1135P - Multi-modal and longitudinal characterization of the tumor and immune microenvironment of Merkel cell carcinoma

Background

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine cancer of the skin, characterized by a high propensity for metastasis and a dismal prognosis particularly for advanced tumor stages. Immune-checkpoint blockade (ICB) is effective in MCC, but 60% of patients show primary or acquired resistance. Predictive biomarkers for the risk of metastasis and response to ICB are lacking. We studied the tumor microenvironment (TME) of 60 MCC patients to identify molecular mechanisms associated with response to ICB and profile the temporal dynamics occurring during tumor progression.

Methods

We collected 115 tissue biopsies from this MCC cohort with detailed clinical documentation and longitudinal follow-up and profiled the TME with high-plex imaging and matched bulk RNAseq that was collected from consecutive sections using laser-capture microdissection. We integrated clinical and molecular data and explored biomarkers using a lasso regressed CoxPH model.

Results

Our multi-modal data integration framework identified Merkel cell polyomavirus positivity, the abundance of CD8+ T cells and PD-L1+ macrophages as independent determinants of metastasis-free survival (DMFS), while the enrichment of cancer-associated fibroblasts at the tumor boundary correlated with distant metastasis. Response to ICB was correlated with the presence of central memory T cells (TCM), and Follicle-like cellular neighborhoods as well as a PD-L1+ tumor phenotype, that associated with an inflammatory macrophage signature (CXCL9, CXCL10, CXCL13) specifically at the tumor invasive front. By contrast, ICB failure associated with a cancer-stem phenotype (SOX2, NELL) and the downregulation of type-II interferon signaling (STAT1, JAK1). Last, we identified that exacerbation of T cell exhaustion, loss of TCM and inflammatory macrophages are critical elements of MCC evolutionary progression.

Conclusions

We demonstrate that high dimensional imaging of the MCC TME provides a framework to interrogate cellular interactions and tissue architecture in-situ at single-cell resolution. This framework enabled to identify genomic and phenotypic correlates for distant metastasis and response to ICB and map evolutionary changes during tumor progression.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Deutsche Forschungsgemeinschaft.

Disclosure

G. Nolan: Financial Interests, Personal, Stocks or ownership: Akoya Bio. All other authors have declared no conflicts of interest.