TY - JOUR
T1 - Disruption of her2-induced pd-l1 inhibits tumor cell immune evasion in patient-derived gastric cancer organoids
AU - Chakrabarti, Jayati
AU - Koh, Vivien
AU - Steele, Nina
AU - Hawkins, Jennifer
AU - Ito, Yoshiaki
AU - Merchant, Juanita L.
AU - Wang, Jiang
AU - Helmrath, Michael A.
AU - Ahmad, Syed A.
AU - So, Jimmy Bok Yan
AU - Yong, Wei Peng
AU - Zavros, Yana
N1 - Funding Information:
This project is supported in part by PHS Grant P30 DK078392 (Integrative Morphology Core) of the Digestive Diseases Research Core Center in Cincinnati. Research reported was also partly supported by the National Cancer Institute of the National Institutes of Health under award number P30 CA023074 (Sweasy). This research is also supported by the Singapore Ministry of Health’s National Medical Research Council under its NMRC Open Fund Large Collaborative Grant (OFLCG18May-0023) awarded to the Singapore Gastric Cancer Consortium. The NIH (NIDDK) 2 R01 DK083402-06A1 grant, NIH 1U19AI116491-01 grant and Yeoh Ghim Seng Visiting Professorship in Surgery research fund from the National University of Singapore was awarded to YZ, and R01 DK 118563 was awarded to J.L.M.Acknowledgments: We are sincerely grateful to Bridgett Wills and Jocelyn Fimbres in the Tissue Acquisition and Cellular/Molecular Analysis Shared Resource (TACMASR) Core for their assistance with embedding, sectioning and immunohistochemistry of tissue and organoids. We would like to acknowledge the assistance of Chet Closson (Live Microscopy Core, University of Cincinnati). We thank Lisa McMillin (Cincinnati Children’s Hospital Medical Center, Pathology Research Core) for her assistance with organoid and tissue embedding and processing. We would also like to acknowledge Patty Jansma (Marley Imaging Core, University Arizona) and Douglas W Cromey (TACMASR core, University of Arizona) for their assistance in the microscopy. We would also like to thank Shing Leng Chan for her critical review of the manuscript.
Funding Information:
Funding: This project is supported in part by PHS Grant P30 DK078392 (Integrative Morphology Core) of the Digestive Diseases Research Core Center in Cincinnati. Research reported was also partly supported by the National Cancer Institute of the National Institutes of Health under award number P30 CA023074 (Sweasy). This research is also supported by the Singapore Ministry of Health’s National Medical Research Council under its NMRC Open Fund Large Collaborative Grant (OFLCG18May-0023) awarded to the Singapore Gastric Cancer Consortium. The NIH (NIDDK) 2 R01 DK083402-06A1 grant, NIH 1U19AI116491-01 grant and Yeoh Ghim Seng Visiting Professorship in Surgery research fund from the National University of Singapore was awarded to YZ, and R01 DK 118563 was awarded to J.L.M.
Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/12/1
Y1 - 2021/12/1
N2 - (1) Background: The expression of programmed death-ligand 1 (PD-L1), which interacts with programmed cell death protein 1 (PD-1) on cytotoxic T lymphocytes (CTLs), enables tumors to escape immunosurveillance. The PD-1/PD-L1 interaction results in the inhibition of CTL prolifera-tion, and effector function, thus promoting tumor cell evasion from immunosurveillance and cancer persistence. Despite 40% of gastric cancer patients exhibiting PD-L1 expression, only a small subset of patients responds to immunotherapy. Human epidermal growth factor receptor2 (HER2) is one of the critical regulators of several solid tumors, including metastatic gastric cancer. Although half of PD-L1-positive gastric tumors co-express HER2, crosstalk between HER2 and PD-1/PD-L1 in gastric cancer remains undetermined. (2) Methods: Human gastric cancer organoids (huTGOs) were generated from biopsied or resected tissues and co-cultured with CTLs and myeloid-derived sup-pressor cells (MDSCs). Digital Spatial Profiling (DSP) was performed on FFPE tissue microarrays of numerous gastric cancer patients to examine the protein expression of immune markers. (3) Results: Knockdown of HER2 in PD-L1/HER2-positive huTGOs led to a concomitant decrease in PD-L1 expression. Similarly, in huTGOs/immune cell co-cultures, PD-L1 expression decreased in huTGOs and was correlated with an increase in CTL proliferation which enhanced huTGO death. Treatment with Nivolumab exhibited similar effects. However, a combinatorial treatment with Mubritinib and Nivolumab was unable to inhibit HER2 expression in co-cultures containing MDSCs. (4) Conclusions: Our study suggested that co-expression of HER2 and PD-L1 may contribute to tumor cell immune evasion. In addition, autologous organoid/immune cell co-cultures can be exploited to effectively screen responses to a combination of anti-HER2 and immunotherapy to tailor treatment for gastric cancer patients.
AB - (1) Background: The expression of programmed death-ligand 1 (PD-L1), which interacts with programmed cell death protein 1 (PD-1) on cytotoxic T lymphocytes (CTLs), enables tumors to escape immunosurveillance. The PD-1/PD-L1 interaction results in the inhibition of CTL prolifera-tion, and effector function, thus promoting tumor cell evasion from immunosurveillance and cancer persistence. Despite 40% of gastric cancer patients exhibiting PD-L1 expression, only a small subset of patients responds to immunotherapy. Human epidermal growth factor receptor2 (HER2) is one of the critical regulators of several solid tumors, including metastatic gastric cancer. Although half of PD-L1-positive gastric tumors co-express HER2, crosstalk between HER2 and PD-1/PD-L1 in gastric cancer remains undetermined. (2) Methods: Human gastric cancer organoids (huTGOs) were generated from biopsied or resected tissues and co-cultured with CTLs and myeloid-derived sup-pressor cells (MDSCs). Digital Spatial Profiling (DSP) was performed on FFPE tissue microarrays of numerous gastric cancer patients to examine the protein expression of immune markers. (3) Results: Knockdown of HER2 in PD-L1/HER2-positive huTGOs led to a concomitant decrease in PD-L1 expression. Similarly, in huTGOs/immune cell co-cultures, PD-L1 expression decreased in huTGOs and was correlated with an increase in CTL proliferation which enhanced huTGO death. Treatment with Nivolumab exhibited similar effects. However, a combinatorial treatment with Mubritinib and Nivolumab was unable to inhibit HER2 expression in co-cultures containing MDSCs. (4) Conclusions: Our study suggested that co-expression of HER2 and PD-L1 may contribute to tumor cell immune evasion. In addition, autologous organoid/immune cell co-cultures can be exploited to effectively screen responses to a combination of anti-HER2 and immunotherapy to tailor treatment for gastric cancer patients.
KW - Myeloid-derived suppressor cells
KW - Organoid-immune cell co-culture
KW - PD-L1
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UR - http://www.scopus.com/inward/citedby.url?scp=85120639243&partnerID=8YFLogxK
U2 - 10.3390/cancers13246158
DO - 10.3390/cancers13246158
M3 - Article
AN - SCOPUS:85120639243
VL - 13
JO - Cancers
JF - Cancers
SN - 2072-6694
IS - 24
M1 - 6158
ER -