Rocca Yamila Sol, Roberti María Paula, Juliá Estefanía Paula, Pampena María Betina, Bruno Luisina, Rivero Sergio, Huertas Eduardo, Sánchez Loria Fernando, Pairola Alejandro, Caignard Anne, Mordoh José, Levy Estrella Mariel
Fundación Instituto Leloir-IIBBA, Ciudad Autónoma de Buenos Aires , Buenos Aires , Argentina.
Centro de Investigaciones Oncológicas CIO-FUCA, Ciudad Autónoma de Buenos Aires , Buenos Aires , Argentina.
Front Immunol. 2016 Oct 10;7:413. doi: 10.3389/fimmu.2016.00413. eCollection 2016.
The clinical outcome of colorectal cancer (CRC) is associated with the immune response; thus, these tumors could be responsive to different immune therapy approaches. Natural killer (NK) cells are key antitumor primary effectors that can eliminate CRC cells without prior immunization. We previously determined that NK cells from the local tumor environment of CRC tumors display a profoundly altered phenotype compared with circulating NK cells from healthy donors (HD). In this study, we evaluated peripheral blood NK cells from untreated patients and their possible role in metastasis progression. We observed profound deregulation in receptor expression even in early stages of disease compared with HD. CRC-NK cells displayed underexpression of CD16, NKG2D, DNAM-1, CD161, NKp46, and NKp30 activating receptors, while inhibitory receptors CD85j and NKG2A were overexpressed. This inhibited phenotype affected cytotoxic functionality against CRC cells and interferon-γ production. We also determined that NKp30 and NKp46 are the key receptors involved in detriment of CRC-NK cells' antitumor activity. Moreover, NKp46 expression correlated with relapse-free survival of CRC patients with a maximum follow-up of 71 months. CRC-NK cells also exhibited altered antibody-dependent cellular cytotoxicity function responding poorly to cetuximab. IL-2 and IL-15 in combination with cetuximab stimulated NK cell, improving cytotoxicity. These results show potential strategies to enhance CRC-NK cell activity.
结直肠癌（CRC）的临床结局与免疫反应相关；因此，这些肿瘤可能对不同的免疫治疗方法有反应。自然杀伤（NK）细胞是关键的抗肿瘤主要效应细胞，能够在无需预先免疫的情况下消除CRC细胞。我们之前确定，与来自健康供体（HD）的循环NK细胞相比，CRC肿瘤局部肿瘤环境中的NK细胞表现出显著改变的表型。在本研究中，我们评估了未经治疗患者的外周血NK细胞及其在转移进展中的可能作用。与HD相比，我们观察到即使在疾病早期受体表达也有严重失调。CRC-NK细胞表现出CD16、NKG2D、DNAM-1、CD161、NKp46和NKp30激活受体的低表达，而抑制性受体CD85j和NKG2A则过度表达。这种抑制性表型影响了对CRC细胞的细胞毒性功能以及干扰素-γ的产生。我们还确定NKp30和NKp46是损害CRC-NK细胞抗肿瘤活性的关键受体。此外，NKp46表达与随访最长71个月的CRC患者的无复发生存相关。CRC-NK细胞还表现出改变的抗体依赖性细胞毒性功能，对西妥昔单抗反应不佳。IL-2和IL-15与西妥昔单抗联合刺激NK细胞，提高了细胞毒性。这些结果显示了增强CRC-NK细胞活性的潜在策略。
