INTRODUCTION
Acute myeloid leukemia (AML) is a heterogeneous group of disorders
characterized by malignant clonal proliferation of myeloid blast cells
in the bone marrow (BM) and peripheral blood, leading to cytopenia,
infections, and bleeding 1,2. Although many
therapeutic interventions have been explored to treat patients with AML,
chemotherapeutic regimens remain a crucial therapy component for these
patients 3. In the AML treatment chemotherapy
guideline, the two antineoplastic agents, fludarabine and busulfan, are
well-known. Fludarabine shows promising results in treating
relapsed/refractory patients with AML; however, the neurotoxicity effect
of this agent limits the use of high-dose fludarabine4. Despite its lower costs and acceptable efficiency
over the decades, the significant side effects of busulfan, including
mucositis of grade 2 or higher, led to the displacement of this agent
with more expensive but secure monoclonal antibody imatinib5. To date, NK cell-based immunotherapy is one of the
most current innovative immunotherapeutic techniques, unleashing the
immunological suppression of NK cells to attack a variety of
malignancies 6. In AML, dysfunctional NK cells or
immunosuppressive features of AML cells and their prognostic relevance
justify using NK cell-based immunotherapy to restore impaired NK cell
cytotoxicity against AML 7. Meanwhile, treatment with
busulfan and fludarabine inactive NK cells (PMID: 2933271) with unknown
mechanism. Another defined mechanism that makes weak NK cells, as well
as T cells in patients with AML, is overexpression of inhibitory immune
checkpoint molecules such as programmed cell death ligand-1 (PD-L1) and
PD-L2 up-regulated in blasts 8. Furthermore, Heat
shock protein 70 KDa (Hsp70) is an essential component of the protein
folding system called chaperones and protects the cells from
stress-induced damage 5. Hsp70 as an antigenic peptide9 can be used as a tumor-specific vaccine10. Furthermore, Hsp70 induces the release of
pro-inflammatory cytokines from innate immune cells, increasing the
expression of costimulatory molecules 11. In addition,
Hsp70 activates the NK cell cytotoxic effects against the Hsp70
representing tumor cells 12. Despite promising
outcomes resulting from investigations performed on PD-1 blocker base
immunotherapy on solid tumors, the efficacy of this approach is not
studied on hematologic malignancies. Therefore, in the present study, we
assessed the combined effect of PD-1 blocker and Hsp70 on the activation
of NK cells derived from patients with relapsed AML under treatment of
Busulfan and fludarabine.