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.
Multiple Myeloma is an incurable hematologic cancer characterized by clonal expansion of cancerous plasma cells in the bone marrow (BM) and its development is supported by a progressive impairment of immunosurveillance, mainly attributable to T lymphocytes and NK cell alterations. In this regard, NK cells significantly contribute to anti-tumor immune response, due to their ability to expand during the early stages of this disease and to recognize and lyse cancer cells. Moreover, emerging evidence in myeloma patients strongly support the anti-tumor potential of NK cells in response to immunomodulatory drugs, or following allogeneic stem cell transplantation.
In this context, BM and peripheral NK cells become unable to efficiently counteract MM as the disease progresses; indeed, MM can inhibit NK cell functions directly by producing immune suppressive factors and/or by reducing their susceptibility to NK cell recognition. Indeed, MM cells undergo decreased surface expression of NK cell-activating ligands (e.g. NKG2DLs), while expressing the ligands of inhibitory receptors such as the ligand of PD-1 (PD-L1) and Gas6, a ligand of TAM receptors, likely providing a mechanism of tumor escape.
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. It remains unclear if in resistant or drug refractory MM patients, the expression and/or function of specific targets/regulators of IMiDs such as Cereblon or MEIS2 proteins may be altered in NK cells, thus affecting their anti-myeloma activity and/or their responsiveness to these drugs.
The comprehension of these mechanisms will help to clarify how IMiDs work and how to improve their activity, leading to the identification of cellular targets and processes affected by these drugs in NK cells. Moreover, it will provide important information about the possible role of these mechanisms in the development of acquired resistance to IMiDs leading also to the identification/use of different therapeutic strategies to fully exploit NK cell antitumor properties in the clinic.
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. The development and study of small molecules able to selectively target chromatin factors has been pursued for cancer therapy and, although a number of studies reveled a possible direct effect on NK cell-mediated functions (Kroesen M, et al. 2014. Oncotarget), still little information is available.
In this context one of the main objective of this proposal will be focused on the search for epigenetic drugs that can inhibit MM tumor growth directly and/or through regulated differentiation, mobilization and activation of NK cells.