Disease recurrence after allogeneic hematopoietic cell transplantation (allo-HCT) is frequently driven by failure of the donor immune system at controlling the outgrowth of residual cancer cells. Intriguingly, acute myeloid leukemia (AML) relapses after allo-HCT often occur in extramedullary (EM) sites, suggesting a causative link between altered tissue homing and immune escape, and exemplifying how the microenvironment can impact on the efficacy of adoptive immunotherapy.
In the present project, a transnational consortium will investigate the mechanisms driving EM AML relapses, leveraging on the key positioning of the six partners in national networks to accrue a sizable cohort of cases, and taking advantage of their consolidated and complementary expertise in the use of cutting-edge methodologies to study primary patient samples.
In particular, we will combine the latest omic technologies to "pixelize" EM relapses into their finest details, and then reconstruct and validate their driver processes through advanced ex vivo functional assays and in vivo animal modeling. We will investigate whether the escape mechanisms described in the bone marrow have a role also in EM sites, if the pathological kinase signaling that is characteristic of EM AML affects the immune microenvironment, and how oxidative stress and lactic acid metabolism come into play in this relapse modality.
Availability of samples collected longitudinally in time will provide the unique controls represented by the same tumor in its microenvironment of origin and before exposure to the immune selective pressure of allo-HCT, allowing to identify features that are unique to EM post-transplantation relapses, and to functionally validate their causative role.
Ultimate goal of the project will be to understand which of the distinctive features of EM relapses is necessary for their emergence and maintenance, and could thus represent a vulnerability to be exploited for targeted therapeutic approaches.