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Cell state and transcription factor modulation during extended CD8+ T-cell expansion ex vivo

ABSTRACT: Adoptive cell therapy is fast becoming a cornerstone of modern tumour immunotherapy. It relies on the relatively long-term (>2 week) ex vivo expansion of T cells either in the form of tumour-infiltrating cells, or bulk cells modified with the expression of heterologous signaling proteins, e.g., chimeric antigen receptors. However, relatively little is known about the developmental trajectories of T cells under these conditions at the systems level, and whether entire genetic pathways could be manipulated for clinical advantage. Using bulk RNA-seq analysis of T cells expanded and rested over a 17-day period, we provide a resource of how gene expression changes as cells transition through distinct cellular states over the course of activation and ex-vivo expansion. We also performed experiments to investigate the role of FOSL1 in T-cell function.

ORGANISM(S): Homo sapiens

PROVIDER: GSE247647 | GEO | 2024/07/22

REPOSITORIES: GEO

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Project description:This mathematical model of T cell-tumour interactions considering the roles of T cell competition and stochastic extinction events in CAR T cell therapy is described by the publication: Kimmel GJ, Locke FL, Altrock PM. "The roles of T cell competition and stochastic extinction events in chimeric antigen receptor T cell therapy." Proc Biol Sci. 2021 Mar 31;288(1947):20210229. doi: 10.1098/rspb.2021.0229 Comment: Reproduction of Fig. 2(a) and (b) was simulated by using the fitted model parameter set given in Table 1 of the manuscript's Supplementary Material, however substituting the values of r_N and rho_C for those stated in Table 1 of the publication manuscript, i.e. r_N = 0.17 and rho_C = 0.0251. Abstract: Chimeric antigen receptor (CAR) T cell therapy is a remarkably effective immunotherapy that relies on in vivo expansion of engineered CAR T cells, after lymphodepletion (LD) by chemotherapy. The quantitative laws underlying this expansion and subsequent tumour eradication remain unknown. We develop a mathematical model of T cell–tumour cell interactions and demonstrate that expansion can be explained by immune reconstitution dynamics after LD and competition among T cells. CAR T cells rapidly grow and engage tumour cells but experience an emerging growth rate disadvantage compared to normal T cells. Since tumour eradication is deterministically unstable in our model, we define cure as a stochastic event, which, even when likely, can occur at variable times. However, we show that variability in timing is largely determined by patient variability. While cure events impacted by these fluctuations occur early and are narrowly distributed, progression events occur late and are more widely distributed in time. We parameterized our model using population-level CAR T cell and tumour data over time and compare our predictions with progression-free survival rates. We find that therapy could be improved by optimizing the tumour-killing rate and the CAR T cells' ability to adapt, as quantified by their carrying capacity. Our tumour extinction model can be leveraged to examine why therapy works in some patients but not others, and to better understand the interplay of deterministic and stochastic effects on outcomes. For example, our model implies that LD before a second CAR T injection is necessary.

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Cell state and transcription factor modulation during extended CD8+ T-cell expansion ex vivo

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