Preventing outgrowth of brain metastases under immunotherapy : Driving T-cells to the brain

Melanoma patients are at high risk of developing brain metastases, and despite being treated, their survival is still measured in weeks or months. Sustained disease control within the brain parenchyma is complicated due to poor drug penetration via blood-brain-barrior (BBB) but also by intrinsic and acquired drug resistance of brain metastases. One reason for this is the high phenotypic plasticity of melanoma cells, which promotes the rapid emergence of resistant cell subpopulations.

The brain microenvironment plays an important role in the development of metastasis, as the nature of the interaction between tumor cells and brain resident cells, as well as the molecules secreted and expressed during this process, collectively influence how the immune system will respond to invasion. In melanoma brain metastases, the interplay of immune suppressor mediators such as indoleamine 2,3-dioxygenase (IDO) and Programmed death-ligand 1 (PD-L1), are not well understood. The expression of both markers was studied in the context of immune cell recruitment both intra- and peritumoral in matched and un-matched patient tissues from metastatic melanoma in the brain. It was found that the main source of IDO was microglia/macrophages, which in turn influenced the recruitment and number of primary CD8+ cells.

In light of these findings, several treatment strategies were established in preclinical models in order to boost the T-cell recruitment to the brain and enhance the effect of ICIs (immune checkpoints inhibitors) on metastatic lesions. The recruitment of TILs (T-infiltrating lymphocytes) to brain and subcutaneous tumors was analysed in two animal models, in a primary melanoma model with spontaneous tumor development (MT/ret) and syngeneic transplantation models. It was demonstrated that regardless of the animal model and differences in therapeutic strategies, the brain metastatic lesions remain difficult to treat, as brain restricts the entry of peripheral immune cells. Despite T cell infiltration increase inside extracranial lesions after ICIs, these peripheral immune cells seem to have no major effect within metastatic lesions in the brain.

Thus, melanoma cell lines, derived from various metastatic tissues, were established from the MT/ret animal model to characterize so called “homing” factors associated with their adaptive success in the challenging environment of the brain. Melanoma cells penetrating the brain have been shown to possess important alterations on the genetic level for migration, intravasation and differentiation that may be essential for colonization and expansion. These multiple genetic variations, favored during the metastatic process, could determine the metastatic behavior seen in vitro and in vivo in contrast to the cells originating from subcutaneous tumors.  In turn the cells´ behavior affects both innate and adaptive immune responses that may influence the outcome inside and outside of the brain parenchyma seen in human to the therapeutic drug.


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