Inflammation-driven reversible dedifferentiation of melanoma cells impairs recognition by CTLs.

  • Major finding: Inflammation-driven reversible dedifferentiation of melanoma cells impairs recognition by CTLs.

  • Mechanism: TNF-α promotes loss of melanocytic antigens and expression of the neural crest marker NGFR.

  • Impact: Targeting of both melanocytic and nonmelanocytic antigens is necessary for successful therapy.

Adoptive T-cell transfer of CD8-positive, tumor antigen-specific cytotoxic T lymphocytes (CTL) induces tumor regression in patients with metastatic melanoma. However, these resp onses are not durable, and tumors frequently reoccur due to acquired resistance to CTL therapy. To identify the mechanisms underlying this resistance, Landsberg and colleagues used a mouse model of melanoma driven by overexpression of hepatocyte growth factor and oncogenic mutant cyclin-dependent kinase 4 together with an adoptive T-cell transfer protocol that recapitulated the tumor regression, remission, and relapse observed in patients with melanoma. In addition to reduced T-cell effector function, a subset of relapsed tumors in these mice exhibited increased immune cell infiltration and loss of melanocytic differentiation antigens such as gp100, resulting in diminished tumor recognition by melanoma antigen-specific CTLs and suggesting that these tumors may have undergone dedifferentiation. In support of this idea, pigmentation gene expression was reduced in relapsed tumors and was accompanied by upregulation of immune-response and mesenchymal genes, as well as induction of the neural crest marker nerve growth factor receptor (NGFR). Intriguingly, this process was reversible, as gp100 expression and CTL recognition were restored in vivo in retransplanted tumor cells but were subsequently reduced again in tumors that developed resistance. These changes in gene expression were dependent on immune-cell–derived TNF-α secretion, which stimulated NGFR and reduced gp100 expression, whereas inhibition of TNF-α enhanced gp100 expression and tumor recognition by CTLs. Importantly, TNF-α induced a similar dedifferentiated phenotype in human melanoma cell lines and resulted in selective impairment of tumor cell recognition by melanoma-specific CTLs compared with CTLs specific for nonmelanocytic antigens. These results implicate dynamic changes in tumor differentiation status induced by the inflammatory microenvironment as a mechanism of resistance to adoptive T-cell transfer and suggest strategies to improve the clinical efficacy of this therapy.

Landsberg J, Kohlmeyer J, Renn M, Bald T, Rogava M, Cron M, et al. Melanomas resist T-cell therapy through inflammation-induced reversible dedifferentiation. Nature 2012;490:412–6.

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