Abstract
MicroRNAs (miRs) are small non-coding RNAs that regulate most cellular protein networks by targeting mRNAs for translational inhibition or degradation. Dicer, a type III endoribonuclease, is a critical component in microRNA biogenesis and is required for mature microRNA production. Abnormal Dicer expression occurs in numerous cancer types and correlates with poor patient prognosis. For example, increased Dicer expression in melanoma is associated with more aggressive tumors (higher tumor mitotic index and depth of invasion) and poor patient prognosis. However, the role that Dicer plays in melanoma development and immune evasion remains unclear. Here, we report on a newly discovered relationship between Dicer expression and tumor immunogenicity. To investigate Dicer's role in regulating melanoma immunogenicity, Dicer knockdown studies were performed. We found that B16F0-Dicer deficient cells exhibited decreased tumor growth compared to control cells and were capable of inducing anti-tumor immunity. The decrease in tumor growth was abrogated in immunodeficient NSG mice and was shown to be dependent upon CD8+ T cells. Dicer knockdown also induced a more responsive immune gene profile in melanoma cells. Further studies demonstrated that CD8+ T cells preferentially killed Dicer knockdown tumor cells compared to control cells. Taken together, we present evidence which links Dicer expression to tumor immunogenicity in melanoma.
Highlights
Immunotherapeutic strategies for treating cancer have become more prevalent over the past few years [1]
These results suggest that Dicer is significantly enhanced in melanoma compared to normal mouse melanocytes and that our Dicer knockdown model does not ablate/delete Dicer expression, but rather restores it to a more homeostatic level
A functional immune system is vital for the anti-tumor effects of HDACi treatment [52]. This potentially www.impactjournals.com/oncotarget links the HDACi regulation of Dicer expression/anti-tumor immunity to the observation that delayed tumor growth of B16F0-Dicer was abrogated in NSG and CD8-/- mice
Summary
Immunotherapeutic strategies for treating cancer have become more prevalent over the past few years [1]. Several hurdles must be overcome for successful immunotherapy treatments. One such hurdle involves the tumor’s immunogenicity and the immune cell’s ability to properly recognize and destroy them [2]. Tumors undergo immune escape by losing antigen expression, acquiring defects in antigen processing/presentation, and/or inducing immunosuppressive molecules [3]. Melanoma cells can undergo immune escape through various mechanisms involving immune gene regulation [4–8 ]. Immunotherapy has achieved some success in certain subsets of melanoma patients; the regulation of immune effector molecules important for melanoma immunogenicity remains poorly understood [9, 10]. Recent work has demonstrated that microRNAs (miRs) may be involved in modulating tumor immunogenicity
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