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

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 chemother...

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Published inMolecular 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
LanguageEnglish
Published United States 01.10.2021
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Abstract 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.
AbstractList 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.
Author Zhao, Yongmei
Mehta, Monika
Rudloff, Udo
Bautista, Wendy
Schlomer, Jerome J
Ock, Chan-Young
Schaub, Nicholas
Chen, Vicky
Bapiro, Tashinga E
Gilbert, Debra J
Sorber, Rebecca
Kozlov, Serguei
Guerin, Theresa M
Richards, Frances M
Talsania, Keyur
Kumar, Parimal
Kim, Seong-Jin
Palena, Claudia
Teper, Yaroslav
Pate, Nathan
Li, Dandan
Jodrell, Duncan I
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  surname: Li
  fullname: Li, Dandan
  organization: Thoracic & GI Oncology Branch, Center for Cancer Research, NCI, Bethesda, Maryland
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  organization: Leonard Lawson Cancer Center, Pikeville Medical Center, Pikeville, Kentucky
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  organization: Center for Advanced Preclinical Research, Frederick National Laboratories for Cancer Research, NCI, Frederick, Maryland
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  givenname: Parimal
  surname: Kumar
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  organization: Sequencing Facility & Single Cell Analysis Facility, Advanced Technology Research Facility, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland
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  givenname: Debra J
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  fullname: Kim, Seong-Jin
  organization: GILO Institute, GILO Foundation, Seoul, Korea
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  givenname: Rebecca
  surname: Sorber
  fullname: Sorber, Rebecca
  organization: Department of Surgery, The Johns Hopkins Hospital, Johns Hopkins University, Baltimore, Maryland
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  surname: Teper
  fullname: Teper, Yaroslav
  organization: Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California
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  fullname: Bautista, Wendy
  organization: Center for Advanced Preclinical Research, Frederick National Laboratories for Cancer Research, NCI, Frederick, Maryland
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  surname: Palena
  fullname: Palena, Claudia
  organization: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
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  surname: Ock
  fullname: Ock, Chan-Young
  organization: Department of Hematology & Oncology, Seoul National University Hospital, Seoul, Korea
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  givenname: Duncan I
  orcidid: 0000-0001-9360-1670
  surname: Jodrell
  fullname: Jodrell, Duncan I
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  givenname: Nathan
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  surname: Pate
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  givenname: Monika
  surname: Mehta
  fullname: Mehta, Monika
  organization: Sequencing Facility & Single Cell Analysis Facility, Advanced Technology Research Facility, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland
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  givenname: Yongmei
  orcidid: 0000-0003-0800-4658
  surname: Zhao
  fullname: Zhao, Yongmei
  organization: CCR-SF Bioinformatics Group, Advanced Biomedical and Computational Sciences, Biomedical Informatics and Data Science, Advanced Technology Research Facility, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland
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  givenname: Serguei
  surname: Kozlov
  fullname: Kozlov, Serguei
  email: kozlovse@mail.nih.gov, rudloffu@mail.nih.gov
  organization: Center for Advanced Preclinical Research, Frederick National Laboratories for Cancer Research, NCI, Frederick, Maryland. kozlovse@mail.nih.gov rudloffu@mail.nih.gov
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  givenname: Udo
  orcidid: 0000-0003-2137-9040
  surname: Rudloff
  fullname: Rudloff, Udo
  email: kozlovse@mail.nih.gov, rudloffu@mail.nih.gov
  organization: Surgery Branch, Center for Cancer Research, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
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Snippet The desmoplastic stroma of pancreatic cancers forms a physical barrier that impedes intratumoral drug delivery. Attempts to modulate the desmoplastic stroma to...
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SubjectTerms 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
Title T Cell-Mediated Antitumor Immunity Cooperatively Induced By TGFβR1 Antagonism and Gemcitabine Counteracts Reformation of the Stromal Barrier in Pancreatic Cancer
URI https://www.ncbi.nlm.nih.gov/pubmed/34376576
Volume 20
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