Location matters: LAG3 levels are lower in renal cell carcinoma metastatic sites compared to primary tumors, and expression at metastatic sites only may have prognostic importance.
Location matters: LAG3 levels are lower in renal cell carcinoma metastatic sites compared to primary tumors, and expression at metastatic sites only may have prognostic importance.
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DOI：
10.3389/fonc.2022.990367
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发表时间：
2022
影响因子：
4.7
通讯作者：
中科院分区：
文献类型：
--
作者：
虽然随着免疫检查点抑制剂（ICI）和VEGF靶向药物的出现，晚期肾细胞癌（RCC）的治疗取得了长足的进步，但相当大比例的患者仍然对前期治疗没有反应，长期反应仅发生在少数患者中。因此，非常需要开发更好的反应预测因子，并增加对这些疗法耐药机制的了解。PD-1/PD-L1轴外的替代免疫检查点，如LAG 3，已被认为是对ICI耐药的一种机制。因此，这些检查点代表了有吸引力的治疗靶点，事实上，LAG 3抑制剂relatlimab最近被批准用于与抗PD-1疗法联合治疗转移性黑色素瘤。LAG 3抑制剂也正在评估RCC。在这种情况下，更好地了解RCC中LAG 3表达模式以及它们如何与疾病的临床病理特征和对免疫治疗的反应相关，可以深入了解PD-1抑制剂耐药的机制，并有助于识别更有可能从某些药物治疗方案中获益的患者亚组。在这项研究中，我们评估了邻近RCC的正常肾脏、原发性RCC肿瘤和匹配的转移性肿瘤（包括大量脑转移瘤）中白细胞中的LAG 3蛋白水平。我们发现，与匹配的原发性肿瘤相比，转移部位的LAG 3蛋白水平平均较低，并且这种差异在具有高风险临床特征的患者中更为明显，包括具有较大的原发性肿瘤大小，4级肿瘤，IMDC低风险疾病和最初表现为脑转移的患者。我们进一步看到LAG 3水平的预后价值根据查询的组织部位而变化（即，原发性肿瘤与转移），并且转移部位相对较高的LAG 3水平可预测对免疫疗法的更好反应和转移性疾病发展后更长的总存活期。这些发现可能对未来涉及LAG 3或其他RCC免疫疗法的研究设计具有重要意义。
While great strides have been made in the treatment of advanced renal cell carcinoma (RCC) with the emergence of immune checkpoint inhibitors (ICIs) and VEGFR-targeting drugs, sizable proportions of patients still do not respond to upfront therapy and long-term responses only occur in a minority of patients. There is therefore a great need for the development of better predictors of response and an increased understanding of mechanisms of resistance to these therapies. Alternative immune checkpoints outside the PD-1/PD-L1 axis, such as LAG3, have been implicated as one mechanism of resistance to ICIs. These checkpoints thus represent attractive therapeutic targets, and indeed the LAG3 inhibitor relatlimab was recently approved for the treatment of metastatic melanoma in combination with anti-PD-1 therapy. LAG3 inhibitors are being evaluated for RCC as well. In this context, a better understanding of LAG3 expression patterns in RCC and how they relate to clinicopathologic features of disease and response to immunotherapy may give insight into mechanisms of resistance to PD-1 inhibitors and aid in the identification of subgroups of patients more likely to benefit from certain drug regimens. In this study, we assessed LAG3 protein levels in leukocytes in normal kidney adjacent to RCC, primary RCC tumors, and matched metastatic tumors, including large numbers of brain metastases. We found that LAG3 protein levels are on average lower at metastatic sites compared to matched primary tumors, and that the difference was more pronounced in patients with high-risk clinical characteristics, including those with larger primary tumor size, grade 4 tumors, IMDC poor-risk disease, and initial presentation with brain metastases. We further saw that the prognostic value of LAG3 levels varies depending on the tissue site queried (i.e., primary tumor versus metastases), and that relatively higher LAG3 levels at metastatic sites may predict a better response to immunotherapy and longer overall survival after the development of metastatic disease. These findings may have important implications for the design of future studies involving LAG3 or other immunotherapies in RCC.
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影响因子：
64.8
作者：
Im SJ;Hashimoto M;Gerner MY;Lee J;Kissick HT;Burger MC;Shan Q;Hale JS;Lee J;Nasti TH;Sharpe AH;Freeman GJ;Germain RN;Nakaya HI;Xue HH;Ahmed R
通讯作者：
Ahmed R
影响因子：
8.8
作者：
Jenkins RW;Barbie DA;Flaherty KT
通讯作者：
Flaherty KT
肾癌中的分子亚群确定了检查点和血管生成阻滞的结果。
影响因子：
50.3
作者：
Motzer RJ;Banchereau R;Hamidi H;Powles T;McDermott D;Atkins MB;Escudier B;Liu LF;Leng N;Abbas AR;Fan J;Koeppen H;Lin J;Carroll S;Hashimoto K;Mariathasan S;Green M;Tayama D;Hegde PS;Schiff C;Huseni MA;Rini B
通讯作者：
Rini B
DOI：
10.1126/science.aan5951
发表时间：
2018-02-16
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Miao D;Margolis CA;Gao W;Voss MH;Li W;Martini DJ;Norton C;Bossé D;Wankowicz SM;Cullen D;Horak C;Wind-Rotolo M;Tracy A;Giannakis M;Hodi FS;Drake CG;Ball MW;Allaf ME;Snyder A;Hellmann MD;Ho T;Motzer RJ;Signoretti S;Kaelin WG Jr;Choueiri TK;Van Allen EM
通讯作者：
Van Allen EM
影响因子：
10.9
作者：
Labriola, Matthew Kyle;Zhu, Jason;Zhang, Tian
通讯作者：
Zhang, Tian