|Publication Type||Journal Article|
|Year of Publication||2021|
|Authors||Penter, L, Zhang, Y, Savell, A, Huang, T, Cieri, N, Thrash, EM, Kim-Schulze, S, Jhaveri, A, Fu, J, Ranasinghe, S, Li, S, Zhang, W, Hathaway, ES, Nazzaro, M, Kim, HT, Chen, H, Thurin, M, Rodig, SJ, Severgnini, M, Cibulskis, C, Gabriel, S, Livak, KJ, Cutler, C, Antin, JH, Nikiforow, S, Koreth, J, Ho, VT, Armand, P, Ritz, J, Streicher, H, Neuberg, D, F Hodi, S, Gnjatic, S, Soiffer, RJ, Liu, XShirley, Davids, MS, Bachireddy, P, Wu, CJ|
|Date Published||2021 Mar 15|
Relapsed myeloid disease after allogeneic stem cell transplantation (HSCT) remains largely incurable. We previously demonstrated the potent activity of immune checkpoint blockade (ICB) in this clinical setting with ipilimumab or nivolumab. To define the molecular and cellular pathways by which CTLA-4 blockade with ipilimumab can reinvigorate an effective graft-versus-leukemia (GvL) response, we integrated transcriptomic analysis of leukemic biopsies with immunophenotypic profiling of matched peripheral blood samples collected from patients treated with ipilimumab following HSCT on the ETCTN 9204 trial. Response to ipilimumab was associated with transcriptomic evidence of increased local CD8+ T cell infiltration and activation. Systemically, ipilimumab decreased naïve and increased memory T cell populations and increased expression of markers of T cell activation and co-stimulation such as PD-1, HLA-DR and ICOS, irrespective of response. However, responding patients were characterized by higher turnover of T cell receptor sequences in peripheral blood and showed increased expression of proinflammatory chemokines in plasma that was further amplified by ipilimumab. Altogether, these data highlight the compositional T cell shifts and inflammatory pathways induced by ipilimumab both locally and systemically that associate with successful GvL outcomes.