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Published on: November 19, 2019
Transforming Growth Factor-β Blockade in Pancreatic Cancer Enhances Sensitivity to Combination Chemotherapy
Li Qiang1, Megan T Hoffman1, Lestat R Ali2
1Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts; Department of Immunology, Harvard Medical School, Boston, Massachusetts.
Background & Aims:
Transforming growth factor-b (TGFb) plays pleiotropic roles in pancreatic cancer, including promoting metastasis, attenuating CD8 T-cell activation, and enhancing myofibroblast differentiation and deposition of extracellular matrix. However, single-agent TGFb inhibition has shown limited efficacy against pancreatic cancer in mice or humans.
Methods:
We evaluated the TGFβ-blocking antibody NIS793 in combination with gemcitabine/nanoparticle (albumin-bound)-paclitaxel or FOLFIRINOX (folinic acid [FOL], 5-fluorouracil [F], irinotecan [IRI] and oxaliplatin [OX]) in orthotopic pancreatic cancer models. Single-cell RNA sequencing and immunofluorescence were used to evaluate changes in tumor cell state and the tumor microenvironment.
Results:
Blockade of TGFβ with chemotherapy reduced tumor burden in poorly immunogenic pancreatic cancer, without affecting the metastatic rate of cancer cells. Efficacy of combination therapy was not dependent on CD8 T cells, because response to TGFβ blockade was preserved in CD8-depleted or recombination activating gene 2 (RAG2-/-) mice. TGFβ blockade decreased total α-smooth muscle actin-positive fibroblasts but had minimal effect on fibroblast heterogeneity. Bulk RNA sequencing on tumor cells sorted ex vivo revealed that tumor cells treated with TGFβ blockade adopted a classical lineage consistent with enhanced chemosensitivity, and immunofluorescence for cleaved caspase 3 confirmed that TGFβ blockade increased chemotherapy-induced cell death in vivo.
Conclusions:
TGFβ regulates pancreatic cancer cell plasticity between classical and basal cell states. TGFβ blockade in orthotropic models of pancreatic cancer enhances sensitivity to chemotherapy by promoting a classical malignant cell state. This study provides scientific rationale for evaluation of NIS793 with FOLFIRINOX or gemcitabine/nanoparticle (albumin-bound) paclitaxel chemotherapy backbone in the clinical setting and supports the concept of manipulating cancer cell plasticity to increase the efficacy of combination therapy regimens.
Insights
Transforming growth factor-b (TGFb) blockade combined with chemotherapy effectively reduces pancreatic tumor burden. This approach enhances chemotherapy sensitivity by shifting cancer cells to a more treatable state.
Area of Science:
- Oncology
- Cancer Biology
- Immunotherapy
Background:
- Transforming growth factor-b (TGFb) promotes pancreatic cancer progression, metastasis, and immune evasion.
- Single-agent TGFb inhibition has shown limited efficacy in pancreatic cancer models and patients.
Purpose of the Study:
- To evaluate the efficacy of TGFb-blocking antibody NIS793 in combination with standard chemotherapy regimens (gemcitabine/nab-paclitaxel or FOLFIRINOX) in orthotopic pancreatic cancer models.
- To investigate the impact of TGFb blockade on tumor cell plasticity and the tumor microenvironment.
Main Methods:
- Orthotopic pancreatic cancer models were treated with NIS793 plus chemotherapy.
- Single-cell RNA sequencing and immunofluorescence were used to analyze tumor cell states and microenvironment changes.
- CD8 T-cell depletion and RAG2-/- mice were used to assess the role of adaptive immunity.
Main Results:
- Combination therapy significantly reduced tumor burden in poorly immunogenic pancreatic cancer.
- Efficacy was independent of CD8 T cells, suggesting a non-immune mediated mechanism.
- TGFb blockade promoted a classical cancer cell lineage, enhancing chemosensitivity and increasing chemotherapy-induced cell death.
Conclusions:
- TGFb blockade, in combination with chemotherapy, enhances pancreatic cancer treatment efficacy by modulating cancer cell plasticity.
- This strategy increases sensitivity to chemotherapy by promoting a classical malignant cell state.
- Findings support clinical evaluation of NIS793 with chemotherapy backbones for pancreatic cancer treatment.
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