Memory T cell-driven differentiation of naive cells impairs adoptive immunotherapy

作者：Klebanoff Christopher A^*; Scott Christopher D; Leonardi Anthony J; Yamamoto Tori N; Cruz Anthony C; Ouyang Claudia; Ramaswamy Madhu; Roychoudhuri Rahul; Ji Yun; Eil Robert L; Sukumar Madhusudhanan; Crompton Joseph G; Palmer Douglas C; Borman Zachary A; Clever David; Thomas Stacy K; Patel Shashankkumar; Yu Zhiya; Muranski Pawel; Liu Hui; Wang Ena; Marincola Francesco M; Gros Alena; Gattinoni Luca; Rosenberg Steven A; Siegel Richard M; Restifo Nicholas P

来源：Journal of Clinical Investigation, 2016, 126(1): 318-334.

DOI：10.1172/JCI81217

Adoptive cell transfer (ACT) of purified naive, stem cell memory, and central memory T cell subsets results in superior persistence and antitumor immunity compared with ACT of populations containing more-differentiated effector memory and effector T cells. Despite a clear advantage of the less-differentiated populations, the majority of ACT trials utilize unfractionated T cell subsets. Here, we have challenged the notion that the mere presence of less-differentiated T cells in starting populations used to generate therapeutic T cells is sufficient to convey their desirable attributes. Using both mouse and human cells, We identified a T cell-T cell interaction whereby antigen-experienced subsets directly promote the phenotypic, functional, and metabolic differentiation of naive T cells. This process led to the loss of less-differentiated T cell subsets and resulted in impaired cellular persistence and tumor regression in mouse models following ACT. The T memory-induced conversion of naive T cells was mediated by a nonapoptotic Fas signal, resulting in Akt-driven cellular differentiation. Thus, induction of Fas signaling enhanced T cell differentiation and impaired antitumor immunity, while Fas signaling blockade preserved the antitumor efficacy of naive cells within mixed populations. These findings reveal that T cell subsets can synchronize their differentiation state in a process similar to quorum sensing in unicellular organisms and suggest that disruption of this quorum-like behavior among T cells has potential to enhance T cell-based immunotherapies.

• 出版日期2016-1
• 单位NIH