Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
Harvard Medical School, Boston, MA, USA.
J Immunother Cancer. 2020 Jun;8(1). doi: 10.1136/jitc-2020-000958.
Rare cases of immune checkpoint inhibitor (ICI)-associated celiac disease (ICI-CeD) have been reported, suggesting that disruption of tolerance mechanisms by ICIs can unmask celiac disease (CeD). This study aims to characterize the clinicopathological and immunophenotypic features of ICI-CeD in comparison to ICI-associated duodenitis (ICI-Duo) and usual CeD.
A medical and pathological records search between 2015 and 2019 identified eight cases of ICI-CeD, confirmed by tTG-IgA. Nine cases of ICI-Duo, 28 cases of moderate CeD, as well as 5 normal controls were used as comparison groups. Clinical information was collected from the electronic medical records. Immunohistochemistry for CD3, CD8, T-cell receptor gamma/delta (γδ), programmed death ligand 1 (PD-L1), and programmed death 1 (PD-1) were performed, with quantification of intraepithelial lymphocyte (IEL) subsets in three well-oriented villi. CD68, PD-L1, and PD-1 were assessed as a percentage of lamina propria surface area infiltrated by positive cells. Statistical significance was calculated by the Student's t-test and Fisher's exact test.
The eight patients with ICI-CeD (F:M=1:3) and nine patients with ICI-Duo (F:M=5:4) presented similarly with diarrhea (13/17) and abdominal pain (11/17) after a median of 1.6 months on ICI therapy. In patients with ICI-CeD, tTG-IgA ranged from 104 to >300 IU/mL. Histological findings in ICI-CeD and ICI-Duo were similar and included expansion of the lamina propria, active neutrophilic duodenitis, variably increased IELs, and villous blunting. Immunohistochemistry showed that the average number of IELs per 100 enterocytes is comparable between ICI-CeD and ICI-Duo, with increased CD3 CD8 T cells compared with normal duodenum but decreased γδ T cells compared with CeD. Average PD-L1 percentage was 9% in ICI-CeD and 18% in ICI-Duo, in comparison to <1% in CeD and normal duodenum; average PD-1 percentage was very low to absent in all cases (<3%). On follow-up, five patients with ICI-CeD improved on a gluten-free diet (GFD) as the sole therapeutic intervention (with down-trending tTG-IgA) while the other three required immunosuppression. All patients who developed ICI-Duo received immunosuppression with variable improvement in symptoms.
ICI-CeD resembles ICI-Duo clinically and histologically but shares the serological features and response to gluten withdrawal with classic CeD. Immunophenotyping of IELs in ICI-CeD and ICI-Duo also shows similar CD3, CD8, γδ T cell subsets, and PD-L1 populations, all of which differed quantitatively from usual CeD. We conclude that ICI-CeD is biologically similar to ICI-Duo and is likely a variant of ICI-Duo, but treatment strategies differ, with ICI-CeD often improving with GFD alone, whereas ICI-Duo requires systemic immunosuppression.
已有罕见的免疫检查点抑制剂（ICI）相关乳糜泻（ICI-CeD）病例报告，这表明 ICI 可能通过破坏耐受机制而引发乳糜泻（CeD）。本研究旨在比较 ICI-CeD 与 ICI 相关十二指肠炎（ICI-Duo）和普通 CeD 的临床病理和免疫表型特征。
在 2015 年至 2019 年期间，通过 tTG-IgA 对 8 例 ICI-CeD 病例进行了医学和病理记录检索。使用 9 例 ICI-Duo、28 例中度 CeD 和 5 例正常对照作为对照组。从电子病历中收集临床信息。进行 CD3、CD8、T 细胞受体 γ/δ（γδ）、程序性死亡配体 1（PD-L1）和程序性死亡 1（PD-1）的免疫组织化学染色，并对三个定向良好的绒毛中的上皮内淋巴细胞（IEL）亚群进行定量分析。CD68、PD-L1 和 PD-1 作为阳性细胞浸润固有层表面面积的百分比进行评估。通过学生 t 检验和 Fisher 确切检验计算统计显著性。
8 例 ICI-CeD 患者（F：M=1：3）和 9 例 ICI-Duo 患者（F：M=5：4）在接受 ICI 治疗后 1.6 个月中位数时出现腹泻（13/17）和腹痛（11/17）。ICI-CeD 患者的 tTG-IgA 范围为 104 至>300 IU/mL。ICI-CeD 和 ICI-Duo 的组织学发现相似，包括固有层扩张、活跃的中性粒细胞性十二指肠炎、不同程度增加的 IEL 和绒毛变钝。免疫组织化学显示，每 100 个肠上皮细胞的 IEL 数量在 ICI-CeD 和 ICI-Duo 之间相似，与正常十二指肠相比，CD3 CD8 T 细胞增加，但与 CeD 相比，γδ T 细胞减少。ICI-CeD 的平均 PD-L1 百分比为 9%，ICI-Duo 为 18%，而 CeD 和正常十二指肠分别为<1%；所有病例的平均 PD-1 百分比均非常低或不存在（<3%）。随访时，5 例 ICI-CeD 患者在接受无麸质饮食（GFD）治疗（同时 tTG-IgA 下降）后病情改善，而其他 3 例则需要免疫抑制治疗。所有出现 ICI-Duo 的患者均接受免疫抑制治疗，症状均有不同程度改善。
ICI-CeD 在临床上和组织学上与 ICI-Duo 相似，但与经典 CeD 具有相同的血清学特征和对麸质戒断的反应。ICI-CeD 和 ICI-Duo 的 IEL 免疫表型也显示出相似的 CD3、CD8、γδ T 细胞亚群和 PD-L1 群体，所有这些都与普通 CeD 在数量上有所不同。我们得出结论，ICI-CeD 与 ICI-Duo 在生物学上相似，可能是 ICI-Duo 的一种变体，但治疗策略不同，ICI-CeD 通常单独接受 GFD 治疗即可改善，而 ICI-Duo 则需要全身免疫抑制治疗。
