BRAF inhibition increases tumor infiltration by T cells and enhances the antitumor activity of adoptive immunotherapy in mice

Chengwen Liu, Weiyi Peng, Chunyu Xu, Yanyan Lou, Minying Zhang, Jennifer A. Wargo, Jie Qing Chen, Haiyan S. Li, Stephanie S. Watowich, Yan Yang, Dennie Tompers Frederick, Zachary A. Cooper, Rina M. Mbofung, Mayra Whittington, Keith T. Flaherty, Scott E. Woodman, Michael A. Davies, Laszlo G. Radvanyi, Willem W. Overwijk, Gregory LizéePatrick Hwu

Research output: Contribution to journalArticle

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Abstract

Purpose: Treatment of melanoma patients with selective BRAF inhibitors results in objective clinical responses in the majority of patients with BRAF-mutant tumors. However, resistance to these inhibitors develops within a few months. In this study, we test the hypothesis that BRAF inhibition in combination with adoptive T-cell transfer (ACT) will be more effective at inducing long-term clinical regressions of BRAFmutant tumors. Experimental Design: BRAF-mutated human melanoma tumor cell lines transduced to express gp100 and H-2Db to allow recognition by gp100-specific pmel-1 T cells were used as xenograft models to assess melanocyte differentiation antigen-independent enhancement of immune responses by BRAF inhibitor PLX4720. Luciferase-expressing pmel-1 T cells were generated to monitor T-cell migration in vivo. The expression of VEGF was determined by ELISA, protein array, and immunohistochemistry. Importantly, VEGF expression after BRAF inhibition was tested in a set of patient samples. Results: We found that administration of PLX4720 significantly increased tumor infiltration of adoptively transferred T cells in vivo and enhanced the antitumor activity of ACT. This increased T-cell infiltration was primarily mediated by the ability of PLX4720 to inhibit melanoma tumor cell production of VEGF by reducing the binding of c-myc to the VEGF promoter. Furthermore, analysis of human melanoma patient tumor biopsies before and during BRAF inhibitor treatment showed downregulation of VEGF consistent with the preclinical murine model. Conclusion: These findings provide a strong rationale to evaluate the potential clinical application of combining BRAF inhibition with T-cell-based immunotherapy for the treatment of patients with melanoma.

Original languageEnglish (US)
Pages (from-to)393-403
Number of pages11
JournalClinical Cancer Research
Volume19
Issue number2
DOIs
StatePublished - Jan 15 2013
Externally publishedYes

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Adoptive Immunotherapy
T-Lymphocytes
Vascular Endothelial Growth Factor A
Melanoma
Neoplasms
Adoptive Transfer
Protein Array Analysis
Melanocytes
Differentiation Antigens
Tumor Cell Line
Luciferases
Heterografts
Immunotherapy
Cell Movement
Research Design
Therapeutics
Down-Regulation
Enzyme-Linked Immunosorbent Assay
Immunohistochemistry
Biopsy

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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BRAF inhibition increases tumor infiltration by T cells and enhances the antitumor activity of adoptive immunotherapy in mice. / Liu, Chengwen; Peng, Weiyi; Xu, Chunyu; Lou, Yanyan; Zhang, Minying; Wargo, Jennifer A.; Chen, Jie Qing; Li, Haiyan S.; Watowich, Stephanie S.; Yang, Yan; Frederick, Dennie Tompers; Cooper, Zachary A.; Mbofung, Rina M.; Whittington, Mayra; Flaherty, Keith T.; Woodman, Scott E.; Davies, Michael A.; Radvanyi, Laszlo G.; Overwijk, Willem W.; Lizée, Gregory; Hwu, Patrick.

In: Clinical Cancer Research, Vol. 19, No. 2, 15.01.2013, p. 393-403.

Research output: Contribution to journalArticle

Liu, C, Peng, W, Xu, C, Lou, Y, Zhang, M, Wargo, JA, Chen, JQ, Li, HS, Watowich, SS, Yang, Y, Frederick, DT, Cooper, ZA, Mbofung, RM, Whittington, M, Flaherty, KT, Woodman, SE, Davies, MA, Radvanyi, LG, Overwijk, WW, Lizée, G & Hwu, P 2013, 'BRAF inhibition increases tumor infiltration by T cells and enhances the antitumor activity of adoptive immunotherapy in mice', Clinical Cancer Research, vol. 19, no. 2, pp. 393-403. https://doi.org/10.1158/1078-0432.CCR-12-1626
Liu, Chengwen ; Peng, Weiyi ; Xu, Chunyu ; Lou, Yanyan ; Zhang, Minying ; Wargo, Jennifer A. ; Chen, Jie Qing ; Li, Haiyan S. ; Watowich, Stephanie S. ; Yang, Yan ; Frederick, Dennie Tompers ; Cooper, Zachary A. ; Mbofung, Rina M. ; Whittington, Mayra ; Flaherty, Keith T. ; Woodman, Scott E. ; Davies, Michael A. ; Radvanyi, Laszlo G. ; Overwijk, Willem W. ; Lizée, Gregory ; Hwu, Patrick. / BRAF inhibition increases tumor infiltration by T cells and enhances the antitumor activity of adoptive immunotherapy in mice. In: Clinical Cancer Research. 2013 ; Vol. 19, No. 2. pp. 393-403.
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abstract = "Purpose: Treatment of melanoma patients with selective BRAF inhibitors results in objective clinical responses in the majority of patients with BRAF-mutant tumors. However, resistance to these inhibitors develops within a few months. In this study, we test the hypothesis that BRAF inhibition in combination with adoptive T-cell transfer (ACT) will be more effective at inducing long-term clinical regressions of BRAFmutant tumors. Experimental Design: BRAF-mutated human melanoma tumor cell lines transduced to express gp100 and H-2Db to allow recognition by gp100-specific pmel-1 T cells were used as xenograft models to assess melanocyte differentiation antigen-independent enhancement of immune responses by BRAF inhibitor PLX4720. Luciferase-expressing pmel-1 T cells were generated to monitor T-cell migration in vivo. The expression of VEGF was determined by ELISA, protein array, and immunohistochemistry. Importantly, VEGF expression after BRAF inhibition was tested in a set of patient samples. Results: We found that administration of PLX4720 significantly increased tumor infiltration of adoptively transferred T cells in vivo and enhanced the antitumor activity of ACT. This increased T-cell infiltration was primarily mediated by the ability of PLX4720 to inhibit melanoma tumor cell production of VEGF by reducing the binding of c-myc to the VEGF promoter. Furthermore, analysis of human melanoma patient tumor biopsies before and during BRAF inhibitor treatment showed downregulation of VEGF consistent with the preclinical murine model. Conclusion: These findings provide a strong rationale to evaluate the potential clinical application of combining BRAF inhibition with T-cell-based immunotherapy for the treatment of patients with melanoma.",
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T1 - BRAF inhibition increases tumor infiltration by T cells and enhances the antitumor activity of adoptive immunotherapy in mice

AU - Liu, Chengwen

AU - Peng, Weiyi

AU - Xu, Chunyu

AU - Lou, Yanyan

AU - Zhang, Minying

AU - Wargo, Jennifer A.

AU - Chen, Jie Qing

AU - Li, Haiyan S.

AU - Watowich, Stephanie S.

AU - Yang, Yan

AU - Frederick, Dennie Tompers

AU - Cooper, Zachary A.

AU - Mbofung, Rina M.

AU - Whittington, Mayra

AU - Flaherty, Keith T.

AU - Woodman, Scott E.

AU - Davies, Michael A.

AU - Radvanyi, Laszlo G.

AU - Overwijk, Willem W.

AU - Lizée, Gregory

AU - Hwu, Patrick

PY - 2013/1/15

Y1 - 2013/1/15

N2 - Purpose: Treatment of melanoma patients with selective BRAF inhibitors results in objective clinical responses in the majority of patients with BRAF-mutant tumors. However, resistance to these inhibitors develops within a few months. In this study, we test the hypothesis that BRAF inhibition in combination with adoptive T-cell transfer (ACT) will be more effective at inducing long-term clinical regressions of BRAFmutant tumors. Experimental Design: BRAF-mutated human melanoma tumor cell lines transduced to express gp100 and H-2Db to allow recognition by gp100-specific pmel-1 T cells were used as xenograft models to assess melanocyte differentiation antigen-independent enhancement of immune responses by BRAF inhibitor PLX4720. Luciferase-expressing pmel-1 T cells were generated to monitor T-cell migration in vivo. The expression of VEGF was determined by ELISA, protein array, and immunohistochemistry. Importantly, VEGF expression after BRAF inhibition was tested in a set of patient samples. Results: We found that administration of PLX4720 significantly increased tumor infiltration of adoptively transferred T cells in vivo and enhanced the antitumor activity of ACT. This increased T-cell infiltration was primarily mediated by the ability of PLX4720 to inhibit melanoma tumor cell production of VEGF by reducing the binding of c-myc to the VEGF promoter. Furthermore, analysis of human melanoma patient tumor biopsies before and during BRAF inhibitor treatment showed downregulation of VEGF consistent with the preclinical murine model. Conclusion: These findings provide a strong rationale to evaluate the potential clinical application of combining BRAF inhibition with T-cell-based immunotherapy for the treatment of patients with melanoma.

AB - Purpose: Treatment of melanoma patients with selective BRAF inhibitors results in objective clinical responses in the majority of patients with BRAF-mutant tumors. However, resistance to these inhibitors develops within a few months. In this study, we test the hypothesis that BRAF inhibition in combination with adoptive T-cell transfer (ACT) will be more effective at inducing long-term clinical regressions of BRAFmutant tumors. Experimental Design: BRAF-mutated human melanoma tumor cell lines transduced to express gp100 and H-2Db to allow recognition by gp100-specific pmel-1 T cells were used as xenograft models to assess melanocyte differentiation antigen-independent enhancement of immune responses by BRAF inhibitor PLX4720. Luciferase-expressing pmel-1 T cells were generated to monitor T-cell migration in vivo. The expression of VEGF was determined by ELISA, protein array, and immunohistochemistry. Importantly, VEGF expression after BRAF inhibition was tested in a set of patient samples. Results: We found that administration of PLX4720 significantly increased tumor infiltration of adoptively transferred T cells in vivo and enhanced the antitumor activity of ACT. This increased T-cell infiltration was primarily mediated by the ability of PLX4720 to inhibit melanoma tumor cell production of VEGF by reducing the binding of c-myc to the VEGF promoter. Furthermore, analysis of human melanoma patient tumor biopsies before and during BRAF inhibitor treatment showed downregulation of VEGF consistent with the preclinical murine model. Conclusion: These findings provide a strong rationale to evaluate the potential clinical application of combining BRAF inhibition with T-cell-based immunotherapy for the treatment of patients with melanoma.

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