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Frontline Science: Functionally impaired geriatric CAR-T cells rescued by increased α5β1 integrin expression
Prajna Guha1, Marissa Cunetta1, Ponnandai Somasundar1
1Division of Surgical Oncology, Department of Surgery, Roger Williams Medical Center, Providence, Rhode Island, USA; and.
Journal of Leukocyte Biology
|May 27, 2017
Summary
CAR-T immunotherapy is less effective in older adults due to impaired T cell function. Enhancing alpha5beta1 integrin expression can improve CAR-T cell production and tumor-killing ability in geriatric donors.
Area of Science:
- Immunology
- Cell Biology
- Cancer Therapy
Background:
- Chimeric antigen receptor (CAR)-T cell therapy shows promise for cancer treatment.
- Age-related immune changes can impact CAR-T cell production and efficacy, but this is not well understood.
Purpose of the Study:
- To investigate the functional differences between CAR-T cells from younger and geriatric donors.
- To identify mechanisms underlying impaired CAR-T cell function in older adults.
- To explore strategies for improving CAR-T cell efficacy in geriatric populations.
Main Methods:
- Comparison of CAR-T cell production, expansion, proliferation, and signaling between younger (yCAR-T) and geriatric (gCAR-T) donors.
- Analysis of cell surface markers, including CD4/CD8 effector memory (EM) cells and alpha5beta1 integrin.
- Assessment of tumor antigen-specific cytotoxicity and levels of cytotoxic mediators (perforin, granzyme B).
- Investigation of the role of alpha5beta1 integrin in CAR expression and function, including rescue experiments with M-CSF and TGF-beta1.
Main Results:
- Geriatric CAR-T (gCAR-T) cells exhibited impaired function compared to younger CAR-T (yCAR-T) cells, with lower transduction efficiency and cell expansion.
- yCAR-T cells showed increased proliferation, signaling activation (pErk, pAkt, pStat3, pStat5), and higher proportions of effector memory cells.
- yCAR-T cells demonstrated superior tumor antigen-specific cytotoxicity, correlated with higher perforin and granzyme B levels.
- Increased alpha5beta1 integrin expression in yCAR-T cells was identified as a key factor; M-CSF or TGF-beta1 treatment rescued gCAR-T transduction by upregulating alpha5beta1 integrin.
Conclusions:
- Age-related immune changes lead to functional impairment in CAR-T cells from geriatric donors.
- Alpha5beta1 integrin expression is critical for CAR expression and function.
- Upregulating alpha5beta1 integrin presents a potential strategy to enhance CAR-T cell therapy efficacy in older adults.
