API5 Confers Tumoral Immune Escape through FGF2- Dependent Cell Survival Pathway

Kyung Hee Noh, Seok Ho Kim, Jin Hee Kim, Kwon Ho Song, Young Ho Lee, Tae Heung Kang, Hee Dong Han, Anil K. Sood, Joanne Ng, Kwanghee Kim, Chung Hee Sonn, Vinay Kumar, Cassian Yee, Kyung-Mi Lee, Tae Woo Kim

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24 Citations (Scopus)

Abstract

Identifying immune escape mechanisms used by tumors may define strategies to sensitize them to immunotherapies to which they are otherwise resistant. In this study, we show that the antiapoptotic gene API5 acts as an immune escape gene in tumors by rendering them resistant to apoptosis triggered by tumor antigen-specificT cells. Its RNAi-mediated silencing in tumor cells expressing high levels of API5 restored antigen-specific immune sensitivity. Conversely, introducing API5 into API5low cells conferred immune resistance. Mechanistic investigations revealed that API5 mediated resistance by upregulating FGF2 signaling through a FGFR1/PKCd/ERK effector pathway that triggered degradation of the proapoptotic molecule BIM. Blockade of FGF2, PKCd, or ERK phenocopied the effect of API5 silencing in tumor cells expressing high levels of API5 to either murine or human antigen-specific T cells. Our results identify a novel mechanism of immune escape that can be inhibited to potentiate the efficacy of targeted active immunotherapies. Cancer Res; 74(13); 3556-66.

Original languageEnglish
Pages (from-to)3556-3566
Number of pages11
JournalCancer Research
Volume74
Issue number13
DOIs
Publication statusPublished - 2014 Jul 1

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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    Noh, K. H., Kim, S. H., Kim, J. H., Song, K. H., Lee, Y. H., Kang, T. H., Han, H. D., Sood, A. K., Ng, J., Kim, K., Sonn, C. H., Kumar, V., Yee, C., Lee, K-M., & Kim, T. W. (2014). API5 Confers Tumoral Immune Escape through FGF2- Dependent Cell Survival Pathway. Cancer Research, 74(13), 3556-3566. https://doi.org/10.1158/0008-5472.CAN-13-3225