Architects of immunity: How dendritic cells shape CD8+ T cell fate in cancer

Abstract

Immune responses against cancer are dominated by T cell exhaustion and dysfunction. Recent advances have underscored the critical role of early priming interactions in establishing T cell fates. In this review, we explore the importance of dendritic cell (DC) signals in specifying CD8⁺ T cell fates in cancer, drawing on insights from acute and chronic viral infection models. We highlight the role of DCs in lymph nodes and tumors in maintaining stem-like CD8⁺ T cells, which are critical for durable antitumor immune responses. Understanding how CD8⁺ T cell fates are determined will enable the rational design of immunotherapies, particularly therapeutic cancer vaccines, that can modulate DC-T cell interactions to generate beneficial CD8⁺ T cell fates.

Fig. 1.. Interactions with DCs shape T cell fate.

interactions with Dcs influence the four depicted T cell fates, with tolerance and anergy not shown. Here, we focus on TFs and cell surface markers used to identify the T cell fates discussed in this review. Some markers listed as “lo” are expressed lower relative to other cD8⁺ T cell subsets described within the cited study. included markers were common across multiple studies. * denotes markers that are different across T_dys cell studies.

Fig. 2.. DC-provided signals 1, 2, and 3 shape CD8⁺ T cell fate.

(A) High levels of signal 1 drive terminal T_ex cells, whereas lower signal 1 levels generate T_pex cells. in contrast, during chronic lcmv infection, higher antigen load leads to increased T_pex cell formation. High levels of signal 2 promote terminal T_ex cell differentiation, whereas suboptimal signal 2 induces either T_pex or T_dys cells, depending on the combination and strength of signals. conventional cD4⁺ T cells and T_regs influence Dc stimulatory capacity by increasing or decreasing signal 2 levels, respectively. Dotted lines represent low levels of signal, and solid lines represent high levels of signal. (B) cytokine signals shape Dc stimulatory capacity and resulting T cell fate. (1) Activated Dcs produce high levels of il-12, needed for T_eff cell differentiation. il-12 production by Dcs can be enhanced by conventional cD4⁺ T cell licensing. (2) in contrast, T_H1-polarized T_regs suppress il-12 production by cDc1s, resulting in T_dys cells. (3) il-2, provided by cD4⁺ or cD8⁺ T cells, induces il-12 receptor expression on cD8⁺ T cells and promotes effector differentiation or T_pex cell maintenance. (4) T_regs, in close proximity to cD8⁺ T cells, can sequester il-2 and thus promote T_dys cells. (5) Type i iFn (iFn-β) can activate Dcs to increase both stem-like and effector-like cD8⁺ T cells. in addition, iFn-β can induce iSg-Dcs, an activation state of cDc2s, which generate effector-like cD8⁺ T cells. (6) il-10 promotes T_reg induction and drives terminal T_ex cell differentiation. (7) il-4 promotes mregDc induction, which suppresses il-12 production. Black arrows and red arrows indicate immune pathways that are beneficial or detrimental to antitumor cD8⁺ T cell responses, respectively.

Fig. 3.. DCs provide signals to maintain T_pex cells within TdLNs and APC-rich niches in tumors.

In the Tdln, Dcs repress T_pex cell differentiation through inhibitory signaling via the (1) PD-l1/PD-1 axis. (2) optimal TcR signaling promotes T_pex cell maintenance, whereas (4) low TcR stimulation drives terminal T_ex cell differentiation. in addition, (3) high levels of costimulatory signals drive T_pex cell proliferation, improve their ability to traffic to tumors, and promote their differentiation into effector-like T cells or terminal T_ex cells.