Virginia Commonwealth University Richmond United States
We investigated how autophagy plays a role in accelerating or delaying recurrence of neu-overexpressing mouse mammary carcinoma MMC following adriamycin ADR treatment, and in affecting response to immunotherapy. We explored two strategies 1 transient blockade of autophagy with chloroquine CQ, which blocks fusion of autophagosomes and lysosomes during ADR treatment, and 2 permanent inhibition of autophagy by a stable knockdown of ATG5 ATG5KD, which inhibits the formation of autophagosomes in MMC during and after ADR treatment. We found that while CQ prolonged tumor dormancy, but that stable knockdown of autophagy resulted in early escape from dormancy and recurrence. Interestingly, ATG5KD MMC contained an increased frequency of ADR-induced polyploid like cells and rendered MMC resistant to immunotherapy. We also determined that expression of IFN-g Ra on tumor cells is not a major determinant of tumor progression and relapse. On the other hand, a transient blockade of autophagy did not affect the sensitivity of MMC to immunotherapy. Our observations suggest that while chemotherapy-induced autophagy may facilitate tumor relapse, cell-intrinsic autophagy delays tumor relapse, in part, by inhibiting the formation of polyploid-like tumor dormancy.