Vaccine Induces Dual T cell plus NK cell Attack against Resistant Tumors

Here we report a cancer vaccine that induced a coordinated attack by diverse T cell and NK cell populations. The vaccine targeted the MICA and MICB (MICA/B) stress proteins expressed by many human cancers due to DNA damage. MICA/B serve as ligands for the activating NKG2D receptor on T cells and NK cells, but tumors evade immune recognition by proteolytic MICA/B cleavage. Vaccine-induced antibodies increased the density of MICA/B proteins on the surface of tumor cells by inhibiting proteolytic shedding, increased presentation of tumor antigens by dendritic cells to T cells, and enhanced the cytotoxic function of NK cells. Importantly, this vaccine maintained efficacy against MHC-I deficient tumors resistant to cytotoxic T cells through the coordinated action of NK cells and CD4 T cells. The vaccine was also efficacious in a clinically important setting: immunization following surgical removal of primary, highly metastatic tumors inhibited the later outgrowth of metastases. This vaccine design enables protective immunity even against tumors with common escape mutations. Single cell RNA-seq on tumor-infiltrating immune cells between the experimental group (MICB-vax + dox) versus the three control groups (control-vax +/- dox, MICB-vax -dox). Bulk RNA-seq of migratory DCs and NK cells between the experimental group (MICB-iso) versus the three control groups (Ferritin-iso, Ferritin-aCD4, MICB-aCD4)