Zhao et al. demonstrate that in a mouse model of autochthonous BrafV600EPten-/- melanoma, TGFβ blockade synergized with concurrently administered anti-CTLA-4 but not anti-PD-L1. TGFβ blockade induced an expansion of cancer-associated fibroblasts (CAFs), which upregulated their expression of MMP-9 upon exposure to melanoma cells; MMP-9 then (presumably) cleaved PD-L1 from the tumor cell surface, enhancing resistance to anti-PD-L1. Delayed administration of TGFβ blockade timed with the development of anti-PD-1 resistance did not upregulate CAFs or MMP-9, increased CD8+ T cell infiltration into the tumor, and reduced tumor growth.

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 pharmacological 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.

Author Info: (1) NIEHS/IIDL, NIH. (2) Internal Medicine/Medical Oncology, Duke University Medical Center. (3) Internal Medicine/Medical Oncology, Duke University Medical Center. (4) Medicine, D

Author Info: (1) NIEHS/IIDL, NIH. (2) Internal Medicine/Medical Oncology, Duke University Medical Center. (3) Internal Medicine/Medical Oncology, Duke University Medical Center. (4) Medicine, Duke University Medical Center. (5) Internal Medicine/Medical Oncology, Duke University Medical Center. (6) Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill. (7) Internal Medicine III, University Hospital Regensburg. (8) Pharmacology & Cancer Biology, Duke University Medical Center. (9) Internal Medicine/Medical Oncology and Pharmacology/Cancer Biology, Duke University Medical Center hanks004@mc.duke.edu.