Cytotoxic Chemotherapy and CD4+ Effector T Cells: An Emerging Alliance for Durable Antitumor Effects

Figure 1

Hypothetical model of the mutually reinforcing effect of chemotherapy and antitumor CD4+ effector T cells. Chemotherapy reduces tumor burden, releases tumor antigens, and induces inflammation. In this highly immunogenic milieu created after chemotherapy, therapeutic immunological maneuvers such as adoptive cell therapy (ACT) using tumor-reactive CD4+ T cells or cancer vaccines can lead to the generation of highly activated CD4+ effector T cells with polyfunctional activities. These CD4+ effector T cells act as the “gatekeepers” of the overall antitumor immunity in postchemotherapy hosts, by helping the activation and function of other immune cells (CD8, DC, and macrophage) and directly attacking the tumor cells. In addition, cytokines produced by CD4+ effector T cells (IFNγ and TNFα) may also target and destroy tumor stroma and thus inhibit tumor angiogenesis. These diverse immune responses superimpose to effectively eradicate residual tumors. In contrast, without properly activated CD4+ effector T cells, an effective host antitumor immunity may not be elicited or is not sustainable, leading to tumor persistence and eventual relapse.