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Stromal Fibroblasts Mediate Anti-PD-1 Resistance via MMP-9 and Dictate TGFβ Inhibitor Sequencing in Melanoma.

Publication ,  Journal Article
Zhao, F; Evans, K; Xiao, C; DeVito, N; Theivanthiran, B; Holtzhausen, A; Siska, PJ; Blobe, GC; Hanks, BA
Published in: Cancer Immunol Res
December 2018

Although anti-PD-1 therapy has improved clinical outcomes for select patients with advanced cancer, many patients exhibit either primary or adaptive resistance to checkpoint inhibitor immunotherapy. The role of the tumor stroma in the development of these mechanisms of resistance to checkpoint inhibitors remains unclear. We demonstrated that pharmacologic inhibition of the TGFβ signaling pathway synergistically enhanced the efficacy of anti-CTLA-4 immunotherapy but failed to augment anti-PD-1/PD-L1 responses in an autochthonous model of BRAFV600E melanoma. Additional mechanistic studies revealed that TGFβ pathway inhibition promoted the proliferative expansion of stromal fibroblasts, thereby facilitating MMP-9-dependent cleavage of PD-L1 surface expression, leading to anti-PD-1 resistance in this model. Further work demonstrated that melanomas escaping anti-PD-1 therapy exhibited a mesenchymal phenotype associated with enhanced TGFβ signaling activity. Delayed TGFβ inhibitor therapy, following anti-PD-1 escape, better served to control further disease progression and was superior to a continuous combination of anti-PD-1 and TGFβ inhibition. This work illustrates that formulating immunotherapy combination regimens to enhance the efficacy of checkpoint blockade requires an in-depth understanding of the impact of these agents on the tumor microenvironment. These data indicated that stromal fibroblast MMP-9 may desensitize tumors to anti-PD-1 and suggests that TGFβ inhibition may generate greater immunologic efficacy when administered following the development of acquired anti-PD-1 resistance.See related Spotlight on p. 1444.

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Published In

Cancer Immunol Res

DOI

EISSN

2326-6074

Publication Date

December 2018

Volume

6

Issue

12

Start / End Page

1459 / 1471

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Tumor Microenvironment
  • Transforming Growth Factor beta
  • Quinolines
  • Pyrazoles
  • Proto-Oncogene Proteins B-raf
  • Mice, Transgenic
  • Mice, Inbred C57BL
  • Mice, Inbred BALB C
  • Melanoma
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Zhao, F., Evans, K., Xiao, C., DeVito, N., Theivanthiran, B., Holtzhausen, A., … Hanks, B. A. (2018). Stromal Fibroblasts Mediate Anti-PD-1 Resistance via MMP-9 and Dictate TGFβ Inhibitor Sequencing in Melanoma. Cancer Immunol Res, 6(12), 1459–1471. https://doi.org/10.1158/2326-6066.CIR-18-0086
Zhao, Fei, Kathy Evans, Christine Xiao, Nicholas DeVito, Balamayooran Theivanthiran, Alisha Holtzhausen, Peter J. Siska, Gerard C. Blobe, and Brent A. Hanks. “Stromal Fibroblasts Mediate Anti-PD-1 Resistance via MMP-9 and Dictate TGFβ Inhibitor Sequencing in Melanoma.Cancer Immunol Res 6, no. 12 (December 2018): 1459–71. https://doi.org/10.1158/2326-6066.CIR-18-0086.
Zhao F, Evans K, Xiao C, DeVito N, Theivanthiran B, Holtzhausen A, et al. Stromal Fibroblasts Mediate Anti-PD-1 Resistance via MMP-9 and Dictate TGFβ Inhibitor Sequencing in Melanoma. Cancer Immunol Res. 2018 Dec;6(12):1459–71.
Zhao, Fei, et al. “Stromal Fibroblasts Mediate Anti-PD-1 Resistance via MMP-9 and Dictate TGFβ Inhibitor Sequencing in Melanoma.Cancer Immunol Res, vol. 6, no. 12, Dec. 2018, pp. 1459–71. Pubmed, doi:10.1158/2326-6066.CIR-18-0086.
Zhao F, Evans K, Xiao C, DeVito N, Theivanthiran B, Holtzhausen A, Siska PJ, Blobe GC, Hanks BA. Stromal Fibroblasts Mediate Anti-PD-1 Resistance via MMP-9 and Dictate TGFβ Inhibitor Sequencing in Melanoma. Cancer Immunol Res. 2018 Dec;6(12):1459–1471.

Published In

Cancer Immunol Res

DOI

EISSN

2326-6074

Publication Date

December 2018

Volume

6

Issue

12

Start / End Page

1459 / 1471

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Tumor Microenvironment
  • Transforming Growth Factor beta
  • Quinolines
  • Pyrazoles
  • Proto-Oncogene Proteins B-raf
  • Mice, Transgenic
  • Mice, Inbred C57BL
  • Mice, Inbred BALB C
  • Melanoma