Depletion of effector regulatory T cells drives major response to induction dual immune checkpoint blockade
Jiang, X.; Rudqvist, N.-P.; Jiang, B.; Ye, S.; He, S.; Liang, Q.; Dou, J.; Williams, M.; Dunn, J. D.; Johnson, J. M.; Akagi, K.; Xiao, W.; Liang, S.; Elayavalli, S.; Sun, B.; Parra Cuentas, E. R.; Ferrarotto, R.; Garden, A.; Fuller, C.; Reddy, J.; Gross, N.; Lango, M.; Leung, C. H.; Liu, S.; Liu, D.; Lee, J. J.; Curran, M. A.; Phan, J.; Chen, K.; Gillison, M. L.
Show abstract
In a phase 2 trial, local-regionally advanced HPV-positive oropharyngeal carcinoma (OPC) patients received ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) as induction immunotherapy and concurrently with radiotherapy (NCT03799445). Co-primary endpoints achieved included 6-month complete metabolic response rate (94%) and 2-year progression-free survival (84%). Induction yielded a 46% major histological response rate. Single-cell profiling revealed responders had higher baseline intratumoral tissue-resident memory (TRM) CD8+ T cells and NK cells expressing Fc Gamma Receptor IIIa (FCGR3A). Decreases in effector regulatory T (eTreg) cells, which highly expressed CTLA4, occurred only in responders, suggesting ipilimumab-dependent depletion by FCGR3A+ NK cells. eTreg depletion correlated with increased Interferon Gamma (IFNG)+ effector CD8+ T cells. CD8+ T-cell clonotypes transitioned from TRM to effector memory and IFNG+ effector cells in responders, whereas clonotypes transitioned to exhausted TRM and proliferating cells in nonresponders. We conclude that eTreg depletion is critical for major response to induction dual immune checkpoint blockade.
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