Tougeron David, Emambux Sheik, Favot Laure, Lecomte Thierry, Wierzbicka-Hainaut Ewa, Samimi Mahtab, Frouin Eric, Azzopardi Nicolas, Chevrier Jocelyn, Serres Laura, Godet Julie, Levillain Pierre, Paintaud Gilles, Ferru Aurélie, Rouleau Laetitia, Delwail Adriana, Silvain Christine, Tasu Jean-Pierre, Morel Franck, Ragot Stéphanie, Lecron Jean-Claude
Gastroenterology Department, Poitiers University Hospital, Poitiers, France.
Laboratory Inflammation, Tissus Epithéliaux Et Cytokines, EA 4331, Poitiers University, Poitiers, France.
Oncoimmunology. 2020 Nov 29;9(1):1848058. doi: 10.1080/2162402X.2020.1848058.
Anti-epidermal growth factor receptor (EGFR) monoclonal antibody is a standard treatment of metastatic colorectal cancer (mCRC) and its most common adverse effect is a papulopustular acneiform rash. The aim of the CUTACETUX study was to characterize the skin inflammatory response associated with this rash and its relation to treatment efficacy. This prospective study included patients with mCRC treated with first-line chemotherapy plus cetuximab. Patients underwent skin biopsies before the initiation of cetuximab (D0) and before the third infusion (D28), one in a rash zone and one in an unaffected zone. Expression of Th17-related cytokines (IL-17A, IL-21, IL-22), antimicrobial peptides (S100A7 and BD-2), innate response-related cytokines (IL-1β, IL-6, TNF-α and OSM), T-reg-related cytokines (IL-10 and TGF-β), Th1-related cytokine (IFN-γ), Th2-related cytokine (IL-4), Thymic stromal lymphopoietin and keratinocyte-derived cytokines (IL-8, IL-23 and CCL20) were determined by RT-PCR. Twenty-seven patients were included. Levels of most of the cytokines increased at D28 in the rash zone compared to D0. No significant association was observed between variations of cytokines levels and treatment response in the rash zone and only the increase of IL-4 ( = .04) and IL-23 ( = .02) levels between D0 and D28 in the unaffected zone was significantly associated with treatment response. Increased levels of IL-8 ( = .02), BD-2 ( = .02), IL-1β ( = .004) and OSM ( = .02) in the rash zone were associated with longer progression-free survival. Expression of Th2-related and keratinocyte-derived cytokines in the skin was associated with anti-EGFR efficacy. If this inflammatory signature can explain the rash, the exact mechanism by which these cytokines are involved in anti-EGFR tumor response remains to be studied.
抗表皮生长因子受体（EGFR）单克隆抗体是转移性结直肠癌（mCRC）的标准治疗方法，其最常见的不良反应是丘疹脓疱样痤疮样皮疹。CUTACETUX研究的目的是明确与这种皮疹相关的皮肤炎症反应及其与治疗疗效的关系。这项前瞻性研究纳入了接受一线化疗联合西妥昔单抗治疗的mCRC患者。患者在开始使用西妥昔单抗前（D0）和第三次输注前（D28）进行皮肤活检，一处取在皮疹部位，另一处取在未受影响部位。通过逆转录聚合酶链反应（RT-PCR）检测Th17相关细胞因子（IL-17A、IL-21、IL-22）、抗菌肽（S100A7和BD-2）、固有免疫反应相关细胞因子（IL-1β、IL-6、TNF-α和OSM）、调节性T细胞（T-reg）相关细胞因子（IL-10和TGF-β）、Th1相关细胞因子（IFN-γ）、Th2相关细胞因子（IL-4）、胸腺基质淋巴细胞生成素和角质形成细胞衍生细胞因子（IL-8、IL-23和CCL20）的表达。共纳入27例患者。与D0相比，大多数细胞因子水平在D28时在皮疹部位升高。皮疹部位细胞因子水平变化与治疗反应之间未观察到显著相关性，仅未受影响部位D0至D28期间IL-4（P = 0.04）和IL-23（P = 0.02）水平升高与治疗反应显著相关。皮疹部位IL-8（P = 0.02）、BD-2（P = 0.02）、IL-1β（P = 0.004）和OSM（P = 0.02）水平升高与更长的无进展生存期相关。皮肤中Th2相关和角质形成细胞衍生细胞因子的表达与抗EGFR疗效相关。如果这种炎症特征可以解释皮疹，那么这些细胞因子参与抗EGFR肿瘤反应的确切机制仍有待研究。
