Single-cell transcriptomics of colorectal cancer metastases identifies enrichment for a therapeutically targetable population of TREM2⁺ macrophages in peritoneal metastases.

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Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B103
Abstract ID: 4784

Presenting Author:
Matthew Alexander Cottam , Staff Scientist at Vanderbilt Univ. Med. Ctr.

Abstract:

Colorectal cancer (CRC) is recognized as the third most common cancer and the second leading cause of cancer-related mortality globally. The primary driver behind this mortality is metastatic disease, which significantly worsens the prognosis for CRC patients. Over the past decade, there has been a modest improvement of only 2% in the 5-year survival rate for metastatic CRC (mCRC). To improve our understanding of the cellular composition in mCRC tumors, we performed single-cell RNAseq (scRNAseq) on matched primary colorectal tumors, metastases to the lung, liver, and peritoneum, and malignant ascites from 14 patients. Tumor-associated macrophages (TAMs) were found to be one of the most abundant populations across all samples and TAMs from metastases had increased expression of M2-like alternative activation markers relative to primary tumors, suggesting that TAMs in mCRC are immunosuppressive. Gene co-expression analysis identified a signature of lipid handling containing genes linked to lipid transport, such as APOE, FABP5, PLTP, and CD9, and genes coding for the scavenger receptors CD36, MSR1, MARCO, and TREM2. Consistent with transcriptomics, the majority of CD11b⁺CD68⁺ TAMs from resected liver and peritoneal metastases had high TREM2 expression by flow cytometry. In a mouse model of peritoneal mCRC, treatment with anti-TREM2 decreased CD11b⁺F4/80⁺ TAMs and increased CD8⁺ effector T cells, suggesting that TREM2 may be an effective target for immunotherapy in mCRC.