效应性抗肿瘤和调节性T细胞反应影响肾移植患者非黑色素瘤皮肤癌的发生发展。

Effector Antitumor and Regulatory T Cell Responses Influence the Development of Nonmelanoma Skin Cancer in Kidney Transplant Patients.

作者信息

Crespo Elena, Fernandez Loreto, Lúcia Marc, Melilli Edoardo, Lauzurica Ricardo, Penin Rosa Maria, Quer Ariadna, Luque Sergio, Quero Maria, Manonelles Anna, Torras Joan, Cruzado Josep Maria, Cañas Laura, Grinyó Josep Maria, Bestard Oriol

机构信息

1 Experimental Nephrology Laboratory, IDIBELL, Barcelona, Spain. 2 Renal Transplant Unit, Nephrology Department, Germans Trias i Pujol University Hospital, Barcelona, Spain. 3 Kidney Transplant Unit, Nephrology Department, Bellvitge University Hospital, IDIBELL, Barcelona, Spain. 4 Pathology Department, Bellvitge University Hospital, IDIBELL, Barcelona, Spain. 5 Pathology Department, Germans Trias i Pujol University Hospital, Barcelona, Spain.

出版信息

Transplantation. 2017 Sep;101(9):2102-2110. doi: 10.1097/TP.0000000000001759.

DOI:10.1097/TP.0000000000001759

PMID:28403126

Abstract

BACKGROUND

Chronic immunosuppression promotes nonmelanocytic squamous cell carcinoma (SCC) after kidney transplantation. Adaptive and innate immunity play a key role controlling tumor growth and are influenced by different immunosuppressive agents. We hypothesized that functional impairment of tumor-specific T cell responses due to calcineurin inhibitors (CNI) could contribute to SCC development, whereas conversion to mammalian target of rapamycin inhibitors (mTOR-i) could recover this protective immune response.

METHODS

Peripheral tumor-specific T cell responses against main SCC-derived antigens using the IFN-γ enzyme-linked immunospot assay and intratumor (IT) and circulating immune phenotypes (CD4 + T, CD8 + T, CD20 + B, CD56 + NK, FOXP3 + regulatory T [Treg] cells) were explored in a cross-sectional analysis in 59 kidney transplant patients with SCC on CNI (KT-CNI-SCC) or mTOR-i (KT-mTORi-SCC), 25 nontransplants developing SCC (NoKT-SCC) and 6 healthy controls. Moreover, 25 KT-CNI-SCC were switched to mTOR-i and evaluated after 12 months.

RESULTS

Kidney transplant patients showed lower IT infiltrates and tumor-specific T cell responses than NoKT-SCC, and intratumoral and circulating FOXP3 + Treg cells were higher in KT-mTORi-SCC (P < 0.05). Tumor-specific T cell responses were significantly lower in KT-CNI-SCC than KT-mTORi-SCC and NoKT-SCC and predicted SCC relapses (area under the curve = 0.837; P < 0.05). One-year after mTOR-i conversion, a significant increase in FOXP3 + Treg cell numbers and tumor-specific T cell responses were observed, reaching similar levels than KT-mTORi-SCC and NoKT-SCC patients.

CONCLUSIONS

Tumor-specific T cell responses are strongly impaired in CNI-treated patients but recover after mTOR-i conversion, reducing SCC relapses.

摘要

背景

慢性免疫抑制会促进肾移植后非黑素细胞性鳞状细胞癌（SCC）的发生。适应性免疫和先天性免疫在控制肿瘤生长中起关键作用，并受到不同免疫抑制剂的影响。我们假设，钙调神经磷酸酶抑制剂（CNI）导致的肿瘤特异性T细胞反应功能受损可能促成SCC的发展，而转换为雷帕霉素靶蛋白抑制剂（mTOR-i）可能恢复这种保护性免疫反应。

方法

采用γ-干扰素酶联免疫斑点试验，对59例接受CNI治疗的肾移植SCC患者（KT-CNI-SCC）或mTOR-i治疗的肾移植SCC患者（KT-mTORi-SCC）、25例发生SCC的非移植患者（NoKT-SCC）和6例健康对照进行横断面分析，探讨外周血中针对主要SCC衍生抗原的肿瘤特异性T细胞反应以及肿瘤内（IT）和循环免疫表型（CD4 + T细胞、CD8 + T细胞、CD20 + B细胞、CD56 + NK细胞、FOXP3 +调节性T [Treg]细胞）。此外，25例KT-CNI-SCC患者转换为mTOR-i治疗，并在12个月后进行评估。

结果

肾移植患者的肿瘤内浸润和肿瘤特异性T细胞反应低于NoKT-SCC患者，KT-mTORi-SCC患者的肿瘤内和循环FOXP3 + Treg细胞更高（P < 0.05）。KT-CNI-SCC患者的肿瘤特异性T细胞反应显著低于KT-mTORi-SCC患者和NoKT-SCC患者，并可预测SCC复发（曲线下面积 = 0.837；P < 0.05）。转换为mTOR-i治疗1年后，观察到FOXP3 + Treg细胞数量和肿瘤特异性T细胞反应显著增加，达到与KT-mTORi-SCC患者和NoKT-SCC患者相似的水平。