# Targeting of the CD161 Inhibitory Receptor Enhances Bone‐Marrow‐Resident Memory CD8+ T‐Cell‐Mediated Immunity against Multiple Myeloma

## TL;DR

Blocking the CD161 receptor improves T-cell function and antitumor immunity in multiple myeloma, offering a new immunotherapy approach.

## Contribution

CD161 is identified as a novel inhibitory receptor on bone marrow resident memory CD8+ T cells in multiple myeloma.

## Key findings

- CD161 interacts with CLEC2D on MM cells to suppress T-cell function and promote immune suppression.
- Blocking CD161 restores T-cell residency, proliferation, and antitumor activity in multiple myeloma.
- CD161 blockade enhances CAR-T cell function and reduces exhaustion ex vivo.

## Abstract

Immune checkpoint inhibitors (ICIs) have transformed the treatment of many solid tumors. Still, their effectiveness in multiple myeloma (MM) remains underwhelming, highlighting the need to explore alternative approaches beyond conventional ICIs. Here, CD161 is identified as a novel inhibitory receptor on bone marrow (BM) tissue resident memory CD8+ T cells (CD8+ TRM), known for their sustained presence and vital role in local immune surveillance in MM BM tumor microenvironments. The CD161–CLEC2D axis, where CD161 interacts with CLEC2D on MM cells, mediates immune suppression and TRM dysfunction. Blocking CD161 enhances TRM function, including tissue residency, proliferation, and antitumor activity. CD161 blockade significantly alleviates chimeric antigen receptor T‐cell (CAR‐T) exhaustion and enhances their antimyeloma function ex vivo. These findings identified the CD161–CLEC2D pathway as a potential novel target for immunotherapy of MM.

CD161 is identified as a novel inhibitory receptor on bone marrow (BM)‐resident CD8⁺ T cells in multiple myeloma (MM). Through interaction with its ligand CLEC2D, CD161 impairs T‐cell function and promotes immune suppression. Blockade of CD161 restores tissue residency and cytotoxicity of CD8⁺ T cells and enhances chimeric antigen receptor T‐cell (CAR‐T) activity, providing a potential immunotherapeutic target in MM.