Inhibiting CD28 inside tumor cells for TNBC

Inhibiting a tumor-intrinsic, non-canonical intracellular function of CD28, best known as a co-stimulatory molecule on T cell surfaces, could help treat triple-negative breast cancer (TNBC) by decreasing its stabilization of mRNA encoding the immunosuppressive checkpoint protein PD-L1 via recruitment of spliceosomal machinery, thereby disrupting cancer cell immune escape.

In a PD-1 inhibitor-resistant, syngeneic mouse model of TNBC, genome-wide CRISPR screening using a lentiviral knockout library in tumor cells before their inoculation in mice showed cells with CD28 loss-of-function were depleted in tumors in vivo. ...