# Tumor‐Derived CDC37 Inhibits Antigen Cross‐Presentation in Dendritic Cells and Impairs Anti‐Tumor Immunity in Breast Cancer

## TL;DR

Tumor cells release CDC37 via EVs, which blocks antigen presentation in immune cells, weakening anti-tumor immunity in breast cancer.

## Contribution

CDC37, delivered via EVs, inhibits antigen cross-presentation in DCs, offering a new target to improve ICB therapy in breast cancer.

## Key findings

- Tumor-derived CDC37 inhibits antigen cross-presentation in DCs by locking HSP90-antigen complexes.
- CDC37 knockdown or inhibition enhances antigen translocation and improves ICB response in TNBC.
- High CDC37 expression correlates with poor ICB efficacy and low CTL infiltration in TNBC patients.

## Abstract

Tumor mutational burden (TMB), usually representing high immunogenicity, cannot always predict treatment response of immune checkpoint blockade (ICB). Here, it is showed that defective antigen cross‐presentation in type 1 conventional dendritic cells (cDC1) is responsible for lacking tumor‐specific cytotoxic T lymphocytes (CTLs) in triple‐negative breast cancer (TNBC) patients. Mechanistically, tumor cytosolic CDC37, shuttled via extracellular vesicles (EVs) into the endosomes of intratumor dendritic cells (DCs), inhibits antigen cross‐presentation by locking antigen binding to HSP90 and precluding their translocation from endosomes to cytoplasm. CDC37 knockdown in tumor cells or inhibiting CDC37/HSP90 interaction in DCs efficiently promotes antigen translocation and enhances their cross‐presentation, which improves ICB therapeutic responses. Clinically, high tumor CDC37 expression is associated with low infiltration of antigen‐specific CTLs and poor ICB efficacy in TNBC patients. Therefore, tumor EV‐shuttled CDC37 locks antigen/chaperone interaction and impairs antigen cross‐presentation in DCs. Moreover, targeting CDC37 is promising to enhance anti‐tumor immunity and reverse ICB resistance.

Extracellular vesicle (EV)‐packaged CDC37 are released from TMBhiCTLlo breast cancer cells with high CDC37 expression, and internalized into endo/phagosomes of dendritic cells (DCs). Within these compartments, CDC37 locked HSP90–antigen complex, preventing antigen release into the cytosol. Consequently, antigens are not processed by cytosolic proteasomes and fail to be presented on MHC class I molecules at the DC surface.