Figure 1. Resistance to adoptive T cell therapy via dedifferentiation. As reported by Landsberg et al., melanoma cells can undergo inflammation-induced dedifferentiation. The process is a potential acquired resistance mechanism against adoptive cell transfer therapies.

(I) Melanoma cells exposed to the proinflammatory cytokine tumor necrosis factor-α (TNF-a) undergo reversible dedifferentiation. Cells with the dedifferentiated phenotype show downregulated expression of melanocytic antigens.

(II) Adoptive cell transfer therapies for melanoma can involve the infusion of T cells engineered to express antigen receptors that recognize melanocytic antigens. The dedifferentiation mechanism could contribute to resistance against such therapies.

Infused T cells recognize antigens expressed by the melanoma cells and trigger an immune response (II[a]). However, TNF-a released by these T cells during the immune response also can trigger the dedifferentiation process (II[b]). The infused T cells are unable to recognize dedifferentiated melanoma cells. Over time, these dedifferentiated cells regrow and become the dominant cellular phenotype in the tumor (II[c]).