An autophagy-dependent anticancer immune response determines the efficacy of melanoma chemotherapy

M Michaud, X Xie, JM Bravo-San Pedro… - …, 2014 - Taylor & Francis
Oncoimmunology, 2014Taylor & Francis
There is ample experimental and clinical evidence that chemotherapies are more efficient if
they succeed in (re) activating immune surveillance, hence triggering a long-term immune
response against residual tumor cells. Most of the preclinical evidence supporting this notion
has been obtained with transplantable cancers, for which it has been shown that
chemotherapy-induced autophagy in cancer cells is mandatory for the recruitment of
myeloid cells into the tumor bed and the subsequent T lymphocyte-mediated reduction in …
There is ample experimental and clinical evidence that chemotherapies are more efficient if they succeed in (re)activating immune surveillance, hence triggering a long-term immune response against residual tumor cells. Most of the preclinical evidence supporting this notion has been obtained with transplantable cancers, for which it has been shown that chemotherapy-induced autophagy in cancer cells is mandatory for the recruitment of myeloid cells into the tumor bed and the subsequent T lymphocyte-mediated reduction in tumor growth. Here, we characterized the chemotherapeutic response of melanomas caused by 4-hydroxy-tamoxifen-induced expression of the Cre recombinase in melanocytes that results in the activation of oncogenic Braf together with the inactivation of the tumor suppressor Pten, as well as the optional inactivation of the essential autophagy gene Atg7. Systemic chemotherapy with the anthracycline Mitoxantrone (MTX) reduced the growth of autophagy-competent melanomas (genotype: BrafCa/+; Ptenfl/fl; Atg7+/+), yet failed to affect the progression of autophagy-deficient melanomas (genotype: BrafCa/+; Ptenfl/fl; Atg7fl/fl). The growth-inhibitory effect of MTX on autophagy-competent melanomas was abolished by the combined depletion of CD4+ or CD8+ T lymphocytes. In conclusion, it appears that the success of chemotherapy against “spontaneous,” genetically induced cancers is governed by the same rules as those applicable to transplantable tumors.
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