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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Zhao, F; Evans, K; Xiao, C; DeVito, N; Theivanthiran, B; Holtzhausen, A; Siska, PJ; Blobe, GC; Hanks, BA

Published Date

  • December 2018

Published In

Volume / Issue

  • 6 / 12

Start / End Page

  • 1459 - 1471

PubMed ID

  • 30209062

Pubmed Central ID

  • PMC6279598

Electronic International Standard Serial Number (EISSN)

  • 2326-6074

Digital Object Identifier (DOI)

  • 10.1158/2326-6066.CIR-18-0086


  • eng

Conference Location

  • United States