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Memory T Cell-Driven Differentiation of Naive Cells Impairs Adoptive Immunotherapy

Memory T Cell-Driven Differentiation of Naive Cells Impairs Adoptive Immunotherapy

Christopher A Klebanoff, Christopher D Scott, Anthony J Leonardi, Tori N Yamamoto, Anthony C Cruz, Claudia Ouyang, Madhu Ramaswamy, Rahul Roychoudhuri, Yun Ji, Robert L Eil, Madhusudhanan Sukumar, Joseph G Crompton, etc.

J Clin Invest. 2016 Jan;126(1):318-34.

PMID: 26657860

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR42412943	Fas Ligand from mouse			Price

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