Borst et al. comprehensively review how CD4+ T cells enhance the cytotoxic T lymphocyte (CTL) antitumor response. Proper CD4+ T cell help leads to clonal expansion and differentiation of CTLs into effector and memory T cells, and increases the cytotoxicity of CTLs, resulting in enhanced antitumor response. Topics reviewed include types and spatiotemporal stages of dendritic cell involvement and the intricate interplay with T cells, co-presentation of CD4+ and CD8+ epitopes, T cell costimulatory ligands (CD40L) and receptors (CD28, CD27), and cytokine (IL-12, IL-15) and chemokine (XCL1) production.
Cancer immunotherapy aims to promote the activity of cytotoxic T lymphocytes (CTLs) within a tumour, assist the priming of tumour-specific CTLs in lymphoid organs and establish efficient and durable antitumour immunity. During priming, help signals are relayed from CD4(+) T cells to CD8(+) T cells by specific dendritic cells to optimize the magnitude and quality of the CTL response. In this Review, we highlight the cellular dynamics and membrane receptors that mediate CD4(+) T cell help and the molecular mechanisms of the enhanced antitumour activity of CTLs. We outline how deficient CD4(+) T cell help reduces the response of CTLs and how maximizing CD4(+) T cell help can improve outcomes in cancer immunotherapy strategies.
