Fernandez Manuel, Todeschini Letizia, Keenan Bridget P, Rosenberg David, Hernandez Sophia, Zampese Marco, Qiao Guilin, Pollini Tommaso, Maker Ajay V
Fred Hutchinson Cancer Center, Seattle, WA, USA.
Department of Surgery, Division of Surgical Oncology, University of California San Francisco, San Francisco, CA, USA.
Ann Surg Oncol. 2025 Jun 21. doi: 10.1245/s10434-025-17599-w.
The microenvironment and immune infiltrate population of colorectal tumors can serve as a stronger predictor of patient survival than microsatellite-status or traditional T- or N-staging. This study aimed to leverage transcriptomic techniques to identify specific immune cell populations and their ratios associated with cancer recurrence in colorectal cancer patients. The goal was to identify patients who could benefit from early adjuvant interventions, identify those at higher risk of recurrence for surveillance, and identify potential combinatorial immunotherapy strategies tailored to this disease. We found that a lower ratio of cytotoxic lymphocyte: monocytic lineage cells, and not microsatellite-status, was associated with cancer recurrence. Additional differential gene expression analysis of the monocytic lineage demonstrated that genes specifically associated with tumor associated macrophages and a protumoral phenotype were overexpressed in the tumor microenvironment in patients that went on to have recurrent disease. Gene Ontology analysis revealed that pathways associated with pro-tumoral extracellular matrix remodeling were suppressed in tumors exhibiting a high cytotoxic lymphocyte: monocytic lineage ratio, suggesting a diminished propensity for tumor progression. The development of these prognostic markers not only associates with colorectal cancer recurrence, aiding in risk stratification and guiding adjuvant therapy decisions for resected early-stage patients, but also suggests that effective colon cancer treatments will likely require a combination of cytotoxic T-cell-directed immunomodulation and targeted inhibition of tumor-associated macrophages.
与微卫星状态或传统的T分期或N分期相比，结直肠癌的微环境和免疫浸润群体可作为患者生存更强有力的预测指标。本研究旨在利用转录组技术，识别与结直肠癌患者癌症复发相关的特定免疫细胞群体及其比例。目标是识别可从早期辅助干预中获益的患者，识别复发风险较高需进行监测的患者，并确定针对该疾病的潜在联合免疫治疗策略。我们发现，细胞毒性淋巴细胞与单核细胞谱系细胞的比例较低而非微卫星状态与癌症复发相关。对单核细胞谱系进行的额外差异基因表达分析表明，与肿瘤相关巨噬细胞和促肿瘤表型特异性相关的基因，在后续发生复发性疾病的患者的肿瘤微环境中过度表达。基因本体分析显示，在细胞毒性淋巴细胞与单核细胞谱系比例高的肿瘤中，与促肿瘤细胞外基质重塑相关的通路受到抑制，提示肿瘤进展倾向降低。这些预后标志物的开发不仅与结直肠癌复发相关，有助于对早期切除患者进行风险分层并指导辅助治疗决策，还表明有效的结肠癌治疗可能需要细胞毒性T细胞导向的免疫调节与肿瘤相关巨噬细胞的靶向抑制相结合。
