Gynecological Cancer Unit, Department of Medicine, Gustave Roussy, France.
Pathology Department, Gustave Roussy, France.
Gynecol Oncol. 2021 Jan;160(1):279-284. doi: 10.1016/j.ygyno.2020.09.045. Epub 2020 Nov 6.
The disappointing activity of single agent immune-checkpoint inhibitors in epitherlial ovarian cancer (EOC) has been attributed in part to its unique tumor microenvironment (TME). IDO, PDL1, LAG3 and TIM3 have been implicated in the immunotolerance of EOC. We investigated the expression of these co-regulators, their change with neoadjuvant chemotherapy (NACT), and their association with outcome.
We identified 98 patients with EOC treated with NACT and performed IDO, PDL1, LAG3 and TIM3 immunohistochemistry on samples obtained before and after NACT. The cut-off threshold to consider a positive sample was set at 5%.
In our cohort, TIM3 was the most prevalent co-regulator, with more than 75% of the samples being TIM3 positive. In comparison, only 22%, 28% and 17% of the samples were considered IDO, PDL1 and LAG3 positive. More than half of ovarian tumors expressed 2, 3 or even all 4 co-inhibitory molecules. However, biomarkers were not correlated with each other. NACT had a marked impact on immune co-regulator expression with over 70% of patients showing a change in biomarker status from negative to positive or vice versa. There was no significant difference in the pattern of co-regulator expression between platinum-sensitive and resistant patients. Co-expression of multiple inhibitory molecules did not appear to affect overall and progression-free survival.
TIM3 is the most abundant co-inhibitory molecule in OC and may represent an attractive target. In addition, OC frequently co-expressed 2 or more markers supporting ICI combinatorial approaches. Finally, NACT significantly altered the expression of immunosuppressive molecules suggesting that the choice of ICI combinations should be adapted to the composition of the post-NACT immune TME.
单药免疫检查点抑制剂在卵巢上皮癌（EOC）中的疗效令人失望，部分原因是其独特的肿瘤微环境（TME）。IDO、PDL1、LAG3 和 TIM3 已被认为与 EOC 的免疫耐受有关。我们研究了这些共调节剂的表达、它们在新辅助化疗（NACT）前后的变化及其与结局的关系。
我们确定了 98 例接受 NACT 治疗的 EOC 患者，并对 NACT 前后获得的样本进行 IDO、PDL1、LAG3 和 TIM3 免疫组化染色。将考虑阳性样本的截止阈值设定为 5%。
在我们的队列中，TIM3 是最常见的共调节剂，超过 75%的样本为 TIM3 阳性。相比之下，只有 22%、28%和 17%的样本被认为是 IDO、PDL1 和 LAG3 阳性。超过一半的卵巢肿瘤表达 2 种、3 种甚至全部 4 种共抑制分子。然而，生物标志物之间没有相关性。NACT 对免疫共调节剂表达有显著影响，超过 70%的患者的生物标志物状态从阴性变为阳性或反之。铂类敏感和耐药患者的共调节剂表达模式没有显著差异。多种抑制性分子的共表达似乎并不影响总生存期和无进展生存期。
TIM3 是 OC 中最丰富的共抑制分子，可能是一个有吸引力的靶点。此外，OC 经常共表达 2 种或更多的标志物，支持 ICI 联合治疗。最后，NACT 显著改变了免疫抑制分子的表达，提示应根据 NACT 后免疫 TME 的组成选择 ICI 联合方案。
