Abstract C029: Chemotherapy backbone alters the mechanism of action of TGFb blockade in pancreatic cancer

Abstract TGFβ plays a critical role in promoting pancreatic tumor progression, attenuating CD8 T cell proliferation and cytokine production, enhancing the differentiation of myofibroblasts and the deposition of extracellular matrix. However, single agent TGFβ blockade has shown limited efficacy in mouse models of pancreatic cancer. Here we showed that in combination with chemotherapy, using either gemcitabine/n(ab)-paclitaxel or FOLFIRINOX, neutralization of TGFβ can reduce tumor burden in the poorly immunogenic 6694c2 orthotopic pancreatic cancer mouse model, without affecting the metastatic rate of cancer cells. As expected, anti-TGFβ with combination chemotherapy significantly increased the mean survival time of the orthotopic mouse models. Surprisingly, the efficacy of both combinational therapies is not dependent on CD8 T cells in either immunogenic or non-immunogenic models, as CD8 depleted or RAG2 knockout mice are responsive to the treatments to similar levels. Instead, comparing to chemotherapy single treatment, in the presence of TGFβ blocking antibody, tumor cells are more vulnerable to chemotherapy-induced cell death, both in vitro and in vivo. Recent studies from Raghavan et al. demonstrated that the plasticity of the classical and basal lineage of pancreatic cancer can be regulated by TGFβ ligand. Consistently, here we show that single-cell analysis and limited bulk RNAseq on tumor cells sorted ex vivo revealed 6694c2 tumor cells treated with TGFβ blockade maintain classical lineage, the state of pancreatic cancer with more sensitivity to chemotherapy and better prognosis. FOLFIRINOX treatments have largely modified tumor stromal landscape, with a unique CAF population presented expressing high levels of PTX3, which further verified by immunohistochemistry. This study provides the scientific rationale for the evaluation of TGFβ with both chemotherapy backbone in the clinical setting, as well as supports the concept of plasticity of pancreatic cancer cell state and plasticity of stromal cell landscape in tumors, providing foundations for future investigations on the mechanisms of TGFβ with different chemotherapy backbone in regulating the crosstalk among fibroblast subsets, immune cells and pancreatic cancer cells. Citation Format: Li Qiang, Lestat Ali, Meggie Hoffman, Jaime Ivan Castillo Silva, Patrick Lenehan, Elisa Bello, Marc Pelletier, Viviana Cremasco, Stephanie Dougan. Chemotherapy backbone alters the mechanism of action of TGFb blockade in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C029.