Abstract
Although it is firmly established that endogenous immunity can prevent cancer outgrowth, with a range of immunomodulatory strategies reaching clinical use, most studies on the topic have been restricted to solid cancers. This applies in particular to cancer initiation, where model constraints have precluded investigations of immunosurveillance and immunoediting during the multistep progression into acute myeloid leukemia (AML). Here, we used a mouse model where the chimeric transcription factor MLL-ENL can be conditionally activated in vivo as a leukemic "first-hit," which is followed by spontaneous transformation into AML. We observed similar disease kinetics regardless of whether AML developed in WT or immunocompromised hosts, despite more permissive preleukemic environments in the latter. When assessing transformed AML cells from either primary immunocompetent or immunocompromised hosts, AML cells from all sources could be targets of endogenous immunity. Our data argue against immunoediting in response to selective pressure from endogenous immunity as a universal primary transformation event in AML.
Highlights
Acute myeloid leukemia (AML) is a highly aggressive form of blood cancer that emanates from hematopoietic progenitor cells arrested in differentiation
It has been a long-standing idea that spontaneously arising cancer cells for the most part are eliminated by the endogenous immune system (Burnet, 1957), and CD8+ cytotoxic T cells and NK
We designed an approach to study the influence of the immune system on the recognition, eradication, and potential immunoediting ofleukemic cells during transformation into AML (Fig 1A)
Summary
Acute myeloid leukemia (AML) is a highly aggressive form of blood cancer that emanates from hematopoietic progenitor cells arrested in differentiation. The key proposed mechanisms include the elimination of cancerous cells via neo- or other tumor-associated antigens that arise as a consequence of mutations and/or alternative molecular changes (DuPage et al, 2012; Matsushita et al, 2012) or the prevention of formation of tumor-promoting environments (Schreiber et al, 2011). In this view, tumor progression represents a continuous battle between endogenous immunity and developing preleukemic cells. The immunogenicity to established AML was mediated by CD8+ cells which rapidly developed signs of exhaustion during propagation of AML
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