TY - JOUR
T1 - Loss of SMAD4 Is Associated With Poor Tumor Immunogenicity and Reduced PD-L1 Expression in Pancreatic Cancer
AU - Principe, Daniel R.
AU - Underwood, Patrick W.
AU - Kumar, Sandeep
AU - Timbers, Kaytlin E.
AU - Koch, Regina M.
AU - Trevino, Jose G.
AU - Munshi, Hidayatullah G.
AU - Rana, Ajay
N1 - Funding Information:
This work was supported by Veterans Affairs Merit Award I01BX004903 and Career Scientist Award IK6BX004855 to AR, by NIH F30CA236031, UIC Award for Graduate Research, and Sigma Xi Grant In the Aid of Research to DP, by NIH R01CA217907 and R21CA255291 and Veterans Affairs Merit Award I01BX002922 to HM, and by NIH R01CA242003 and the Joseph and Ann Matella Fund for Pancreatic Cancer Research to JT. Per the funding policy of the U.S. Department of Veterans Affairs, we are required to state that these contents do not represent the views of the U.S. Department of Veterans Affairs or the United States Government.
Publisher Copyright:
Copyright © 2022 Principe, Underwood, Kumar, Timbers, Koch, Trevino, Munshi and Rana.
PY - 2022/1/28
Y1 - 2022/1/28
N2 - Transforming Growth Factor β (TGFβ) is a key mediator of immune evasion in pancreatic ductal adenocarcinoma (PDAC), and the addition of TGFβ inhibitors in select immunotherapy regimens shows early promise. Though the TGFβ target SMAD4 is deleted in approximately 55% of PDAC tumors, the effects of SMAD4 loss on tumor immunity have yet to be fully explored. Using a combination of genomic databases and PDAC specimens, we found that tumors with loss of SMAD4 have a comparatively poor T-cell infiltrate. SMAD4 loss was also associated with a reduction in several chemokines with known roles in T-cell recruitment, which was recapitulated using knockdown of SMAD4 in PDAC cell lines. Accordingly, JURKAT T-cells were poorly attracted to conditioned media from PDAC cells with knockdown of SMAD4 and lost their ability to produce IFNγ. However, while exogenous TGFβ modestly reduced PD-L1 expression in SMAD4-intact cell lines, SMAD4 and PD-L1 positively correlated in human PDAC samples. PD-L1 status was closely related to tumor-infiltrating lymphocytes, particularly IFNγ-producing T-cells, which were more abundant in SMAD4-expressing tumors. Low concentrations of IFNγ upregulated PD-L1 in tumor cells in vitro, even when administered alongside high concentrations of TGFβ. Hence, while SMAD4 may have a modest inhibitory effect on PD-L1 in tumor cells, SMAD4 indirectly promotes PD-L1 expression in the pancreatic tumor microenvironment by enhancing T-cell infiltration and IFNγ biosynthesis. These data suggest that pancreatic cancers with loss of SMAD4 represent a poorly immunogenic disease subtype, and SMAD4 status warrants further exploration as a predictive biomarker for cancer immunotherapy.
AB - Transforming Growth Factor β (TGFβ) is a key mediator of immune evasion in pancreatic ductal adenocarcinoma (PDAC), and the addition of TGFβ inhibitors in select immunotherapy regimens shows early promise. Though the TGFβ target SMAD4 is deleted in approximately 55% of PDAC tumors, the effects of SMAD4 loss on tumor immunity have yet to be fully explored. Using a combination of genomic databases and PDAC specimens, we found that tumors with loss of SMAD4 have a comparatively poor T-cell infiltrate. SMAD4 loss was also associated with a reduction in several chemokines with known roles in T-cell recruitment, which was recapitulated using knockdown of SMAD4 in PDAC cell lines. Accordingly, JURKAT T-cells were poorly attracted to conditioned media from PDAC cells with knockdown of SMAD4 and lost their ability to produce IFNγ. However, while exogenous TGFβ modestly reduced PD-L1 expression in SMAD4-intact cell lines, SMAD4 and PD-L1 positively correlated in human PDAC samples. PD-L1 status was closely related to tumor-infiltrating lymphocytes, particularly IFNγ-producing T-cells, which were more abundant in SMAD4-expressing tumors. Low concentrations of IFNγ upregulated PD-L1 in tumor cells in vitro, even when administered alongside high concentrations of TGFβ. Hence, while SMAD4 may have a modest inhibitory effect on PD-L1 in tumor cells, SMAD4 indirectly promotes PD-L1 expression in the pancreatic tumor microenvironment by enhancing T-cell infiltration and IFNγ biosynthesis. These data suggest that pancreatic cancers with loss of SMAD4 represent a poorly immunogenic disease subtype, and SMAD4 status warrants further exploration as a predictive biomarker for cancer immunotherapy.
KW - interferon γ (IFNγ)
KW - pancreatic ductal adenocarcinoma (PDAC)
KW - programmed death-ligand 1 (PD-L1)
KW - transforming growth factor β (TGFβ)
KW - tumor immunology
KW - tumor mircorenvironment
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UR - http://www.scopus.com/inward/citedby.url?scp=85124282443&partnerID=8YFLogxK
U2 - 10.3389/fonc.2022.806963
DO - 10.3389/fonc.2022.806963
M3 - Article
C2 - 35155243
AN - SCOPUS:85124282443
SN - 2234-943X
VL - 12
JO - Frontiers in Oncology
JF - Frontiers in Oncology
M1 - 806963
ER -