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相较于微卫星稳定肿瘤,微卫星高度不稳定的肿瘤明显会表达更多的新抗原(P<2e-16)。在原发结直肠癌患者中,肿瘤新抗原负荷与总淋巴细胞评分(P=4.9e-9)和肿瘤浸润淋巴细胞(P=1.6e-15)显著相关。在T细胞亚群的分析中,肿瘤新抗原负荷仅与CD45RO+ T细胞亚群(P=0.0003)显著相关。肿瘤新抗原负荷越高预示着CRC特异性和总生存率更高(分别为P=0.014,P=0.048)。





Comprehensive molecular characterization of colorectal cancer reveals genomic predictors of immune cell infiltrates.(Abstract 3505)

Authors:Marios Giannakis, Sachet Shukla,et al.

Session Type:Oral Abstract Session

Background:Colorectal cancer (CRC) is a molecularly heterogeneous disease that arises and progresses in the context of a complex microenvironment. Tumor immune cell infiltrates have been shown to be associated with an improved CRC-specific and overall survival. However, the genomic features of CRC that determine the number and types of immune infiltrates remain largely uncharacterized.

Methods:We performed Whole Exome Sequencing and microsatellite instability (MSI) analysis on primary CRCs from 689 patients (pts) identified from two large prospective cohorts, the Nurses’ Health Study and the Health Professionals Follow-Up Study. We also immunohistochemically characterized the immune infiltrate (peritumoral, intratumoral periglandular, Crohn’s-like, tumor-infiltrating, and total lymphocyte score) and conducted tissue microarray imaging analysis for T-cell subsets (CD3+, CD8+, CD45RO+, FoxP3+). We utilized a novel computational pipeline to calculate tumor neoantigen load (peptides resulting from somatic mutations and recognized by the immune system as foreign) and subsequently correlated the tumor neoantigen load with the aforementioned immune variables and with pt survival.

Results:When compared to microsatellite-stable cancers, MSI-high tumors expressed significantly more neoantigens (P < 2e-16). Tumor neoantigen load significantly correlated with total lymphocytic score in the primary CRCs (P = 4.9e-9) and was most significantly associated with tumor infiltrating lymphocytes (P = 1.6e-15). Among T-cell subsets, tumor neoantigen load was only significantly associated with the CD45RO+ T-cell subset (P = 0.0003). Higher tumor neoantigen load predicted significantly improved CRC-specific and overall survival (P = 0.014 and P = 0.048, respectively).

Conclusions:In the large prospective study of molecularly characterized CRCs, tumor neoantigen load predicts greater tumor-infiltrating lymphocytes and memory T-cell infiltration and represents a novel genomic predictor of CRC survival. Our findings link tumor genomics to specific immune response elements and have implications for the therapeutic manipulation of the latter in CRC.