Laboratorio de Glicómica Funcional y Molecular, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, C1428ADN Buenos Aires, Argentina.
Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, C1428ADN Buenos Aires, Argentina.
Proc Natl Acad Sci U S A. 2021 May 25;118(21). doi: 10.1073/pnas.2102950118.
Colorectal cancer (CRC) represents the third most common malignancy and the second leading cause of cancer-related deaths worldwide. Although immunotherapy has taken center stage in mainstream oncology, it has shown limited clinical efficacy in CRC, generating an urgent need for discovery of new biomarkers and potential therapeutic targets. Galectin-1 (Gal-1), an endogenous glycan-binding protein, induces tolerogenic programs and contributes to tumor cell evasion of immune responses. Here, we investigated the relevance of Gal-1 in CRC and explored its modulatory activity within the CD8 regulatory T cell (Treg) compartment. Mice lacking Gal-1 ( ) developed a lower number of tumors and showed a decreased frequency of a particular population of CD8CD122PD-1 Tregs in the azoxymethane-dextran sodium sulfate model of colitis-associated CRC. Moreover, silencing of tumor-derived Gal-1 in the syngeneic CT26 CRC model resulted in reduced number and attenuated immunosuppressive capacity of CD8CD122PD-1 Tregs, leading to slower tumor growth. Moreover, stromal Gal-1 also influenced the fitness of CD8 Tregs, highlighting the contribution of both tumor and stromal-derived Gal-1 to this immunoregulatory effect. Finally, bioinformatic analysis of a colorectal adenocarcinoma from The Cancer Genome Atlas dataset revealed a particular signature characterized by high CD8 Treg score and elevated Gal-1 expression, which delineates poor prognosis in human CRC. Our findings identify CD8CD122PD-1 Tregs as a target of the immunoregulatory activity of Gal-1, suggesting a potential immunotherapeutic strategy for the treatment of CRC.
结直肠癌（CRC）是全球第三大常见恶性肿瘤，也是癌症相关死亡的第二大主要原因。尽管免疫疗法已成为主流肿瘤学的核心，但在 CRC 中的临床疗效有限，因此迫切需要发现新的生物标志物和潜在的治疗靶点。半乳糖凝集素-1（Gal-1）是一种内源性糖结合蛋白，可诱导耐受程序，并有助于肿瘤细胞逃避免疫反应。在这里，我们研究了 Gal-1 在 CRC 中的相关性，并探讨了其在 CD8 调节性 T 细胞（Treg）中的调节活性。缺乏 Gal-1 的小鼠（ ）在结肠炎相关 CRC 的氧化偶氮甲烷-葡聚糖硫酸钠模型中发展出较少的肿瘤，并且 CD8CD122PD-1 Treg 的特定群体的频率降低。此外，在同源 CT26 CRC 模型中沉默肿瘤衍生的 Gal-1 导致 CD8CD122PD-1 Treg 的数量减少和免疫抑制能力减弱，导致肿瘤生长速度减慢。此外，基质 Gal-1 也影响 CD8 Treg 的适应性，突出了肿瘤和基质衍生的 Gal-1 对这种免疫调节作用的贡献。最后，对来自癌症基因组图谱数据集的结直肠腺癌的生物信息学分析显示出一种特征性的特征，其特征是 CD8 Treg 评分高和 Gal-1 表达升高，这描绘了人类 CRC 的预后不良。我们的研究结果确定 CD8CD122PD-1 Treg 为 Gal-1 的免疫调节活性的靶标，提示针对 CRC 的潜在免疫治疗策略。
