2. Academic Validation
  3. Pressure increases PD-L1 expression in A549 lung adenocarcinoma cells and causes resistance to anti-ROR1 CAR T cell-mediated cytotoxicity

Pressure increases PD-L1 expression in A549 lung adenocarcinoma cells and causes resistance to anti-ROR1 CAR T cell-mediated cytotoxicity

  • Sci Rep. 2022 Apr 28;12(1):6919. doi: 10.1038/s41598-022-10905-6.
Zhenglin Ou 1 2,  Xiaolin Dou 1 2,  Neng Tang  # 3 4,  Guodong Liu  # 5 6 7
Affiliations

Affiliations

  • 1 Department of General Surgery, Xiangya Hospital Central South University, Xiangya Road 87#, Changsha, 410008, Hunan, China.
  • 2 National Clinical Research Center for Geriatric Disorders, Central South University, Changsha, Hunan, China.
  • 3 Department of General Surgery, Xiangya Hospital Central South University, Xiangya Road 87#, Changsha, 410008, Hunan, China. tangneng245104@163.com.
  • 4 National Clinical Research Center for Geriatric Disorders, Central South University, Changsha, Hunan, China. tangneng245104@163.com.
  • 5 Department of General Surgery, Xiangya Hospital Central South University, Xiangya Road 87#, Changsha, 410008, Hunan, China. guodongliu@csu.edu.cn.
  • 6 National Clinical Research Center for Geriatric Disorders, Central South University, Changsha, Hunan, China. guodongliu@csu.edu.cn.
  • 7 Department of Geriatric Surgery, Xiangya Hospital Central South University, Xiangya Road 87#, Changsha, 410008, Hunan, China. guodongliu@csu.edu.cn.
  • # Contributed equally.
PMID: 35484298 DOI: 10.1038/s41598-022-10905-6
Abstract

Due to the abnormal vasculation and proliferation, the tumor microenvironment is hypoxic, lacking nutrients, and under high interstitial pressure. Compared to oxygen and nutrients, the effect of pressure on Cancer biology remains poorly studied. Here we constructed αROR1-CAR T cells and co-cultured with A549 cells with and without elevated pressure. We then measured Apoptosis and cell death by flow cytometry and luciferase activity. We also measured cytokine (IL-2, IFN-γ, and TNF-α) release by ELISA. The results show that pressure-preconditioned A549 cells are much resistant to αROR1-CAR T cell-mediated cytotoxicity. Pressure preconditioning does not appear to affect the expression of αROR1-CAR or cytokine production. However, pressure preconditioning upregulates PD-L1 expression in A549 cells and decreases cytokine release from αROR1-CAR T cells. In addition, Pembrolizumab and Cemiplimab that block PD-1::PD-L1 interaction increase the cytokine production in αROR1-CAR T cells, increase the apoptotic cell death in A549 cells, and improve the αROR1-CAR T-mediated cytotoxicity. In xenograft mice, pressure preconditioning increases tumorigenesis of A549 cells, which can be blocked by a combined therapy using Pembrolizumab and αROR1-CAR T cells. Together, our studies suggest that elevated pressure in the tumor microenvironment could blunt the T cell therapy by upregulating PD-L1 expression, which could be overcome by combining CAR T therapy with immune checkpoint inhibitors.

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