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. Overall design: 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)