Zhao, Fei and Evans, Kathy and Xiao, Christine and DeVito, Nicholas and Theivanthiran, Balamayooran and Holtzhausen, Alisha and Siska, Peter J. and Blobe, Gerard C. and Hanks, Brent A. (2018) Stromal Fibroblasts Mediate Anti-PD-1 Resistance via MMP-9 and Dictate TGF beta Inhibitor Sequencing in Melanoma. CANCER IMMUNOLOGY RESEARCH, 6 (12). pp. 1459-1471. ISSN 2326-6066, 2326-6074
Full text not available from this repository. (Request a copy)Abstract
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 TGF beta 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 BRAF(V600E) melanoma. Additional mechanistic studies revealed that TGF beta 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 TGF beta signaling activity. Delayed TGF beta 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 TGF beta 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 TGF beta inhibition may generate greater immunologic efficacy when administered following the development of acquired anti-PD-1 resistance. (C) 2018 AACR.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | DESMOPLASTIC MALIGNANT-MELANOMA; ANTITUMOR IMMUNE-RESPONSE; ACQUIRED-RESISTANCE; ACTIVATION PROTEIN; PD-L1 EXPRESSION; CANCER; GROWTH; CELLS; MATRIX-METALLOPROTEINASE-9; OPPORTUNITIES; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 04 Oct 2019 09:54 |
| Last Modified: | 04 Oct 2019 09:54 |
| URI: | https://pred.uni-regensburg.de/id/eprint/13432 |
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