Immune escape mechanism behind resistance to anti-PD-1 therapy in gastrointestinal tract metastasis in malignant melanoma patients with multiple metastases
Immune escape mechanism behind resistance to anti-PD-1 therapy in gastrointestinal tract metastasis in malignant melanoma patients with multiple metastases
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DOI：
10.1007/s00262-022-03154-z
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发表时间：
2022-01-30
影响因子：
5.8
通讯作者：
Kono, Koji
中科院分区：
文献类型：
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作者：
Ito, Misato;Mimura, Kosaku;Kono, Koji
靶向PD-1轴的免疫治疗最近已成为恶性黑色素瘤患者的标准治疗。然而，在报告的最初对抗PD-1 mAb免疫治疗有反应的恶性黑色素瘤患者中，约有25%的患者出现疾病进展，并且在临床环境中对抗PD-1治疗耐药背后的免疫逃逸机制尚未完全了解。在本研究中，我们纳入了4例恶性黑色素瘤患者，其中除胃肠道转移外的多发性转移灶消失或在包括抗PD-1治疗在内的多学科治疗下得到控制。使用IHC，我们评估了手术切除的胃肠道转移瘤标本的免疫状态，作为抗PD-1治疗的获得性耐药病变。我们在此报告，在转移性胃肠道肿瘤中的肿瘤细胞上观察到HLA I类的下调表达和抑制性免疫检查点配体CD 155（T细胞免疫球蛋白和ITIM结构域的配体，TIGIT）和癌胚抗原相关粘附分子-1（TIM-3的配体）的上调表达。此外，我们的研究结果还表明，间质TGF-β可能与肿瘤细胞上HLA I类表达的下调有关。总之，在恶性黑色素瘤患者中，抗PD-1治疗期间，在胃肠道转移中可能获得了肿瘤细胞上HLA I类表达的下调和PD-L1以外的抑制性免疫检查点配体的额外表达。
Immunotherapy targeting the PD-1 axis has recently become a standard treatment for patients with malignant melanoma. However, approximately 25% of reported malignant melanoma patients who initially responded to immunotherapy with anti-PD-1 mAb had progressive disease, and the immune escape mechanism behind resistance to anti-PD-1 therapy is not yet fully understood in the clinical setting. In the present study, we included four malignant melanoma patients, in whom multiple metastases other than gastrointestinal tract metastasis had disappeared or were controlled under multidisciplinary treatment that included anti-PD-1 therapy. Using IHC, we evaluated the immune status of surgically resected specimens of gastrointestinal tract metastases as acquired resistant lesion to anti-PD-1 therapy. We herein report that the down-regulated expression of HLA class I and up-regulated expression of inhibitory immune checkpoint ligands, CD155 (ligand for T cell immunoglobulin and ITIM domain, TIGIT) and carcinoembryonic antigen-related adhesion molecule-1 (ligand for TIM-3), were observed on the tumor cells in the metastatic gastrointestinal tract tumors. Moreover, our results also suggest that stromal TGF-beta may be related to this down-regulation of HLA class I expression on the tumor cells. In conclusion, it is likely that the down-regulated expression of HLA class I and additional expression of inhibitory immune checkpoint ligands other than PD-L1 on the tumor cells were acquired in the gastrointestinal tract metastasis during anti-PD-1 therapy in the malignant melanoma patients.