(ChemotherapyAdvisor) – Inflammation can trigger reversible losses of antigens from melanoma cell surfaces, cloaking tumors from T-cell detection, report authors of a study published in the journal Nature. The finding might help explain melanoma resistance and relapse after initially-effective immunotherapy, the authors reported.
“Adaptive cell transfer therapies (ACTs) using cytotoxic T-cells that target melanocytic antigens can achieve remissions in patients with metastatic melanomas, but tumors frequently relapse,” wrote Thomas Tüting, MD, Director of the Laboratory for Experimental Dermatology at the Bonn University in Germany. “Our results demonstrate that the phenotypic plasticity of melanoma cells in an inflammatory microenvironment contributes to tumor relapse after initially successful T-cell immunotherapy.”
Using genetically-engineered mice and human melanoma cells, the team found that melanomas can “acquire ACT resistance through an inflammation-induced reversible loss of melanocytic antigens,” the authors wrote. In serial transplantation experiments, the team was able to switch melanoma cell phenotypes back and forth between differentiated and dedifferentiated states, using T-cell-mediated inflammation.
“We identified the proinflammatory cytokine tumor necrosis factor (TNF)-α as a crucial factor that directly caused reversible dedifferentiation of mouse and human melanoma cells,” the authors reported.
TNF-α-exposed tumor cells were not well recognized by T cells specific for melanocytic antigens, but recognition by T cells specific for non-melanocytic antigens was “unaffected or even increased,” they noted.
The results bolster increasing evidence for the “important role of dynamic changes in the (tumor) microenvironment as a mechanism of therapy resistance that is at present also emerging for targeted inhibitors of signal transduction pathways in BRAF(V600E) mutant melanomas,” they wrote.
“On the basis of our work, we propose that future ACT protocols should simultaneously target melanocytic and non-melanocytic antigens to ensure broad recognition of both differentiated and dedifferentiated melanoma cells, and include strategies to sustain T-cell effector functions by blocking immune-inhibitory mechanisms in the tumor microenvironment,” they concluded.