Intratumoral CD4⁺ T Cells Recognize Melanoma Neoantigens

Cancers with high mutational loads, such as melanoma, are considered attractive candidates for immunotherapy because mutations can create tumor-specific neoantigens that are foreign to the immune system. Tumor-infiltrating CD8⁺ T cells have been shown to recognize neoantigens, but despite the known importance of CD4⁺ T cells (“helper T cells”) in tumor control in preclinical models, it is unclear whether neoantigen-specific CD4⁺ T-cell reactivity is a common feature of human cancers. Linnemann, van Buuren, Bies, and colleagues developed a screening platform to evaluate CD4⁺ T-cell responses to tumor neo-epitopes in patients with melanoma in which peptides spanning tumor-specific nonsynonymous mutations identified by whole-exome sequencing were loaded onto immortalized autologous B cells and incubated with intratumoral CD4⁺ T cells, after which supernatants were evaluated for the presence of cytokines such as IFNγ as a measure of CD4⁺ T-cell activation. Overall, neoantigen reactivity was observed in 4 out of 5 patients, and against multiple neoantigens in two patients. In all cases, the neoantigen was preferentially or exclusively recognized when compared with the nonmutated parental peptides, and all mutations for which CD4⁺ T-cell reactivity was detected were unique to that tumor among over 400 melanomas. Two of the patients analyzed experienced clinical responses to adoptive T-cell therapy, and in both patients, neoantigen-specific CD4⁺ T-cell responses in peripheral blood were induced by therapy. In one case, these neoantigen-reactive CD4⁺ T cells produced IFNγ when incubated with the tumor cells themselves, providing evidence for direct recognition of neoantigens displayed on tumor cells, at least in some cases. These results indicate that CD4⁺ T-cell reactivity toward patient-specific neoantigens is a common feature of melanoma and suggest that therapeutic strategies to boost CD4⁺ T-cell responses may be effective in melanoma and other cancers with similar mutational loads.

Linnemann C, van Buuren MM, Bies L, Verdegaal EM, Schotte R, Calis JJ, et al. High-throughput epitope discovery reveals frequent recognition of neo-antigens by CD4⁺ T cells in human melanoma. Nat Med 2015;21:81–5.

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