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Published on: May 2, 2025
The advantages of PD1 activating chimeric receptor (PD1-ACR) engineered lymphocytes for PDL1(+) cancer therapy
Xiaolong Tang1, Qingguo Li2, Yongqiang Zhu3
1Stem Cell Engineering Research Center, School of Medicine, Anhui University of Science & Technology Huainan 232001, China ; State Key Laboratory of Virology/Institute of Medical Virology, School of Basic Medical Sciences, Wuhan University Wuhan 430071, PR China.
Abstract:
Tumors exploit immunoregulatory checkpoints to attenuate T cell responses as a means of circumventing immunologic rejection. By activating the inhibitory costimulatory pathway of Programmed Death 1 (PD1)/PDL1 which provides tumor cells an escape mechanism from immune surveillance, Programmed Death Ligand1 (PDL1)(+) tumors hamper activated tumor-specific T cell functions and render them functionally exhausted. To overcome the inhibitory costimulatory effects of PDL1 on the adoptively transferred T cells, we sought to convert PD1 to a T cell costimulatory receptor by exchanging its transmembrane and cytoplasmic tail with CD28 and 4-1BB signaling domains (PD1-CD28-4-1BB, PD1-ACR), anticipating the genetically modified effector T lymphocytes expressing PD1-ACR would exhibit enhanced functional attributes. And the results showed that PD1-ACR expressed T cells retained the ability to bind PDL1, resulting in T cell activation as evidenced by the elevated activity of phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), the augmentation of cytokine secretion and the increased proliferative capacity. Moreover, when systemically administered in the mouse model of glioblastoma metastases, PD1-ACR T cells localized at the area of U87 invasive tumor, which results in suppressed tumor growth and enhanced survival of mice with established U87 glioblastoma. Together, these data demonstrated that PD1-ACR has a high potential to serve as a novel strategy to overcome PDL1 mediated immunosuppression of T cells for cancer therapy.
Insights
This study engineered a novel T cell receptor, PD1-ACR, to overcome tumor immune evasion. PD1-ACR T cells effectively target glioblastoma, suppressing tumor growth and improving survival in mice.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Tumors evade immune rejection by activating inhibitory checkpoints like Programmed Death 1 (PD1)/Programmed Death Ligand1 (PDL1).
- PDL1-expressing tumors suppress anti-tumor T cell responses, leading to T cell exhaustion and immune escape.
Purpose of the Study:
- To engineer a modified PD1 receptor (PD1-ACR) that converts the inhibitory PD1 signal into a costimulatory signal for T cells.
- To evaluate the anti-tumor efficacy of T cells engineered to express PD1-ACR in a glioblastoma mouse model.
Main Methods:
- Genetic modification of T cells to express PD1-ACR, which fuses the PD1 extracellular domain with CD28 and 4-1BB signaling tails.
- Assessing T cell activation markers (PI3K/Akt pathway, cytokine secretion, proliferation) upon PDL1 binding.
- Administering PD1-ACR T cells systemically in a mouse model of U87 glioblastoma and monitoring tumor growth and survival.
Main Results:
- Engineered T cells expressing PD1-ACR maintained PDL1 binding and showed enhanced activation, including increased PI3K/Akt activity, cytokine secretion, and proliferation.
- PD1-ACR T cells effectively infiltrated U87 glioblastoma tumors in mice.
- Systemic administration of PD1-ACR T cells led to suppressed tumor growth and significantly improved survival in mice with established glioblastoma.
Conclusions:
- The PD1-ACR construct successfully converts the inhibitory PD1-PDL1 interaction into a potent T cell activation signal.
- PD1-ACR represents a promising novel immunotherapy strategy to overcome PDL1-mediated immunosuppression in cancer treatment, particularly for glioblastoma.
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