# Neoadjuvant PD-1 blockade induces the autophagy of immune cells: a new target for synergistic therapy of recurrent glioblastoma

## TL;DR

This study explores how neoadjuvant PD-1 blockade affects immune cell autophagy in glioblastoma and identifies potential drug targets to improve treatment outcomes.

## Contribution

The study identifies specific immune cell subsets and ligand-receptor interactions influenced by neoadjuvant PD-1 blockade and proposes ribavirin as a potential synergistic drug.

## Key findings

- Neoadjuvant PD-1 blockade increases autophagy in lymphoid cells, particularly in L + M cells.
- HLA-DRA–CD4 and GZMA–F2R interactions are crucial for immune response modulation.
- Ribavirin may enhance PD-1 blockade efficacy by targeting CXCL8 and IL6.

## Abstract

Neoadjuvant PD-1 blockade may incidentally modulate autophagy in immune cells, which could contribute to drug resistance and tumor relapse. However, the specific immune cell subsets affected by neoadjuvant PD-1 blockade in terms of autophagy remain to be fully elucidated, as well as the drugs that might influence these processes.

Single-cell sequencing data from tissues of recurrent glioblastoma (GBM.rec) and GBM treated with neoadjuvant PD-1 blockade (GBM.PD1) were analyzed to investigate the changes in autophagy within immune cells in the GBM.PD1 group. Subsequently, the functional characteristics of subtypes regulated by membrane proteins were explored, and potential drugs targeting key immune cell subsets mediated by these proteins were identified.

Neoadjuvant PD-1 blockade significantly increased the proportion of lymphoid cells with elevated autophagy. This elevated autophagy level was associated with specific ligand-receptor interactions in GBM, such as HLA-DRA–CD4. Immune cell subtypes, particularly those with both lymphoid and myeloid signatures (L + M cells, APOE + cells), exhibited strong associations with autophagy. These L + M cells demonstrated significantly more T cell-related interactions in the GBM.PD1 group, with notable receptor-ligand interactions like GZMA-F2R. Furthermore, ribavirin, which targets CXCL8 and IL6, was identified as a potential drug candidate for targeting L + M cells.

L + M cells may represent critical immune components involved in autophagy induced by neoadjuvant PD-1 blockade. The interactions between HLA-DRA and CD4, as well as between GZMA and F2R, are crucial for modulating immune responses. Moreover, ribavirin, targeting CXCL8 and IL6, has the potential to enhance the efficacy of neoadjuvant PD-1 blockade.

•L + M cells may be critical immune components involved in autophagy induced by neoadjuvant PD-1 blockade.•Interactions between HLA-DRA and CD4, as well as GZMA and F2R, are crucial for modulating immune responses.•Ribavirin, targeting CXCL8 and IL6, could potentially enhance the efficacy of neoadjuvant PD-1 blockade.

L + M cells may be critical immune components involved in autophagy induced by neoadjuvant PD-1 blockade.

Interactions between HLA-DRA and CD4, as well as GZMA and F2R, are crucial for modulating immune responses.

Ribavirin, targeting CXCL8 and IL6, could potentially enhance the efficacy of neoadjuvant PD-1 blockade.