Tumor DNA methylation subtypes and expression levels of CFISH predict response and overall survival to immunochemotherapy.

BACKGROUND

Predicting patient response to immunochemotherapy is vital but challenging and poorly studied in the (neo)adjuvant setting. We showed that tumor monocyte content (TMC) predicts overall survival of advanced esophageal cancer (OC) in response to immunochemotherapy. We report clinical outcomes of 35 operable OC patients receiving ICI-based therapy and molecular profiling of the unique phase-2 LUD2015-005 trial treating 73 OC patients (38 advanced/inoperable and 35 operable) in the (neo)adjuvant setting.

METHODS

LUD2015-005 trial patients were treated with 4-week immune checkpoint inhibitor (ICI)-only before combination with standard of care. Paired and longitudinally collected biopsies of tumor and multiple adjacent normal sites were bi-dissected to extract DNA and RNA. Whole-genome, methylome, single-cell and bulk RNA sequencing data generated from the entire LUD2015-005 cohort were used for cell-deconvolution and data integration analysis.

FINDINGS: Neoadjuvant ICI-based combination therapy of operable OC in the LUD2015-005 trial revealed improved overall outcomes. Tumor monocytes contribute to tumor immune microenvironment (TiME) remodeling and associate with tumor reactive CD8+ T cells upon ICI+ chemotherapy/chemoradiotherapy. We identified five DNA-methylation subtypes with distinct TiME and a TMC-related five-gene signature CFISH (CXCL8, FCN1, IFI30, SLC11A1, and HLA-DRA) as highly predictive biomarkers of overall survival in OC and beyond.

CONCLUSIONS

These findings highlight the importance of the myeloid compartment in ICI response and the potential of CFISH and tumor DNA methylation in patient stratification for immunochemotherapy.

FUNDING: This work is mainly funded by Ludwig Institute for Cancer Research, CRUK Grants A21998 and C30423/A2541, and NIHR Oxford Biomedical Research Center. AstraZeneca UK Limited provided durvalumab and tremelimumab for LUD2015-005.