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Antitumor adaptive immunity remains intact following inhibition of autophagy and antimalarial treatment
Hanna Starobinets, … , Matthew Krummel, Jayanta Debnath
Hanna Starobinets, … , Matthew Krummel, Jayanta Debnath
Published October 24, 2016
Citation Information: J Clin Invest. 2016;126(12):4417-4429. https://doi.org/10.1172/JCI85705.
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Research Article Immunology Oncology Article has an altmetric score of 32

Antitumor adaptive immunity remains intact following inhibition of autophagy and antimalarial treatment

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Abstract

The rising success of cancer immunotherapy has produced immense interest in defining the clinical contexts that may benefit from this therapeutic approach. To this end, there is a need to ascertain how the therapeutic modulation of intrinsic cancer cell programs influences the anticancer immune response. For example, the role of autophagy as a tumor cell survival and metabolic fitness pathway is being therapeutically targeted in ongoing clinical trials that combine cancer therapies with antimalarial drugs for the treatment of a broad spectrum of cancers, many of which will likely benefit from immunotherapy. However, our current understanding of the interplay between autophagy and the immune response remains incomplete. Here, we have evaluated how autophagy inhibition impacts the antitumor immune response in immune-competent mouse models of melanoma and mammary cancer. We observed equivalent levels of T cell infiltration and function within autophagy-competent and -deficient tumors, even upon treatment with the anthracycline chemotherapeutic doxorubicin. Similarly, we found equivalent T cell responses upon systemic treatment of tumor-bearing mice with antimalarial drugs. Our findings demonstrate that antitumor adaptive immunity is not adversely impaired by autophagy inhibition in these models, allowing for the future possibility of combining autophagy inhibitors with immunotherapy in certain clinical contexts.

Authors

Hanna Starobinets, Jordan Ye, Miranda Broz, Kevin Barry, Juliet Goldsmith, Timothy Marsh, Fanya Rostker, Matthew Krummel, Jayanta Debnath

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Figure 5

Dox-treated autophagy-deficient tumors elicit equivalent T cell responses despite altered secretion of immunomodulatory factors.

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Dox-treated autophagy-deficient tumors elicit equivalent T cell response...
(A) Autophagy-competent (shCTL) and -deficient (shAtg7 or shAtg12) B16 cells treated with 10 μM Dox or vehicle control. ATP and HMGB1 secretion measured in conditioned medium and surface PD-L1 measured by flow cytometry. Data points represent biological replicates; bars represent mean values. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001; not significant (NS) using 2-way ANOVA multiplicity-adjusted P values (Dunnett’s correction). (B) Autophagy-competent (shCTL) and -deficient (shAtg7) B16 cells were treated for 24 hours with 8.8 μM and 7.5 μM Dox, respectively, and subsequently injected into WT C57BL/6 mice (n = 5). Control mice were injected with Matrigel (n = 10). Mice were rechallenged with WT B16 cells 1 week later; tumor incidence was monitored daily. (C) Autophagy-competent and -deficient B16 cells were injected into GREAT reporter mice; mice were then treated with 5 mg/kg Dox weekly. Tumor growth curves: arrows indicate Dox treatment; error bars represent SD (B16-shCTL: n = 6; B16-shATG7: n = 7; B16-shCTL + Dox: n = 8; B16-shATG7 + Dox: n = 8). Resected tumor mass: box and whisker plots indicate minimum, median, and maximum values. Untreated tumors are also included in Figure 1A. (D) Resected and digested tumors were immunoblotted for LC3 (autophagy deficiency) and γH2AX (DNA damage). Expression quantified normalized to GAPDH. Error bars represent SD. *P < 0.05; NS, not significant, using unpaired t test. (E) T cell infiltration and functional status (CD44, PD-1, eYFP) in control and Dox-treated autophagy-competent and -deficient B16 tumors from 2 experimental cohorts. Each data point represents a distinct tumor from an individual host mouse. Bars represent mean values. *P < 0.05; ***P < 0.001; ****P < 0.0001, using 2-way ANOVA multiplicity-adjusted P values (Tukey’s correction). Measurements of untreated tumors are also included in Figures 2B and 3B.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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