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Regular and Young Investigator Award Abstracts
Combination Immunotherapies
798 TGFβ blockade in pancreatic cancer enhances sensitivity to combination chemotherapy
  1. Li Qiang1,
  2. Megan Hoffman2,
  3. Lestat Ali2,
  4. Jaime Ivan Castillo Silva2,
  5. Ayantu Temesgen4,
  6. Patrick Lenehan2,
  7. Lauren Kageler3,
  8. Jennifer Wang2,
  9. Elisa Bello2,
  10. Victoire Cardot-Ruffino2,
  11. Giselle Uribe2,
  12. Annan Yang2,
  13. Michael Dougan4,
  14. Andrew J Aguirre2,
  15. Srivatsan Raghavan2,
  16. Marc Pelletier5,
  17. Viviana Cremasco6 and
  18. Stephanie Dougan2
  1. 1Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
  2. 2Dana-Farber Cancer Institute, Boston, MA, USA
  3. 3Harvard Medical School, Boston, MA, USA
  4. 4Massachusetts General Hospital, Boston, MA, USA
  5. 5Novartis Institute for Biomedical Research, Cambridge, MA, USA
  6. 6Novartis Institutes of BioMedical Resear, Cambridge, MA, USA

Abstract

Background TGFβ 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 TGFβ inhibition has shown limited efficacy against pancreatic cancer in mice or humans.

Methods We evaluated the TGFβ blocking antibody NIS793 in combination with either gemcitabine/n(ab)-paclitaxel or FOLFIRINOX chemotherapy in orthotopic pancreatic cancer models.1 Single-cell RNA-seq 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. Surprisingly, efficacy of combination therapy was not dependent on CD8 T cells, as response to TGFβ blockade was preserved in CD8-depleted or RAG2-/- mice. TGFβ blockade decreased total αSMA+ fibroblasts but had minimal effect on fibroblast heterogeneity. Bulk RNA-seq 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 along the classical to basal lineage. TGFβ blockade in orthotopic mouse models of pancreatic cancer synergizes with chemotherapy by maintaining a classical-like chemotherapy-sensitive state. This study provides scientific rationale for evaluation of NIS793 with either FOLFIRINOX or gemcitabine/n(ab)paclitaxel chemotherapy backbone in the clinical setting (NCT04390763, NCT04935359, NCT05546411, NCT05417386). We also support the concept of manipulating cancer cell plasticity to increase efficacy of combination therapy regimens.

Reference

  1. Qiang L, Hoffman MT, Ali LR, Castillo JI, Kageler L, Temesgen A, Lenehan P, Wang SJ, Bello E, Cardot-Ruffino V, Uribe GA, Yang A, Dougan M, Aguirre AJ, Raghavan S, Pelletier M, Cremasco V, Dougan SK. TGFβ blockade in pancreatic cancer enhances sensitivity to combination chemotherapy. Gastroenterology. 2023 May 30:S0016–5085(23)00809–0. doi: 10.1053/j.gastro.2023.05.038. Epub ahead of print. PMID: 37263309.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/jitc-2023-SITC2023.0798

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