Autophagosome vaccine cross-protects and breaks tumor immunology paradigm: a p62-dependent mechanism? (41.41)

Abstract

Vaccination with MCA sarcoma cells protects from a subsequent challenge with the same, but not other MCA sarcomas. This observation of unique tumor-specific protection is a well-established paradigm (Prehn and Main 1957). We postulated that all MCA sarcomas overexpress common mutated gene products with a short half-life (SLiPs), but only the unique tumor-rejection antigens are stable enough to be cross-presented and induce anti-tumor immunity. We recently reported that with proteosomal blockade, SLiPs could be isolated in autophagic-containing (LC-3) vesicles (termed DRibble) that were efficient for cross-presentation of antigens (Li, Y. et al). Here we examined if vaccination with DRibbles from one MCA sarcoma would cross-protect from a challenge with an antigenically distinct MCA sarcoma. While whole tumor cell vaccines provide protection to unrelated tumor in 0 of 9 comparisons, DRibble vaccines provided significant (p<0.05) protection for 8 of 9 tumors (n=10-25 mice/group). Using a model system we showed that SLiPs play a critical role in providing antigen to DRibbles and that siRNA knock down of p62 reduced SLiPs and the capacity of DRibble to stimulate T cells. These results have shaped a model where polyubiquitinated SLiPs spared degradation by the proteasome, are picked up by p62 and delivered to autophagic vesicles. Used as a vaccine, these vesicles can cross-present neo-antigens capable of inducing cross-protection of chemically induced sarcomas. Supported by CA80964 (BAF), CA107243 (HH) the Chiles Foundation and the Murdoch Trust.