Decreased local immune response and retained HPV gene expression during chemoradiotherapy are associated with treatment resistance and death from cervical cancer.
Decreased local immune response and retained HPV gene expression during chemoradiotherapy are associated with treatment resistance and death from cervical cancer.
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DOI：
10.1002/ijc.32793
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发表时间：
2020-04-01
影响因子：
6.4
通讯作者：
Wang X
中科院分区：
文献类型：
--
作者：
Cosper PF;McNair C;González I;Wong N;Knudsen KE;Chen JJ;Markovina S;Schwarz JK;Grigsby PW;Wang X
超过三分之一的局部晚期宫颈癌患者对放化疗（CRT）无反应。我们旨在描述CRT治疗前和治疗期间配对的人类宫颈肿瘤的转录图谱，以便深入了解治疗反应的演变并阐明治疗抵抗的机制。我们前瞻性地收集了115名患者在CRT治疗前和治疗3周时的宫颈肿瘤活检样本。对20对在治疗中期有足够肿瘤组织的样本进行了RNA测序、基因集富集分析和人乳头瘤病毒（HPV）基因表达分析。在最后一次随访时无疾病证据（NED）的患者的肿瘤在治疗前和治疗中期都在免疫反应相关通路中富集，而死于疾病（DOD）的患者的肿瘤在生物合成和有丝分裂通路中富集，但在免疫相关通路中没有富集。与NED患者相比，DOD患者在治疗中期T细胞和溶细胞基因表达降低，PD - L2表达增加。组织学和免疫组化分析显示，所有患者在CRT期间肿瘤相关淋巴细胞（TAL）都减少，但DOD患者的肿瘤在治疗中期TAL和CD8 +细胞的减少更为显著，这在一个更大的治疗中期队列中得到了验证。最后，DOD患者在CRT期间保留了更多的HPV E6/E7基因表达，这与驱动有丝分裂的基因表达增加有关，这在体外得到了证实。我们的研究结果表明，局部免疫反应降低和HPV基因表达保留可能共同作用，促进宫颈癌患者在CRT期间的治疗抵抗。
More than one-third of patients with locally advanced cervical cancer do not respond to chemoradiation therapy (CRT). We aimed to characterize the transcriptional landscape of paired human cervical tumors before and during CRT in order to gain insight into the evolution of treatment response and to elucidate mechanisms of treatment resistance. We prospectively collected cervical tumor biopsies from 115 patients both before and 3 weeks into CRT. RNA-sequencing, Gene Set Enrichment Analysis, and HPV gene expression was performed on 20 paired samples that had adequate neoplastic tissue mid-treatment. Tumors from patients with no evidence of disease (NED) at last follow-up had enrichment in pathways related to the immune response both pre- and mid-treatment, while tumors from patients dead of disease (DOD) demonstrated enrichment in biosynthetic and mitotic pathways but not in immune-related pathways. Patients DOD had decreased expression of T-cell and cytolytic genes and increased expression of PD-L2 mid-treatment compared to patients NED. Histological and immunohistochemical analysis revealed a decrease in tumor-associated lymphocytes (TAL) during CRT in all patients but tumors from patients DOD had a significantly more pronounced decrease in TALs and CD8+ cells mid-treatment, which was validated in a larger mid-treatment cohort. Finally, patients DOD retained more HPV E6/E7 gene expression during CRT and this was associated with increased expression of genes driving mitosis, which was corroborated in vitro. Our results suggest that decreased local immune response and retained HPV gene expression may be acting together to promote treatment resistance during CRT in patients with cervical cancer.
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影响因子：
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作者：
Liberzon, Arthur;Subramanian, Aravind;Mesirov, Jill P.
通讯作者：
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影响因子：
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影响因子：
8.8
作者：
Burnet, NG;Jefferies, SJ;Benson, RJ;Hunt, DP;Treasure, FP
通讯作者：
Treasure, FP
DOI：
10.1016/j.ijrobp.2007.10.068
发表时间：
2008-05-01
影响因子：
7
作者：
Klopp, Ann H.;Jhingran, Anuja;Buchholz, Thomas A.
通讯作者：
Buchholz, Thomas A.