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Major histocompatibility complex class I molecule expression by pancreatic cancer cells is regulated by activation and inhibition of the epidermal growth factor receptor

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A Correction to this article was published on 05 December 2023

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Abstract

Pancreatic cancer is one of the deadliest neoplasms, with a dismal 5-year survival rate of only 10%. The ability of pancreatic cancer cells to evade the immune system hinders an anti-tumor response and contributes to the poor survival rate. Downregulation of major histocompatibility complex (MHC) class I cell-surface expression can aid in immune evasion by preventing endogenous tumor antigens from being presented to cytotoxic T cells. Earlier studies suggested that epidermal growth factor receptor (EGFR) signaling can decrease MHC class I expression on certain cancer cell types. However, even though erlotinib (a tyrosine kinase inhibitor that targets EGFR) is an approved drug for advanced pancreatic cancer treatment, the impact of EGFR inhibition or stimulation on pancreatic cancer cell MHC class I surface expression has not previously been analyzed. In this current study, we discovered that EGFR affects MHC class I mRNA and protein expression by human pancreatic cancer cell lines. We demonstrated that cell-surface MHC class I expression is downregulated upon EGFR activation, and the MHC class I level at the surface is elevated following EGFR inhibition. Furthermore, we found that EGFR associates with MHC class I molecules. By defining a role in pancreatic cancer cells for activated EGFR in reducing MHC class I expression and by revealing that EGFR inhibitors can boost MHC class I expression, our work supports further investigation of combined usage of EGFR inhibitors with immunotherapies against pancreatic cancer.

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Funding

This work was supported by the National Institutes of Health (R21 CA223429, P30 CA036727, T32 CA009476, U54 GM115458, P50 CA127297), the State of Nebraska, and a Graduate Studies Office Fellowship. The University of Nebraska Medical Center (UNMC) Flow Cytometry Research Facility is supported through the Office of the Vice Chancellor for Research, the Nebraska Research Initiative, the Fred and Pamela Buffett Cancer Center, the University of Nebraska Foundation, the Nebraska Bankers Fund, and the National Institutes of Health Shared Instrument Grant Program. Assistance was also provided for this project by the UNMC Molecular Diagnostics Histocompatibility Laboratory.

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Authors and Affiliations

  1. Eppley Institute for Research in Cancer & Allied Diseases, University of Nebraska Medical Center, Omaha, NE, 68198, USA

    Shelby M. Knoche, Alaina C. Larson, Gabrielle L. Brumfield & Joyce C. Solheim

  2. Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA

    Shelby M. Knoche, Alaina C. Larson, Gabrielle L. Brumfield & Joyce C. Solheim

  3. Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA

    Steven Cate & William H. Hildebrand

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  1. Shelby M. Knoche
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  2. Alaina C. Larson
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  3. Gabrielle L. Brumfield
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  4. Steven Cate
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  5. William H. Hildebrand
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  6. Joyce C. Solheim
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Contributions

Shelby Knoche and Joyce Solheim contributed to the design of the study. Shelby Knoche performed experiments and bioinformatics analysis with assistance from Alaina Larson and Gabrielle Brumfield, and Shelby Knoche and Joyce Solheim completed the analysis of the data. Steven Cate and William Hildebrand provided HLA class I typing of the S2-013 cell line. The manuscript was drafted by Shelby Knoche and edited by Alaina Larson, Gabrielle Brumfield, Steven Cate, William Hildebrand, and Joyce Solheim. All authors approved the final version.

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Correspondence to Joyce C. Solheim.

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Knoche, S.M., Larson, A.C., Brumfield, G.L. et al. Major histocompatibility complex class I molecule expression by pancreatic cancer cells is regulated by activation and inhibition of the epidermal growth factor receptor. Immunol Res 70, 371–391 (2022). https://doi.org/10.1007/s12026-022-09262-3

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