T Cell-Mediated Antitumor Immunity Cooperatively Induced By TGFβR1 Antagonism and Gemcitabine Counteracts Reformation of the Stromal Barrier in Pancreatic Cancer

• Published in: Molecular cancer therapeutics Vol. 20; no. 10; pp. 1926 - 1940
• Main Authors: Li, Dandan, Schaub, Nicholas, Guerin, Theresa M, Bapiro, Tashinga E, Richards, Frances M, Chen, Vicky, Talsania, Keyur, Kumar, Parimal, Gilbert, Debra J, Schlomer, Jerome J, Kim, Seong-Jin, Sorber, Rebecca, Teper, Yaroslav, Bautista, Wendy, Palena, Claudia, Ock, Chan-Young, Jodrell, Duncan I, Pate, Nathan, Mehta, Monika, Zhao, Yongmei, Kozlov, Serguei, Rudloff, Udo
• Format: Journal Article
• Language: English
• Published: United States 01.10.2021
• Subjects: Animals; Antimetabolites, Antineoplastic - pharmacology; Apoptosis; Carcinoma, Pancreatic Ductal - drug therapy; Carcinoma, Pancreatic Ductal - immunology; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - pathology; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell Proliferation; Combined Modality Therapy; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; Gemcitabine; Humans; Mice; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - immunology; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Receptor, Transforming Growth Factor-beta Type I - antagonists & inhibitors; Stromal Cells - drug effects; Stromal Cells - immunology; Stromal Cells - metabolism; Tumor Cells, Cultured; Tumor Microenvironment; Xenograft Model Antitumor Assays
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-20-0620

The desmoplastic stroma of pancreatic cancers forms a physical barrier that impedes intratumoral drug delivery. Attempts to modulate the desmoplastic stroma to increase delivery of administered chemotherapy have not shown positive clinical results thus far, and preclinical reports in which chemotherapeutic drugs were coadministered with antistromal therapies did not universally demonstrate increased genotoxicity despite increased intratumoral drug levels. In this study, we tested whether TGFβ antagonism can break the stromal barrier, enhance perfusion and tumoral drug delivery, and interrogated cellular and molecular mechanisms by which the tumor prevents synergism with coadministered gemcitabine. TGFβ inhibition in genetically engineered murine models (GEMM) of pancreas cancer enhanced tumoral perfusion and increased intratumoral gemcitabine levels. However, tumors rapidly adapted to TGFβ-dependent stromal modulation, and intratumoral perfusion returned to pre-treatment levels upon extended TGFβ inhibition. Perfusion was governed by the phenotypic identity and distribution of cancer-associated fibroblasts (CAF) with the myelofibroblastic phenotype (myCAFs), and myCAFs which harbored unique genomic signatures rapidly escaped the restricting effects of TGFβ inhibition. Despite the reformation of the stromal barrier and reversal of initially increased intratumoral exposure levels, TGFβ inhibition in cooperation with gemcitabine effectively suppressed tumor growth via cooperative reprogramming of T regulatory cells and stimulation of CD8 T cell-mediated antitumor activity. The antitumor activity was further improved by the addition of anti-PD-L1 immune checkpoint blockade to offset adaptive PD-L1 upregulation induced by TGFβ inhibition. These findings support the development of combined antistroma anticancer therapies capable of impacting the tumor beyond the disruption of the desmoplastic stroma as a physical barrier to improve drug delivery.