CD4(+) cytotoxic T cells: an emerging effector arm of anti-tumor immunity

While CD8(+) cytotoxic T cells have long been considered the primary effector in controlling tumors, the involvement of CD4(+) “helper” T cells in anti-tumor immunity has been underappreciated. The investigations of intra-tumoral T cells, fueled by the recent advances in genomic technologies, have led to a rethinking of the indirect role of CD4(+) T cells that have traditionally been described as a “helper”. Accumulating evidence from preclinical and clinical studies indicates that CD4(+) T cells can acquire intrinsic cytotoxic properties and directly kill various types of tumor cells in a major histocompatibility complex class II (MHC-II)-dependent manner, as opposed to the indirect “helper” function, thus underscoring a potentially critical contribution of CD4(+) cytotoxic T cells to immune responses against a wide range of tumor types. Here, we discuss the biological properties of anti-tumor CD4(+) T cells with cytotoxic capability and highlight the emerging observations suggesting their more significant role in anti-tumor immunity than previously appreciated.