Comparison of naïve and central memory derived CD8+ effector cell engraftment fitness and function following adoptive transfer

Abstract

Human CD8⁺ effector T cells derived from CD45RO⁺CD62L⁺ precursors enriched for central memory (T_CM) precursors retain the capacity to engraft and reconstitute functional memory upon adoptive transfer, whereas effectors derived from CD45RO⁺CD62L^- precursors enriched for effector memory precursors do not. Here we sought to compare the engraftment fitness and function of CD8⁺ effector T cells derived from CD45RA⁺CD62L⁺ precursors enriched for naïve and stem cell memory precursors (T_N/SCM) with that of T_CM. We found that cytotoxic T cells (CTLs) derived from T_CM transcribed higher levels of CD28, FOS, INFγ, Eomesodermin (Eomes), and lower levels of BCL2L11, maintained higher levels of phosphorylated AKT, and displayed enhanced sensitivity to the proliferative and anti-apoptotic effects of γ-chain cytokines compared to CTLs derived from T_N/SCM. Higher frequencies of CTLs derived from T_CM retained CD28 expression and upon activation secreted higher levels of IL-2. In NOD/Scid IL-2RγC^null mice, CD8⁺ T_CM derived CTLs engrafted to higher frequencies in response to human IL-15 and mounted robust proliferative responses to an immunostimulatory vaccine. Similarly, CD8⁺ T_CM derived CD19CAR⁺ CTLs exhibited superior antitumor potency following adoptive transfer compared to their CD8⁺ T_N/SCM derived counterparts. These studies support the use of T_CM enriched cell products for adoptive therapy of cancer.

Keywords: Antitumor activity; adoptive therapy; central memory T cell derived CTLs; engraftment fitness; naïve T cell derived CTLs.