Claeys Arne, Van den Eynden Jimmy
Department of Human Structure and Repair, Unit of Anatomy and Embryology, Ghent University, Ghent, Belgium.
Cancer Research Institute Ghent, Ghent University, Ghent, Belgium.
Commun Med (Lond). 2024 Sep 30;4(1):184. doi: 10.1038/s43856-024-00612-w.
Immune checkpoint blockade is a highly successful anti-cancer immunotherapy. Both CTLA4 and PD1 checkpoint blockers are clinically available for melanoma treatment, with anti-PD1 therapy reaching response rates of 35-40%. These responses, which are mediated via neoantigen presentation by the polymorphic MHC complex, are hard to predict and the tumor mutation burden is currently one of the few available biomarkers. While MHC genotypes are expected to determine therapy responses, association studies have remained largely elusive.
We developed an overall MHC genotype binding score (MGBS), indicative of a patient's MHC class I (MHC-I) and class II (MHC-II) neoantigen binding capacity and solely based on the germline MHC-I (MGBS-I) and MHC-II (MGBS-II) genotypes. These scores were then correlated to survival and clinical responses following anti-PD1 immunotherapy in a previously published dataset of 144 melanoma patients.
We demonstrate that MGBS scores are TMB-independent predictors of anti-PD1 immunotherapy responses in melanoma. Opposite outcomes were found for both MHC classes, with high MGBS-I and MGBS-II predicting good and bad outcomes, respectively. Interestingly, high MGBS-II is mainly associated with treatment response failure in a subgroup of anti-CTLA4 pretreated patients.
Our results suggest that MGBS, calculated solely from the MHC genotype, has clinical potential as a non-invasive and tumor-independent biomarker to guide anti-cancer immunotherapy in melanoma.
免疫检查点阻断是一种非常成功的抗癌免疫疗法。CTLA4和PD1检查点阻断剂在临床上均可用于黑色素瘤治疗，抗PD1疗法的缓解率达到35%-40%。这些反应是通过多态性MHC复合物呈递新抗原介导的，难以预测，肿瘤突变负荷是目前少数可用的生物标志物之一。虽然预计MHC基因型可决定治疗反应，但关联研究在很大程度上仍不明确。
我们开发了一种总体MHC基因型结合评分（MGBS），它可指示患者的MHC I类（MHC-I）和II类（MHC-II）新抗原结合能力，并且仅基于种系MHC-I（MGBS-I）和MHC-II（MGBS-II）基因型。然后，在先前发表的144例黑色素瘤患者的数据集中，将这些评分与抗PD1免疫治疗后的生存率和临床反应进行关联。
我们证明，MGBS评分是黑色素瘤抗PD1免疫治疗反应的TMB独立预测指标。在两个MHC类别中均发现了相反的结果，高MGBS-I和MGBS-II分别预测良好和不良结果。有趣的是，高MGBS-II主要与抗CTLA4预处理患者亚组的治疗反应失败相关。
我们的结果表明，仅根据MHC基因型计算出的MGBS具有作为非侵入性且与肿瘤无关的生物标志物的临床潜力，可用于指导黑色素瘤的抗癌免疫治疗。
