.A.F. and S.I.T.).
Conflict-of-interest disclosure: C.H. is currently an employee of Orion Pharma, Finland. V.B. received research funding from Bristol Myers Squib, Incyte, Gamida Cell, and FATE Therapeutics, received consultancy fees from Karyopharma and Gamida Cell, and is a board member of Miltenyi DSMB. M.A.F. received research funding from Merck. The remaining authors declare no competing financial interests.
© 2022 American Society of Hematology
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