The histocompatibility barrier prevents the transfer of both normal and tumor cells between individuals; however, clonally transmissible cancers in dogs, Tasmanian devils, and soft-shell clams can naturally transmit as allografts. To understand if cancer cells can more generally evolve to escape the histocompatibility barrier, we have serially passaged a mouse melanoma into increasingly mismatched mouse strains until a transplantable tumor emerged. The transplantable melanoma cells are characterized by an antiviral immune signature and the upregulation of endogenous retrotransposable elements (RTEs), major histocompatibility complex class I (MHC class I), programmed cell death ligand-1 (PD-L1), and Qa-1 non-classical MHC molecules. Knockout of the RNA sensor retinoic acid-inducible gene I (RIG-I) reduces expression of PD-L1 and Qa-1, and antibody-mediated blockade of PD-L1 and Qa-1 induces tumor rejection. Thus, an immune antiviral signature linked to RTEs upregulation facilitates escape of the melanoma from allogeneic rejection, simultaneously making the tumor sensitive to PD-L1 and Qa-1 antagonism. A similar immune signature is found in human melanomas that respond to PD-L1 blockade.
Rokan et al. (Fri,) studied this question.