Roles of CD4+ T cells as mediators of antitumor immunity

Abstract

It has been well established that CD8+ T cells serve as effector cells of the adaptive immune response against tumors, whereas CD4+ T cells either help or suppress the generation of CD8+ cytotoxic T cells. However, in several experimental models as well as in cancer patients, it has been shown that CD4+ T cells can also mediate antitumor immunity either directly by killing tumor cells or indirectly by activating innate immune cells or by reducing tumor angiogenesis. In this review, we discuss the growing evidence of this underappreciated role of CD4+ T cells as mediators of antitumor immunity.

Keywords: CD4+ T cells; MHC; adoptive cell therapy; cytotoxicity; immunotherapy.

Figure 1

Mechanisms of CD4+ T cells as effectors of antitumor immunity independent of CD8+ T cells. Professional antigen-presenting cells (APCs), like activated dendritic cells (DCs, yellow), in the tumor microenvironment (TME) take up tumor antigens. Starting on the left-hand side of the figure, activated DCs present antigens to CD4+ T cells via MHC-II, in turn activating CD4+ T cells to secrete cytokines like IFNγ, TNFα, and IL-2 that activate effector CD8+ T cells (not shown here). Additionally, IFNγ from activated CD4+ T cells can act on tumor cells (gold) or stromal cells (grey) to increase the expression of monokine induced by IFNγ (Mig) and interferon-gamma-induced protein 10 (IP-10), causing inhibition of tumor angiogenesis and thus contributing to tumor cell death. Another possibility is that CD4+ T cells can contribute to tumor vessel normalization (not shown here). Activated DCs also secrete IL-12, stimulating CD4+ T cells to secrete more IFNγ which can feed back to activate more DCs, setting up a reciprocal interaction that further amplifies the immune cell activation cascade in the TME. Activated CD4+ T cells that differentiate into the Th1 subtype also release IFNγ that activates macrophages (blue) to an M1 phenotype through upregulation of inducible nitric oxide synthase (iNOS). Nitric oxide (NO) secreted by these M1 macrophages in the TME causes apoptosis of tumor cells. Finally, activated APCs, including DCs, may also stimulate the development of cytotoxic CD4+ T cell subsets. These cytotoxic CD4+ T cells may attack the tumor through two mechanisms. They may directly recognize MHC-II-positive tumor cells via their T-cell receptor and use contact-mediated delivery to release perforin (Prf) and granzyme B (GrB) to cause tumor cell death. Alternatively, cytotoxic CD4+ T cells may potentially recognize tumor cells in an MHC-independent fashion (like NK cells do) and use other activating receptors to identify activating ligands for those receptors that are selectively expressed by tumor cells to enable contact-mediated release of Prf and GrB into the tumor cells to eliminate MHC-deficient tumor cells through an MHC-independent mechanism. The ongoing tumor cell death from all these synergistic mechanisms may drive further antigen uptake by APCs and the development of a more robust antitumor immune response in the TME.