# Anti-PD-1 antibody enhances homeostatic proliferation–induced antitumor immunity during lymphopenia recovery

## TL;DR

Blocking PD-1 during recovery from lymphopenia improves T-cell function and antitumor immunity in melanoma.

## Contribution

The study reveals that PD-1 signaling limits homeostatic proliferation-induced antitumor immunity and that PD-1 blockade can sustain it.

## Key findings

- PD-1 expression on T cells increases during homeostatic proliferation and correlates with reduced cytotoxicity.
- Anti-PD-1 therapy enhances T-cell recognition of tumor antigens and boosts IFN-γ+ CD8+ T-cell numbers.
- Blocking PD-1 promotes memory T-cell differentiation and sustained antitumor immunity in lymphopenic conditions.

## Abstract

Lymphopenia induced by radiotherapy or chemotherapy can promote homeostatic proliferation of residual or adoptive lymphocytes, potentially enhancing antitumor immunity. However, this immunity diminishes rapidly with tumor progression, and the underlying mechanisms remain unclear. This study investigates the role of PD-1 signaling in homeostatic proliferation–induced antitumor immunity in malignant melanoma.

We evaluated T-cell dynamics in lymphopenic mice, analyzing PD-1 expression, IFN-γ production by CD8+ T cells, and T-cell cytotoxicity during homeostatic proliferation. The PD-1/PD-L1 axis was blocked using anti-PD-1 antibodies to assess its impact on T-cell function, dendritic cell (DC) activation, and memory T-cell differentiation.

Although T cells proliferated continuously in lymphopenic mice, IFN-γ+ CD8+ T cells declined over time. PD-1 expression on T cells increased progressively and correlated negatively with effector T-cell cytotoxicity. PD-1 blockade enhanced the recognition of tumor-associated antigens (TAAs) by homeostatically proliferating (HP) T cells, activated DCs, and increased IFN-γ+ CD8+ T-cell numbers. Additionally, it boosted T-cell cytotoxicity and promoted the conversion of tumor-specific effector T cells into central memory T cells.

These findings indicate that the PD-1/PD-L1 axis plays a critical role in immune tolerance during homeostatic proliferation. Anti-PD-1 therapy may enhance antitumor immunity during lymphopenia recovery after chemotherapy or radiotherapy, offering a potential strategy to sustain T-cell–mediated tumor control.