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Cancer Immunology Research
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Research Article

Targeted Therapy Given after Anti–PD-1 Leads to Prolonged Responses in Mouse Melanoma Models through Sustained Antitumor Immunity

Manali S. Phadke, Zhihua Chen, Jiannong Li, Eslam Mohamed, Michael A. Davies, Inna Smalley, Derek R. Duckett, Vinayak Palve, Brian J. Czerniecki, Peter A. Forsyth, David Noyes, Dennis O. Adeegbe, Zeynep Eroglu, Kimberly T. Nguyen, Kenneth Y. Tsai, Uwe Rix, Christin E. Burd, Yian A. Chen, Paulo C. Rodriguez and Keiran S.M. Smalley
Manali S. Phadke
1The Department of Tumor Biology, The Moffitt Cancer Center and Research Institute, Tampa, Florida.
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Zhihua Chen
2The Department of Biostatistics and Bioinformatics, The Moffitt Cancer Center and Research Institute, Tampa, Florida.
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Jiannong Li
2The Department of Biostatistics and Bioinformatics, The Moffitt Cancer Center and Research Institute, Tampa, Florida.
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Eslam Mohamed
3The Department of Immunology, The Moffitt Cancer Center and Research Institute, Tampa, Florida.
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Michael A. Davies
4The Department of Melanoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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  • ORCID record for Michael A. Davies
Inna Smalley
1The Department of Tumor Biology, The Moffitt Cancer Center and Research Institute, Tampa, Florida.
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  • ORCID record for Inna Smalley
Derek R. Duckett
5The Department of Drug Discovery, The Moffitt Cancer Center and Research Institute, Tampa, Florida.
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Vinayak Palve
5The Department of Drug Discovery, The Moffitt Cancer Center and Research Institute, Tampa, Florida.
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  • ORCID record for Vinayak Palve
Brian J. Czerniecki
3The Department of Immunology, The Moffitt Cancer Center and Research Institute, Tampa, Florida.
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Peter A. Forsyth
6The Department of Neurooncology, The Moffitt Cancer Center and Research Institute, Tampa, Florida.
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  • ORCID record for Peter A. Forsyth
David Noyes
7The Department of Malignant Hematology, The Moffitt Cancer Center and Research Institute, Tampa, Florida.
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Dennis O. Adeegbe
3The Department of Immunology, The Moffitt Cancer Center and Research Institute, Tampa, Florida.
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Zeynep Eroglu
8The Department of Cutaneous Oncology, The Moffitt Cancer Center and Research Institute, Tampa, Florida.
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Kimberly T. Nguyen
1The Department of Tumor Biology, The Moffitt Cancer Center and Research Institute, Tampa, Florida.
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  • ORCID record for Kimberly T. Nguyen
Kenneth Y. Tsai
1The Department of Tumor Biology, The Moffitt Cancer Center and Research Institute, Tampa, Florida.
8The Department of Cutaneous Oncology, The Moffitt Cancer Center and Research Institute, Tampa, Florida.
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Uwe Rix
5The Department of Drug Discovery, The Moffitt Cancer Center and Research Institute, Tampa, Florida.
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Christin E. Burd
9Department of Cancer Biology and Genetics, Ohio State University, Columbus, Ohio.
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Yian A. Chen
2The Department of Biostatistics and Bioinformatics, The Moffitt Cancer Center and Research Institute, Tampa, Florida.
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Paulo C. Rodriguez
3The Department of Immunology, The Moffitt Cancer Center and Research Institute, Tampa, Florida.
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Keiran S.M. Smalley
1The Department of Tumor Biology, The Moffitt Cancer Center and Research Institute, Tampa, Florida.
8The Department of Cutaneous Oncology, The Moffitt Cancer Center and Research Institute, Tampa, Florida.
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  • For correspondence: keiran.smalley@moffitt.org
DOI: 10.1158/2326-6066.CIR-20-0905
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Abstract

Immunotherapy (IT) and targeted therapy (TT) are both effective against melanoma, but their combination is frequently toxic. Here, we investigated whether the sequence of IT (anti–PD-1)→ TT (ceritinib–trametinib or dabrafenib–trametinib) was associated with improved antitumor responses in mouse models of BRAF- and NRAS-mutant melanoma. Mice with NRAS-mutant (SW1) or BRAF-mutant (SM1) mouse melanomas were treated with either IT, TT, or the sequence of IT→TT. Tumor volumes were measured, and samples from the NRAS-mutant melanomas were collected for immune-cell analysis, single-cell RNA sequencing (scRNA-seq), and reverse phase protein analysis (RPPA). scRNA-seq demonstrated that the IT→TT sequence modulated the immune environment, leading to increased infiltration of T cells, monocytes, dendritic cells and natural killer cells, and decreased numbers of tumor-associated macrophages, myeloid-derived suppressor cells, and regulatory T cells. Durable responses to the IT→TT sequence were dependent on T-cell activity, with depletion of CD8+, but not CD4+, T cells abrogating the therapeutic response. An analysis of transcriptional heterogeneity in the melanoma compartment showed the sequence of IT→TT enriched for a population of melanoma cells with increased expression of MHC class I and melanoma antigens. RPPA analysis demonstrated that the sustained immune response induced by IT→TT suppressed tumor-intrinsic signaling pathways required for therapeutic escape. These studies establish that upfront IT improves the responses to TT in BRAF- and NRAS-mutant melanoma models.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/).

  • Cancer Immunol Res 2021;XX:XX–XX

  • Received October 30, 2020.
  • Revision received January 14, 2021.
  • Accepted February 23, 2021.
  • Published first March 2, 2021.
  • ©2021 American Association for Cancer Research.
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This OnlineFirst version was published on March 26, 2021
doi: 10.1158/2326-6066.CIR-20-0905

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Targeted Therapy Given after Anti–PD-1 Leads to Prolonged Responses in Mouse Melanoma Models through Sustained Antitumor Immunity
Manali S. Phadke, Zhihua Chen, Jiannong Li, Eslam Mohamed, Michael A. Davies, Inna Smalley, Derek R. Duckett, Vinayak Palve, Brian J. Czerniecki, Peter A. Forsyth, David Noyes, Dennis O. Adeegbe, Zeynep Eroglu, Kimberly T. Nguyen, Kenneth Y. Tsai, Uwe Rix, Christin E. Burd, Yian A. Chen, Paulo C. Rodriguez and Keiran S.M. Smalley
Cancer Immunol Res March 26 2021 DOI: 10.1158/2326-6066.CIR-20-0905

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Targeted Therapy Given after Anti–PD-1 Leads to Prolonged Responses in Mouse Melanoma Models through Sustained Antitumor Immunity
Manali S. Phadke, Zhihua Chen, Jiannong Li, Eslam Mohamed, Michael A. Davies, Inna Smalley, Derek R. Duckett, Vinayak Palve, Brian J. Czerniecki, Peter A. Forsyth, David Noyes, Dennis O. Adeegbe, Zeynep Eroglu, Kimberly T. Nguyen, Kenneth Y. Tsai, Uwe Rix, Christin E. Burd, Yian A. Chen, Paulo C. Rodriguez and Keiran S.M. Smalley
Cancer Immunol Res March 26 2021 DOI: 10.1158/2326-6066.CIR-20-0905
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