[HTML][HTML] Memory T cell–driven differentiation of naive cells impairs adoptive immunotherapy

CA Klebanoff, CD Scott, AJ Leonardi… - The Journal of …, 2016 - Am Soc Clin Investig
CA Klebanoff, CD Scott, AJ Leonardi, TN Yamamoto, AC Cruz, C Ouyang, M Ramaswamy…
The Journal of clinical investigation, 2016Am Soc Clin Investig
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 …
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.
The Journal of Clinical Investigation