Although CD4+ T cells are found to be necessary for sustaining high avidity tumor-specific CD8+ T cell responses (30–34), it is unclear if and how this extends to established ICB-resistant neoplastic disease where low-to-moderate avidity CD8+ Tex typically dominate the TME and whether natural CD4+ T cell tumor specificity is needed for the immunotherapeutic treatment of MHC II− tumors in this context (19, 22, 24, 35–37). The gene discussed is CD4; the disease is neoplasm.