Zucca Luis Eduardo Rosa, Laus Ana Carolina, Sorroche Bruna Pereira, Paro Eduarda, Sussuchi Luciane, Marques Rui Ferreira, Teixeira Gustavo Ramos, Berardinelli Gustavo Noriz, Arantes Lidia Maria Rebolho Batista, Reis Rui Manuel, Cárcano Flavio Mavignier
Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil; Instituto do Câncer Brasil, Taubaté, Brazil.
Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil.
Transl Oncol. 2024 Aug;46:102003. doi: 10.1016/j.tranon.2024.102003. Epub 2024 Jun 4.
One-hundred-six patients diagnosed with non-muscle invasive bladder cancer and treated with intravesical BCG were included and divided into two groups, BCG-responsive (n = 47) and -unresponsive (n = 59). Immunohistochemistry was used to evaluate PD-L1 expression and MSI was assessed by a commercial multiplex PCR kit. The mRNA expression profile of 15 immune checkpoints was performed using the nCounter technology. For in silico validation, two distinct cohorts sourced from the Gene Expression Omnibus (GEO) database were used.
Among the 106 patients, only one (<1 %) exhibited MSI instability. PD-L1 expression was present in 9.4 % of cases, and no association was found with BCG-responsive status. We found low gene expression of canonic actionable immune checkpoints PDCD1 (PD-1), CD274 (PD-L1), and CTLA4, while high expression was observed for CD276 (B7-H3), CD47, TNFRSF14, IDO1 and PVR (CD155) genes. High IDO1 expression levels was associated with worst overall survival. The PDCD1, CTLA4 and TNFRSF14 expression levels were associated with BCG responsiveness, whereas TIGIT and CD276 were associated with unresponsiveness. Finally, CD276 was validated in silico cohorts.
In NMIBC, MSI is rare and PD-L1 expression is present in a small subset of cases. Expression levels of PDCD1, CTLA4, TNFRSF14, TIGIT and CD276 could constitute predictive biomarkers of BCG responsiveness.
纳入106例诊断为非肌层浸润性膀胱癌并接受膀胱内卡介苗治疗的患者，分为两组，卡介苗反应组（n = 47）和无反应组（n = 59）。采用免疫组织化学评估PD-L1表达，并用商用多重PCR试剂盒评估微卫星不稳定性（MSI）。使用nCounter技术检测15种免疫检查点的mRNA表达谱。为进行电子验证，使用了来自基因表达综合数据库（GEO）的两个不同队列。
106例患者中，仅1例（<1%）表现出MSI不稳定。9.4%的病例存在PD-L1表达，且未发现与卡介苗反应状态相关。我们发现经典可操作免疫检查点PDCD1（PD-1）、CD274（PD-L1）和CTLA4的基因表达较低，而CD276（B7-H3）、CD47、TNFRSF14、IDO1和PVR（CD155）基因表达较高。IDO1高表达水平与最差的总生存期相关。PDCD1、CTLA4和TNFRSF14的表达水平与卡介苗反应性相关，而TIGIT和CD276与无反应性相关。最后，在电子队列中验证了CD276。
在非肌层浸润性膀胱癌中，MSI罕见，PD-L1表达存在于一小部分病例中。PDCD1、CTLA4、TNFRSF14、TIGIT和CD276的表达水平可能构成卡介苗反应性的预测生物标志物。
