CD4+ T Cells: Multitasking Cells in the Duty of Cancer Immunotherapy

Simple Summary T cells bearing the co-receptor CD4 on their cell surface are a heterogeneous group of T lymphocytes that exert pro- or anti-inflammatory functions. Evidence from mouse models and cancer patients reveal that various CD4+ T cell subsets play an antagonistic role in the antitumor immune response. This review summarizes current knowledge on CD4+ T cell subsets, on how they impact tumor growth in patients, and which role these cells play in newest cancer immunotherapies. Abstract Cancer immunotherapy activates the immune system to specifically target malignant cells. Research has often focused on CD8+ cytotoxic T cells, as those have the capacity to eliminate tumor cells after specific recognition upon TCR-MHC class I interaction. However, CD4+ T cells have gained attention in the field, as they are not only essential to promote help to CD8+ T cells, but are also able to kill tumor cells directly (via MHC-class II dependent recognition) or indirectly (e.g., via the activation of other immune cells like macrophages). Therefore, immunotherapy approaches have shifted from only stimulating CD8+ T cells to targeting and assessing both, CD4+ and CD8+ T cell subsets. Here, we discuss the various subsets of CD4+ T cells, their plasticity and functionality, their relevance in the antitumor immune response in patients affected by cancer, and their ever-growing role in therapeutic approaches for human cancer.