Harnessing NK cells by genetic and epigenetic rerouting to overcome Multiple Myeloma immune evasion.
Multiple myeloma (MM) is a clonal B cell malignancy characterized by an excess of mature plasma cells (PCs) in the bone marrow (BM). Natural Killer (NK) cells represent a subset of innate lymphoid cells that play a key role in the immunosurveillance of MM thanks to their capability to directly recognize and kill MM cells. MM is intrinsically linked with the immune system and its development can induce relevant NK cell alterations resulting in poor disease control. In addition, increasing evidence show the extreme heterogeneity and plasticity of NK cell populations in terms of functional response.
A number of evidence in MM patients strongly support the antitumor potential of NK cells in response to the immunomodulatory drugs (IMiDs). However, the molecular mechanisms mediating these effects and the resistance to these drugs remain largely undefined. On the other hand, epigenetic modulation is emerging as a novel target for cancer therapy. Based on these observations, several innovative approaches to enhance NK cell responsiveness to fight MM and reverse tumor mediated immune paralysis may be promising.
We hypothesize that different factors contribute to alter NK cell subset maturation, distribution and functionality during MM progression and that the NK cell "reprogramming" by epigenetic drugs can be a successful strategy to modulate and increase NK cell functionality during therapy.
In this context, the identification of distinct NK cell subsets endowed with peculiar functional competence will help to understand how their function is deregulated during MM progression and in response to IMiDs therapy.
The characterization of epigenetic drugs able to modulate and reset NK cell subset functions will allow to design new therapeutic strategies in high risk/refractory MM patients, aimed at promoting and "resetting" NK cell-based anti-MM immune response.