Melanoma–T Cell Interactions Affect the Neoantigen Repertoire

Cancer immunotherapies, such as adoptive T-cell transfer (ACT), are predicated on the ability of lymphocytes to recognize tumor neoantigens, which arise from tumor-specific somatic mutations. However, T cell–dependent immunoselection drives cancer immunoediting in animal models and induces the loss of defined neoantigens, which results in the outgrowth of nonimmunogenic clones and may lead to therapeutic resistance. To ascertain the stability of T cell–recognized neoantigens in patients, Verdegaal and colleagues characterized the expression and T-cell recognition of neoantigens in two patients with melanoma treated with ACT. For both patients, melanoma cell lines were generated from metastatic and recurrent lesions and tumor-infiltrating lymphocyte (TIL) cell lines were generated either independently or concurrently with the melanoma cell lines. In the first patient, T-cell reactivity to the neoepitopes KIA0020^P451L and RPL28^S76F was detectable in peripheral blood before ACT, increased after ACT, and decreased after tumor regression. TILs isolated from the brain metastasis exhibited reactivity for KIA0020^P451L, but not RPL28^S76F, in the primary tumor. Consistent with this finding, KIA0020^P451L, but not RPL28^S76F, was clonally present in the cell line and archived tissue from the brain metastasis. In the second patient, tumor-reactive T cells obtained by repeated stimulation of peripheral blood mononuclear cells with pre-ACT melanoma cells reacted to three different neoantigens that were lost or showed reduced expression in tumor cells from a recurrent lesion. Post-ACT TILs exhibited reactivity to an additional neoantigen that was expressed in the pre-ACT cell line and expression was increased in the post-ACT cell line, suggesting that changes in the tumor neoantigen repertoire may induce novel neoantigen-specific T-cell responses. These findings provide evidence that T cell–mediated immunoselection drives cancer immunoediting in patients with melanoma and suggest that broadening neoantigen-specific T-cell responses may overcome immunoediting-induced therapeutic resistance.

Verdegaal EM, de Miranda NF, Visser M, Harryvan T, van Buuren MM, Andersen RS, et al. Neoantigen landscape dynamics during human melanoma–T cell interactions. Nature 2016 Jun 27 [Epub ahead of print].

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