Response to Adoptive Cell Therapy Is Predicted by Stem-Like T Cells

In one form of adoptive cell therapy, patient-derived tumor-infiltrating lymphocytes (TIL) are expanded ex vivo and reintroduced into the patient. This can lead to tumor regression, but it is not clear what factors dictate whether such autologous TIL infusions are successful. Krishna, Lowery, and colleagues retrospectively examined the phenotypes of infused TILs in seven patients with stage IV melanoma who exhibited complete responses to TIL adoptive cell therapy and compared them with the TIL phenotypes associated with disease progression in nine additional patients. Single-cell mass cytometry analyses revealed a complete response–associated cluster of CD8⁺ T cells with high expression of CD44, CD27, and CD28 along with low expression of TIM3; this phenotype had previously been identified as memory-like and stem-like. Additionally, T cells in the complete response–associated cluster had low expression of CD39, an inhibitory marker, and CD69, an activation marker. In an independent cohort of 38 patients treated with TIL adoptive cell therapy, a higher frequency of CD8⁺CD39⁻CD69⁻ (double-negative) TILs was more common in patients with complete responses compared with patients whose disease did not respond. Single-cell RNA-sequencing analyses showed that double-negative TILs expressed the memory stem-like T-cell marker TCF7 at much higher levels than double-positive TILs. Correspondingly, double-negative TILs exhibited self-renewal characteristics and gave rise to single-positive and double-positive TILs, whereas double-positive TILs mostly remained double-positive. Previous studies had suggested that CD39⁻ TILs are bystanders; indeed, CD39⁺ TILs constituted the majority of tumor neoantigen–reactive TILs. However, it was a higher proportion of stem-like tumor neoantigen–reactive CD39⁻ TILs, rather than a higher proportion of neoantigen-reactive CD39⁺ TILs or higher total TIL count, that was predictive of complete response. CD39⁻ neoantigen-reactive TILs were also associated with increased T-cell persistence in posttreatment blood of patients. Finally, in vivo, adoptive transfer of double-negative T cells was associated with significant dose-dependent melanoma shrinkage and extended survival, whereas adoptive transfer of double-positive T cells had a much less substantial effect. Together, these findings identify a TIL subset that appears critical to the success of TIL adoptive cell therapy.

Krishna S, Lowery FJ, Copeland AR, Bahadiroglu E, Mukherjee R, Jia L, et al. Stem-like CD8 T cells mediate response of adoptive cell immunotherapy against human cancer. Science 2020;370:1328–34.

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