Kefah Mokbel, Chair of Breast Cancer Surgery at London Breast Institute and Honorary Professor of Medicine at Cardiff University School of Medicine, shared a post on LinkedIn:
“High stromal CD8+ T-cells in ER+/HER2− breast cancer: a signal to rethink chemotherapy in the intermediate-risk group
A paper published this week in Nature Communications challenges our approach to adjuvant chemotherapy in early-stage ER+/HER2− breast cancer for patients with an intermediate Oncotype DX Recurrence Score (RS 16–25).
The key finding: patients with higher stromal CD8+ TIL density had significantly worse outcomes on chemoendocrine therapy— validated on whole-resection specimens, independent of menopausal status, and potentially affecting treatment decisions in up to 50% of intermediate-risk patients.
Why might chemotherapy be harmful here?
These tumours show features of T-cell exhaustion (TOX, CXCL13), checkpoint expression (CTLA4, TIGIT, VISTA), and ECM remodelling by immunosuppressive SPP1+ macrophages. Chemotherapy may amplify suppressive pathways rather than enhance tumour killing.
Two pathways deserve prospective exploration:
- De-escalation: omitting chemotherapy where stromal CD8+ density is high
- Checkpoint blockade combination: exhausted progenitor-like T-cells (TCF7+) may respond to ICB, consistent with Checkmate 7FL, KEYNOTE-756, and I-SPY2 data
Validation in the full TAILORx dataset is needed, but the signal is compelling. The immune landscape — not genomic risk alone — must inform chemotherapy decisions in luminal breast cancer.”
Title: Spatial analyses implicate high stromal tumour-infiltrating CD8+ lymphocytes as a negative predictive marker for chemotherapy in estrogen receptor-positive breast cancer
Authors: Zak Kinsella, Chowdhury Arif Jahangir, Hannah Nyarkoah Nyarko, Daria Kalinska-Lysiak, Claudia Gonzalez, Verena Murphy, Tony O’Grady, Joanna Fay, Katherine Sheehan, Arman Rahman, John Crown, Catherine Kelly, Simon McDade, Ina Woods, Niamh Connolly, Jochen Prehn, William Gallagher, Darran O’Connor
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