The Stoichiometric Production of IL-2 and IFN-γ mRNA Defines Memory T Cells That Can Self-Renew After Adoptive Transfer in Humans

Abstract

Adoptive immunotherapy using ex vivo-expanded tumor-reactive lymphocytes can mediate durable cancer regression in selected melanoma patients. Analyses of these trials have associated the in vivo engraftment ability of the transferred cells with their antitumor efficacy. Thus, there is intensive clinical interest in the prospective isolation of tumor-specific T cells that can reliably persist after transfer. Animal studies have suggested that central memory CD8(+) T cells (T(CM)) have divergent capabilities including effector differentiation to target antigen and stem cell-like self-renewal that enable long-term survival after adoptive transfer. We sought to isolate human melanoma-specific T(CM) to define their in vivo fate and function after autologous therapeutic transfer to metastatic patients. To facilitate the high-throughput identification of these rare cells from patients, we report that T(CM) have a defined stoichiometric production of interleukin-2 (IL-2) and interferon-γ (IFN-γ) mRNA after antigen stimulation. Melanoma-specific T cells screened for high relative IL-2 production had a T(CM) phenotype and superior in vitro proliferative capacity compared to cells with low IL-2 production. To investigate in vivo effector function and self-renewal capability, we allowed melanoma-specific T(CM) to undergo in vitro expansion and differentiation into lytic effector clones and then adoptively transferred them back into their hosts. These clones targeted skin melanocytes in all five patients and persisted long term and reacquired parental T(CM) attributes in four patients after transfer. These findings demonstrate the favorable engraftment fitness for human T(CM)-derived clones, but further efforts to improve their antitumor efficacy are still necessary.

The Quantity of Autocrine IL-2 Governs the Expansion Potential of CD8+ T Cells

“…Autocrine IL-2 production is part of the polyfunctional central-memory T cell profile, and our study now provides direct evidence that autocrine IL-2 production contributes to a greater expansion capacity of CD8 + T cells. Also in case of antitumor immunity, it has been suggested that IL-2 production of tumor-infiltrating CD8 + lymphocytes could be considered as a pharmacodynamic biomarker for clinical responses (32,33). However, IL-2-independent processes are likely important as well and may also be implicated in the self-renewal of central-memory CD8 + T cells (34,35).…”

Heteroclitic XBP1 peptides evoke tumor-specific memory cytotoxic T lymphocytes against breast cancer, colon cancer, and pancreatic cancer cells

“…[51][52][53] However, there remain controversies in defining the immune response of the specific memory T subsets within antigen-specific CTL against tumor cells. 54,55 In these studies, we characterized the antitumor activities of the two different memory cell subsets, CM and EM, from XBP1 antigen-specific CTL against a variety of solid tumor cells. We chose to evaluate the XBP1-CTL after the fourth round of peptide stimulation, due to high levels of antigen-specific cells within both memory cell subsets of the CD3 C CD8 C T cells population.…”

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

“…Apparently, these intrinsic attributes of the CTLs derived from T CM was not compromised by the acquisition of effector cell transcriptional program such as higher IFNg and Eomes. 35 These results led to the postulation that T CM derived CTLs would perform better in both persistence and function upon adoptive transfer compared to T N/SCM derived CTLs.…”