Donor Variability and PD-1 Expression Limit BK Polyomavirus-specific T-cell Function and Therapy

Area of Science:

• Immunology
• Transplantation Medicine
• Cell Therapy

Background:

• BK polyomavirus (BKPyV) nephropathy is a leading cause of kidney transplant failure.
• Current treatments focus on reducing immunosuppression to restore BKPyV-specific immunity.
• Ex vivo expanded T cells offer potential but have suboptimal efficacy due to donor variability.

Purpose of the Study:

• To optimize ex vivo expansion protocols for BKPyV-specific T cells.
• To compare conventional and G-Rex culture systems for T-cell expansion.
• To assess the impact of immune checkpoint inhibitors on T-cell function.

Main Methods:

• Compared conventional and G-Rex expansion cultures for BKPyV-specific T cells.
• Stimulated T cells with BKPyV peptide pools and assessed cytokine/cytotoxic responses.
• Evaluated programmed cell death protein 1 (PD-1) and PD-1 ligand 1 (PD-1L) expression.
• Assessed the effect of pembrolizumab on T-cell responses and cytotoxicity.

Main Results:

• G-Rex cultures yielded higher cell counts than conventional cultures.
• Expanded T cells demonstrated polyfunctional cytokine production and cytotoxicity against BKPyV-infected cells.
• G-Rex-expanded T cells showed increased PD-1 expression.
• Pembrolizumab reduced PD-1 expression, enhanced T-cell responses, and increased cytotoxicity.

Conclusions:

• Upregulated PD-1 on ex vivo expanded T cells contributes to donor variability and may limit adoptive cell therapy efficacy.
• BKPyV-infected renal proximal tubule epithelial cells (RPTECs) upregulate PD-L1 under inflammatory conditions.
• Ex vivo addition of immune checkpoint inhibitors warrants evaluation to enhance BKPyV-specific T-cell therapy for kidney transplant patients.