The role of CD4 T cells in rejection of solid tumors

Abstract

The focus in cancer immunotherapy has mainly been on CD8 T cells, as they can directly recognize cancer cells. CD4 T cells have largely been neglected, because most cancers lack MHC II expression and cannot directly be recognized by CD4 T cells. Yet, tumor antigens can be captured and cross-presented by MHC II-expressing tumor stromal cells. Recent data suggest that CD4 T cells act as a swiss army knife against tumors. They can kill cancer cells, if they express MHC II, induce tumoricidal macrophages, induces cellular senescence of cancer cells, destroy the tumor vasculature through cytokine release and help CD8 T cells in the effector phase. We foresee a great future for CD4 T cells in the clinic, grafted with tumor antigen specificity by T cell receptor gene transfer, either alone or in combination with engineered CD8 T cells.

Figure 1

Mechanisms how CD4 T cells contribute to anti-tumor immunity. (a) How CD4 T cells get activated. Tumor stromal cells, especially macrophages, internalize antigens from cancer cells via taking up necrotic cancer cells or secreted antigen. Upon presentation of the contained antigens on MHC II on the macrophage, antigen-specific CD4 T cells get activated by recognizing their target and in turn activate the macrophage, for example, through CD40/CD40L interaction. High cytokine levels can occur by IFNγ and TNFα secretion by CD4 T cells and macrophages. (b) Effector mechanisms by activated CD4 T cells. 1) Direct cytotoxicity by CD4 T cells can occur when cancer cells themselves express MHC II on their surface. A cytotoxic phenotype involving granzymes and cytokines renders CD4 T cells cytotoxic [7,8]. 2) Macrophages become effectors when activated by CD4 T cells and destroy tumor cells by upregulating nitric oxide synthetase (iNOS) and producing NO [11^•,12]. 3) Growth arrest of cancer cells can be achieved by inducing senescence through IFNγ and TNFα produced by CD4 T cells [14]. 4) IFNγ and TNFα produced by CD4 T cells and macrophages synergize to destruct blood vessels in an early phase of tumor rejection [23^••].

Figure 2

CD4 and CD8 T cell cooperation in the effector phase. CD4 effector T cells (CD4 T_E) recognize their target cross-presented on macrophages (Mφ) leading to cytokine production. CD8 effector T cells (CD8 T_E) recognize their target on the cancer cell and get additionally activated by neighboring CD4 T cells. CD8 T cells exert direct kill on cancer cells and high cytokine levels by CD4 and CD8 T cells lead to vessel destruction and changes in the tumor microenvironment, for example, MHC upregulation. Apoptotic cancer cells are taken up by macrophages that cross-present tumor antigens to CD4 T cells to feed the circle.