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

doi:10.1158/0008-5472.CAN-13-3225

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

Research output: Contribution to journal › Article › peer-review

46 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 language	English
Pages (from-to)	3556-3566
Number of pages	11
Journal	Cancer Research
Volume	74
Issue number	13
DOIs	https://doi.org/10.1158/0008-5472.CAN-13-3225
Publication status	Published - 2014 Jul 1

ASJC Scopus subject areas

Oncology
Cancer Research

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1158/0008-5472.CAN-13-3225

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@article{35997a83fd634eadbf74b8f1204c47f8,

title = "API5 Confers Tumoral Immune Escape through FGF2- Dependent Cell Survival Pathway",

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.",

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

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doi = "10.1158/0008-5472.CAN-13-3225",

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AU - Noh, Kyung Hee

AU - Kim, Seok Ho

AU - Kim, Jin Hee

AU - Song, Kwon Ho

AU - Lee, Young Ho

AU - Kang, Tae Heung

AU - Han, Hee Dong

AU - Sood, Anil K.

AU - Ng, Joanne

AU - Kim, Kwanghee

AU - Sonn, Chung Hee

AU - Kumar, Vinay

AU - Yee, Cassian

AU - Lee, Kyung Mi

AU - Kim, Tae Woo

PY - 2014/7/1

Y1 - 2014/7/1

N2 - 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.

AB - 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.

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

Abstract

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