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Review
. 2020 Aug;11(8):549-564.
doi: 10.1007/s13238-020-00707-9. Epub 2020 Mar 27.

Memory T cells: strategies for optimizing tumor immunotherapy

Qingjun Liu  1   2   3 , Zhongjie Sun  4 , Ligong Chen  5   6
Affiliations
Review

Memory T cells: strategies for optimizing tumor immunotherapy

Qingjun Liu et al. Protein Cell. 2020 Aug.

Abstract

Several studies have demonstrated that memory T cells including stem cell memory (Tscm) T cells and central memory (Tcm) T cells show superior persistence and antitumor immunity compared with effector memory T (Tem) cells and effector T (Teff) cells. Furthermore, the Tcm/Teff ratio has been reported to be a predictive biomarker of immune responses against some tumors. Thus, a system-level understanding of the mechanisms underlying the differentiation of effector and memory T cells is of increasing importance for developing immunological strategies against various tumors. This review focuses on recent advances in efficacy against tumors, the origin, formation mechanisms of memory T cells, and the role of the gut microbiota in memory T cell formation. Furthermore, we summarize strategies to generate memory T cells in (ex) vivo that, might be applicable in clinical practice.

Keywords: gut microbiota; memory T cells; metabolism; tumor immunology.

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Figures

Figure 1
Figure 1
Three models of memory T cell formation. (A) Memory T cells differentiate from naïve T cells in a stepwise manner as they progress from Tscmto Tcm, and then Tem, a more terminally differentiated phenotype. (B) Memory T cells are from discrete subsets that contain memory precursor genes in the naïve T cell population. (C) Memory T cells are derived from surviving effector T cells as the methylation patterns in memory T cells are similar to those in effector T cells
Figure 2
Figure 2
Molecular and metabolic regulation of effector and memory T cell differentiation. Following immunization or infection, naïve CD4+ T cells are activated by cognate antigens presented by DCs through MHC class II and upregulated CD40L expressions. Then, DCs are licensed by cognate CD4+ T cells through a CD40-CD40L interaction, which enables the DCs to obtain sufficient antigen-presenting and co-stimulation capacities to induce a robust CD8+ T cell response. In some cases, DC functional maturation is mediated by TLR ligands and bypasses the requirement for CD4+ T cells. The differentiation of effector and memory T cells is orchestrated by three major signals: TCR, co-stimulatory molecules and cytokines. Effector T cells formation initiates with TCR signals delivered by DCs through MHC class I in the presence of antigen, while memory T cells are generated after the antigen is quickly cleared. Integration of TCR signals, co-stimulatory signals including CD28-CD80/CD86, CD40-CD40L, OX40-OX40L, CD27-CD70 and 4-1BB-4-1BBL plays important roles in certain inflammatory settings. Cytokines can affect T-cell differentiation, proliferation and survival at many stages of the immune response. For example, IFN-γ α/β, IL-27, and IL-12 derived from mature DCs and IFN-γ and IL-2 derived from helper CD4+ T cells activate the JAK-STAT signaling pathway mediated through STAT1/STAT4 or STAT5 in effector T cells, while IL-10 and IL-21 secreted by helper CD4+ T cells selectively activate STAT3 and STAT5 in memory T cells. In addition, memory T cells are maintained in an antigen-independent, cytokine-independent manner mainly through the action of stromal cell derived IL-7 and DC derived IL-15, which promotes cell survival by upregulating the levels of anti-apoptotic proteins such as BCL-2 and BCL-xL. These three classes of signals are closely linked and act collaboratively to endow T cells with different transcriptional profiles. Therefore, effector T cells, characterized as KLRG1high IL7Rαlow IL2Rαhigh express high level of transcriptional factors such as T-bet, Blimp1, and ID2, and epigenetic regulators including DNMT3a and TET2. In contrast, memory T cells characterized as KLRG1low IL7Rαhigh CD27high CXCR3high express high level of EOMES, BCL-6, ID3, BATCH2, SOCS3, FOXO1, TCF1 and LEF1. Additionally, effector and memory T cell differentiation are coupled with metabolic reprogramming. In effector T cells, activation of the PI3K-AKT-mTOR pathway promotes aerobic glycolysis, a hall-mark of activated T cells. In contrast, in memory T cells, cellular stress, such as growth factor deprivation or a low ratio of ATP/AMP, will activate AMPK and inhibit mTOR signaling. Moreover, extracellular ATP released from dying cells can activate P2RX7, which further induces AMPK expression and mitochondrial homeostasis. As a result, anabolism is shut down, and metabolism switched to fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS). Accordingly, pharmacological inhibitors of mTOR pathway such as rapamycin can be useful to memory T cell induction. Recently elevating L-arginine level was also reported to promote the metabolic shift from glycolysis to oxidative phosphorylation and promote cell survival, providing another potential strategy for memory T cell generation in vitro
Figure 3
Figure 3
Methods to transform Teff cells into T cells with a memory phenotype by conditional culturein(ex)vivo. These approaches would endow T cells specific to tumor antigens with superior persistence and antitumor immune function in cancer patients
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References

    1. Adachi K, Kano Y, Nagai T, Okuyama N, Sakoda Y, Tamada K. IL-7 and CCL19 expression in CAR-T cells improves immune cell infiltration and CAR-T cell survival in the tumor. Nat Biotechnol. 2018;36:346–351. - PubMed
    1. Ahlers JD, Belyakov IM. Memories that last forever: strategies for optimizing vaccine T-cell memory. Blood. 2010;115:1678–1689. - PMC - PubMed
    1. Ahlers JD, Belyakov IM, Terabe M, Koka R, Donaldson DD, Thomas EK, Berzofsky JA. A push-pull approach to maximize vaccine efficacy: abrogating suppression with an IL-13 inhibitor while augmenting help with granulocyte/macrophage colony-stimulating factor and CD40L. Proc Natl Acad Sci U S A. 2002;99:13020–13025. - PMC - PubMed
    1. Ahonen CL, Doxsee CL, McGurran SM, Riter TR, Wade WF, Barth RJ, Vasilakos JP, Noelle RJ, Kedl RM. Combined TLR and CD40 triggering induces potent CD8+ T cell expansion with variable dependence on type I IFN. J Exp Med. 2004;199:775–784. - PMC - PubMed
    1. Akondy RS, Fitch M, Edupuganti S, Yang S, Kissick HT, Li KW, Youngblood BA, Abdelsamed HA, McGuire DJ, Cohen KW, et al. Origin and differentiation of human memory CD8 T cells after vaccination. Nature. 2017;552:362–367. - PMC - PubMed

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