Introduction: Acute myeloid leukaemia (AML) is an age-related disease with a median age at diagnosis of 71. Combined with co-morbidities, survival of patients with AML above this age bracket is poor with 90% of older adults dying of their disease. Even in younger patients who achieve remission with chemotherapy, relapse is common and occurs from minimal residual disease sequestered in protective niches in the bone marrow microenvironment (BMM). AML as a disease is highly dependent on the bone marrow microenvironment and accordingly it is envisaged that improved outcomes will come from novel treatment strategies derived from an improved understanding of the biology of AML within the bone marrow and their interaction with the immune cells therein.
Objective: Here, we investigate a possible immune evasive mechanism imparted by AML blasts attributed to their localization within the BMM.
Methods and Results: Using RNA-seq data generated from bone marrow derived AML (BM-AML) compared to peripheral blood derived AML (PB-AML) (GEO ID: GSE49642, GSE48846) we identified SDF-1 as the most differentially expressed in favour of BM-AML. Further investigation using matched primary clinical samples (BM verses PB) by real-time PCR analysis and ELISA confirmed the in-silico findings. In addition, primary AML engrafted into NSG mice demonstrated high SDF-1 in the BM derived AML blasts compared to AML blasts derived from the spleen. Lentiviral knock-down of SDF-1 in the AML blasts impaired blast engraftment and prolonged survival of the animals. SDF1-mediated migration of T-cell subsets have been previously identified using varying concentrations of SDF1. We therefore, investigated the migration of CD8+ T cells when co-cultured with AML. We show that CD8+ T-cells migrate away from AML when in culture and this fugetaxis is reduced by the knock-down of SDF1 in the blasts.
Conclusion: We conclude that SDF-1 is secreted by the AML blasts within the BMM contributing to fugetaxis of CD8+ cells away from the blasts. Implications of these finding suggest a possible immune evasive mechanism by the blasts that can be manipulated to potentiate CD8+ infiltration into the AML bone marrow.
Citation Format: Manar S. Shafat, Amina A. Abdul-Aziz, Christopher Marlien, Rachel Piddock, Kristian M. Bowles, Stuart A. Rushworth. Acute myeloid leukemia derived SDF1 repels tumor infiltrating lymphocytes in the bone marrow microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3131.