Revisiting the role of CD4+ T cells in cancer immunotherapy-new insights into old paradigms

Abstract

Cancer immunotherapy has revolutionised cancer treatment, with immune checkpoint blockade (ICB) therapy and adoptive cell therapy (ACT) increasingly becoming standard of care across a growing number of cancer indications. While the majority of cancer immunotherapies focus on harnessing the anti-tumour CD8⁺ cytotoxic T cell response, the potential role of CD4⁺ 'helper' T cells has largely remained in the background. In this review, we give an overview of the multifaceted role of CD4⁺ T cells in the anti-tumour immune response, with an emphasis on recent evidence that CD4⁺ T cells play a bigger role than previously thought. We illustrate their direct anti-tumour potency and their role in directing a sustained immune response against tumours. We further highlight the emerging observation that CD4⁺ T cell responses against tumours tend to be against self-derived epitopes. These recent trends raise vital questions and considerations that will profoundly affect the rational design of immunotherapies to leverage on the full potential of the immune system against cancer.

Fig. 1. Development of CD4 T cells and functional diversity of CD4 subsets in immunity.

CD4⁺ T cells are T lymphocytes that express T cell receptors (TCRs) recognising peptide antigens presented in the context of Class II major histocompatibility complex (MHC II) molecules. CD4⁺ T cells express the TCR co-receptor CD4, which binds to the β2 domain of MHC II and facilitates TCR engagement with peptide-MHC II complexes on antigen-presenting cells [111]. During thymic development, the cell fate of developing thymocytes is decided by their TCR affinity for self-peptide-MHC complexes presented by thymic epithelial cells. Thymocytes that have little to no affinity for self-peptide do not initiate activating signals from their TCR complexes and thus die by neglect. Conversely, thymocytes with high self-reactivity are negatively selected and deleted by apoptosis. Thymocytes with intermediate TCR affinities below the negative selection threshold receive positive selection via activating TCR signals and complete thymic maturation as naïve conventional T cells (T_H0). Some thymocytes with moderately high affinities to self-antigen are redirected into the regulatory T cell (Treg) developmental pathway, where they acquire immunosuppressive function to regulate tissue homoeostasis and resolution of immune responses [53, 112]. Upon receiving cues from the cytokine milieu together with TCR activation, naive CD4⁺ T cells upregulate expression of key transcription factors regulating subset differentiation, which in turn drive the expression of major effector cytokines associated with each particular subtype [113, 114]. Key transcription factors and cytokines involved are indicated for individual subtypes. CD4⁺ T cells augment the development of the CTL response [21, 24] and are required for the development of CD8⁺ T cell immunity (reviewed extensively here [115]) in their role as central co-ordinators of adaptive immunity. Unlike CD8⁺ T cells, whose primary function is to mediate cell contact-dependent cytotoxicity of infected or malignant cells, CD4⁺ T cells exhibit a diverse repertoire of effector functions and exhibit considerable phenotypic plasticity and heterogeneity depending on local context and microenvironment [113, 114]. CD4⁺ T cells activated in the periphery can also differentiate into induced Tregs (iTregs), which are able to mediate immunosuppression similar to thymic Tregs (tTregs).

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 [–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.

Fig. 3. Open questions for research into harnessing the therapeutic potential of tumour-specific CD4⁺ T cells.

a The majority of tumour-reactive CD4⁺ T cells have been found to recognise self-derived antigens, but have thus far only been shown to become activated in the tumour microenvironment (TME) and not in surrounding tissues, suggesting that there may be mechanisms specific to within the TME that permit the breaking of self-tolerance. Another possible avenue for loss of CD4⁺ T cell self-tolerance is the conversion of self-specific Tregs into conventional effector T cells within the TME. b Because CD4⁺ T cells are MHC II-restricted, their activation within the TME requires antigen presentation in the context of MHC II molecules. In principle, MHC II⁺ tumours could directly present antigen and activate CD4⁺ T cells, or antigen presentation could occur indirectly via antigen-presenting cells (APCs) resident within tumours or tumour-draining lymphoid sites. c The mutually reinforcing interaction between myeloid-derived suppressor cells (MDSCs) and regulatory CD4⁺ T cells (Tregs) (above) is a negative mirror image of the APC-effector CD4⁺ T cell synergy that drives the generation of effective immunity (below). Understanding the molecular circuitry is crucial to developing targeted strategies to disrupt and convert these negative interactions into cycles that drive anti-tumour immunity.