It is noteworthy that specific pre-clinical models that support a role for CD4-dependent responses to checkpoint inhibition do not invariably support a contribution for CD4-dependent cytotoxicity, as in an immunocompetent model of urothelial carcinoma derived from chemical carcinogenesis where CD4-dependent tumor rejection after combination anti-CTLA-4 plus anti-PD-1 therapy does not require tumor cell expression of MHC class I or II (Sato et al., 2018). Here, CD4 is linked to neoplasm.