Polarized dendritic cells as cancer vaccines: directing effector-type T cells to tumors

Abstract

Ex vivo generation and antigen loading of dendritic cells (DCs) from cancer patients helps to bypass the dysfunction of endogenous DCs. It also allows to control the process of DC maturation and to imprint in maturing DCs several functions essential for induction of effective forms of cancer immunity. Recent reports from several groups including ours demonstrate that distinct conditions of DC generation and maturation can prime DCs for preferential interaction with different (effector versus regulatory) subsets of immune cells. Moreover, differentially-generated DCs have been shown to imprint different effector mechanisms in CD4(+) and CD8(+) T cells (delivery of "signal three") and to induce their different homing properties (delivery of "signal four"). These developments allow for selective induction of tumor-specific T cells with desirable effector functions and tumor-relevant homing properties and to direct the desirable types of immune cells to tumors.

Figure 1. Unique tasks of therapeutic vaccines against cancer

In contrast to protective vaccines, therapeutic vaccines need to function in cancer patients in spite of the dysfunction of endogenous DCs and the presence of tumor-induced suppressive immune cells, such as regulatory T_(reg) cells. Even more importantly, their role needs to go beyond the induction of long-lived memory cells, the key task of protective vaccines. Since in contrast to infections, cancer is a poor source of pro-inflammatory alarm signals capable of inducing effector functions and peripheral homing potential in Ag-specific T cells, the effectiveness of therapeutic vaccines may require provision of such signals by vaccines themselves or by additional factors used in combination with vaccines. Since some tumors show limited production of the chemokines capable of attracting effector cells (CTLs, Th1- and NK cells), instead overproducing T_reg-attracting chemokines, the immunotherapies of such tumors may benefit from the combination of vaccines with the additional modulation of the production of effector cell-attracting versus T_reg-attracting chemokines within tumor tissues.

Figure 2

Unique features of polarized DC1s, as compared to non-polarized mature DCs (used in “second-generation” DC-based vaccines) and immature DCs (used in the “first generation” DC-based vaccines). While all the above DC types can provide T cells with antigen (“signal 1”) and different levels of costimulation (“signal 2”) needed for activation and expansion of tumor-specific T cells. Polarized DCs are particularly capable of providing an polarizing “signal 3”, promoting the development of type-1 effector mechanisms in naïve/resting immune cells (63) and “signal 4” allowing the differentiating cells to acquire the expression of peripheral homing receptors, including CCR5 and CXCR3. In addition, to preferentially inducing the desirable immune effector cells, unique chemokine production profile of polarized DC1s may also help them to preferentially interact with pre-existing (or induced by previous cycles of vaccination) effector and memory cells, rather than with T_regs.