PD-1 blockade in combination with dasatinib potentiates induction of anti-acute lymphocytic leukemia immunity.
Paul B KollerNatalia BaranKarine HarutyunyanAntonio CavazosSaradhi MallampatiRenee L ChinZhou JiangXian SunHeng-Huan LeeJennifer L HsuPatrick WilliamsXuelin HuangMichael A CurranMien-Chie HungMarina KonoplevaPublished in: Journal for immunotherapy of cancer (2023)
Immunotherapy, in the form of hematopoietic stem cell transplantation (HSCT), has been part of the standard of care in the treatment of acute leukemia for over 40 years. Trials evaluating novel immunotherapeutic approaches, such as targeting the programmed death-1 (PD-1) pathway, have unfortunately not yielded comparable results to those seen in solid tumors. Major histocompatibility complex (MHC) proteins are cell surface proteins essential for the adaptive immune system to recognize self versus non-self. MHC typing is used to determine donor compatibility when evaluating patients for HSCT. Recently, loss of MHC class II (MHC II) was shown to be a mechanism of immune escape in patients with acute myeloid leukemia after HSCT. Here we report that treatment with the tyrosine kinase inhibitor, dasatinib, and an anti-PD-1 antibody in preclinical models of Philadelphia chromosome positive B-cell acute lymphoblastic leukemia is highly active. The dasatinib and anti-PD-1 combination reduces tumor burden, is efficacious, and extends survival. Mechanistically, we found that treatment with dasatinib significantly increased MHC II expression on the surface of antigen-presenting cells (APC) in a tumor microenvironment-independent fashion and caused influx of APC cells into the leukemic bone marrow. Finally, the induction of MHC II may potentiate immune memory by impairing leukemic engraftment in mice previously cured with dasatinib, after re-inoculation of leukemia cells. In summary, our data suggests that anti-PD-1 therapy may enhance the killing ability of dasatinib via dasatinib driven APC growth and expansion and upregulation of MHC II expression, leading to antileukemic immune rewiring.
Keyphrases
- acute myeloid leukemia
- chronic myeloid leukemia
- acute lymphoblastic leukemia
- bone marrow
- induced apoptosis
- poor prognosis
- cell cycle arrest
- allogeneic hematopoietic stem cell transplantation
- end stage renal disease
- chronic kidney disease
- cell surface
- type diabetes
- metabolic syndrome
- adipose tissue
- palliative care
- stem cells
- gene expression
- electronic health record
- ejection fraction
- binding protein
- drug delivery
- risk factors
- deep learning
- liver failure
- intensive care unit
- cell proliferation
- respiratory failure
- replacement therapy
- acute respiratory distress syndrome
- health insurance
- high fat diet induced
- insulin resistance
- aortic dissection