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

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 naive 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, INF gamma, 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 gamma-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-2R gamma C-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.