Fig. 2: Multifaceted roles of CD4⁺ T cells in anti-tumour immunity.

CD4⁺ T cells play key roles in tumour immunity through several different mechanisms. a A major role of CD4⁺ T cells is the provision of help for anti-tumour CTLs through both direct and indirect mechanisms (discussed in-depth here [116]). Activated CD4⁺ T cells secrete interleukin (IL)-2, which directly activates CD8⁺ CTLs expressing the high-affinity IL-2 receptor α subunit (CD25) by driving their effector function, differentiation, and proliferation. CD4⁺ T cells also indirectly provide help for the anti-tumour CD8⁺ CTL response by supporting and maintaining pro-inflammatory cross-presenting dendritic cells (DCs) [101], which in turn provide the three activating signals for CD8⁺ CTLs [115, 117]. This is primarily mediated by the upregulation of CD40 ligand (CD154) [22, 23, 118] on activated CD4⁺ T cells, which engages its cognate receptor CD40 on DCs to induce and maintain the type I profile of DCs (expression of B7 family ligands, CD70, and secretion of IL-12) [116]. These signals strongly induce anti-tumour effector functions in CD8⁺ CTLs such as the acquisition of cytotoxicity and the secretion of tumoricidal cytokines such as interferon-γ (IFNγ), and also stimulate the effector [117, 119, 120] and memory [121,122,123,124] phenotype differentiation of CD8⁺ T cells. b CD4⁺ T cells also produce effector cytokines such as IFNγ and tumour necrosis factor-α (TNFα), which have direct anti-tumour activity, following activation and polarisation into the T_H1 phenotype [125] in response to signals from DCs, particularly IL-12. In addition, CD4⁺ T cells can mediate direct cytotoxicity against tumour cells in a similar manner to their CD8⁺ T cell counterparts under specific conditions in both preclinical mouse tumour models [45, 46, 126] and in patient-derived CD4⁺ T cells [127]. c CD4⁺ T cells are also indispensable for the induction of humoral responses against tumour antigens by providing help via CD40 ligand signalling to CD40 on B cells to drive their differentiation and maturation into affinity-matured, class-switched plasma cells. Their activity correlates with the presence of serum antibodies specific to tumour antigens [17, 128], and they likely play a role in driving local antibody responses in tertiary lymphoid structures [129] adjacent to solid tumours.