# Role of immunosuppressive JNK pathway in the tumor microenvironment among TNBC subtypes in IBCSG trial 22-00

## TL;DR

This study shows that high JNK phosphorylation in immune-related triple-negative breast cancer tumors is linked to a worse prognosis but may respond to low-dose chemotherapy.

## Contribution

Developed an RNA-based signature to estimate JNK phosphorylation and its role in immunosuppressive tumor environments in TNBC.

## Key findings

- High pJNK levels correlate with immunosuppressive TME, marked by increased Tregs and lower CD8+/Treg ratios.
- High pJNK immune tumors showed improved disease-free survival with low-dose CM treatment.
- pJNK signature may serve as a biomarker to guide immunotherapy strategies in TNBC.

## Abstract

Phosphorylation of the JNK (pJNK) protein promotes an immunosuppressive tumor microenvironment (TME), enhancing aggressiveness in inflammatory triple-negative breast cancer (TNBC). This study evaluated the role of JNK signaling using a gene signature. RNA sequencing was performed on 347 TNBC tumors from the phase 3 International Breast Cancer Study Group (IBCSG) 22-00 trial, which evaluated adjuvant low-dose cyclophosphamide and methotrexate (CM). Immune-related tumors were identified by TNBC subtype or tumor-infiltrating lymphocytes (TILs). Associations between JNK and outcomes were analyzed using Cox models. Low pJNK levels were associated with better disease-free survival (DFS) in immune-related tumors. These tumors also had lower Treg levels and higher CD8+/Treg ratios. Notably, immunomodulatory (IM) tumors with high pJNK showed improved DFS when treated with CM. High pJNK expression identifies immunosuppressive TMEs with poor prognosis in inflamed TNBC. However, these tumors may benefit from CM, supporting pJNK as a potential biomarker for immunotherapy strategies.

•Developed an RNA-based signature to estimate JNK phosphorylation in TNBC•High pJNK levels correlate with immunosuppressive TME: more Tregs, lower CD8+/Treg ratios•High pJNK immune tumors respond to low-dose CM, possibly reversing pJNK-driven suppression•pJNK signature may guide immunotherapy strategies in TNBC

Developed an RNA-based signature to estimate JNK phosphorylation in TNBC

High pJNK levels correlate with immunosuppressive TME: more Tregs, lower CD8+/Treg ratios

High pJNK immune tumors respond to low-dose CM, possibly reversing pJNK-driven suppression

pJNK signature may guide immunotherapy strategies in TNBC

Immunology; Cancer; Transcriptomics