UnTAM
Unleashing the tumour associated macrophage (TAM) workforce to fight against cancer from the inside
Tumor-associated macrophages (TAMs) constitute as much as 50% of the mass in certain tumour tissues. New trends in the field of cancer treatment are starting to consider this particular type of cells as a therapeutic target, particularly in tumor subtypes where other targets are not available (a good example is triple-negative breast cancer, TNBC). However, it is still an open question whether TAMs can be safely utilized as a therapeutic target. Macrophages in general can be polarized into M1 or M2 phenotypes by their local environment. While M1 macrophages present bactericidal, pro-inflammatory and immunostimulatory activities, M2 phenotype promote tissue repair, angiogenesis, matrix remodeling and immunosuppression.
Overall, M1 type TAMs are considered to present anti-tumor activity while M2 are regarded as pro-tumoral. Unfortunately, TAMs are largely polarized into the M2 phenotype, giving support to the growth and metastasis of the tumor mass. Thus, a depletion of TAMs via a targeted strategy would have a dual positive effect on tumor progression, i) tumor burden would be greatly reduced and ii) the local immunosuppressive environment of the tumor would be (to some extend) relieved.
A number of strategies have been proposed and tested in this direction. Here we propose to go a step further and instead of targeting TAMs aiming at their depletion, we hypothesize that these large colony of macrophages already in the tumour site can be reprogrammed into M1 anti-tumor macrophages and they can be unleashed to lead the attack against cancer from the inside. In order for this strategy to be successful, the reprogramming of TAMs must take place at a local level, because the systemic activation of M1 macrophages would have dramatic consequences.
To achieve this specific M1 TAM polarization we propose to combine a TAM targeted drug delivery system (DDS) to deliver immunostimulating drugs, with local external triggering of the drug release. On top of this, a longitudinal monitoring of the response-to-treatment will be implemented through non-invasive magnetic resonance imaging(MRI).