Intragenic Rearrangement Burden Associates with Immune Cell Infiltration and Response to Immune Checkpoint Blockade in Cancer.
Intragenic Rearrangement Burden Associates with Immune Cell Infiltration and Response to Immune Checkpoint Blockade in Cancer.
复制标题
基因内重排负担与癌症中免疫细胞浸润和对免疫检查点阻断的反应相关。
DOI：
10.1158/2326-6066.cir-22-0637
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发表时间：
2024
影响因子：
10.1
通讯作者：
Wang,Xiao-Song
中科院分区：
文献类型：
--
作者：
Zhang,Han;Lee,Sanghoon;Muthakana,ReneeR;Lu,Binfeng;Boone,DavidN;Lee,Daniel;Wang,Xiao-Song
免疫检查点阻断（ICB）可以诱导持久的癌症缓解。然而，只有一小部分患者受益。虽然肿瘤突变负荷（TMB）在某些情况下区分了应答者和无应答者，但它在低突变率的肿瘤类型中是一个弱预测因子。因此，存在未满足的需要，以发现预测这些肿瘤类型中的ICB反应的新的遗传畸变类别。在这里，我们报告了泛癌全基因组的分析，揭示了基因内重排（IGR）负荷与乳腺癌，卵巢癌，食管癌和子宫内膜癌的免疫浸润显着相关，特别是与增加M1巨噬细胞和CD8+ T细胞的签名。对乳腺癌、子宫内膜癌和卵巢癌中肿瘤浸润淋巴细胞空间计数的多变量回归表明，IGR负荷是这些癌症中比其他遗传畸变更有影响力的协变量。在MEDI4736试验中，评估了durvalumab治疗食管腺癌的效果，IGR负荷与患者获益相关。在评估atezolizumab治疗尿路上皮癌的IMVigor210试验中，IGR负荷随铂暴露量增加而增加，并预测了TMB低水平、铂暴露肿瘤的患者获益。总之，我们已经证明IGR负荷与T细胞炎症相关，并预测TMB低，IGR占主导地位的肿瘤和铂暴露的肿瘤中的ICB益处。
Immune checkpoint blockade (ICB) can induce durable cancer remission. However, only a small subset of patients gains benefits. While tumor mutation burden (TMB) differentiates responders from nonresponders in some cases, it is a weak predictor in tumor types with low mutation rates. Thus, there is an unmet need to discover a new class of genetic aberrations that predict ICB responses in these tumor types. Here, we report analyses of pan-cancer whole genomes which revealed that intragenic rearrangement (IGR) burden is significantly associated with immune infiltration in breast, ovarian, esophageal, and endometrial cancers, particularly with increased M1 macrophage and CD8+T-cell signatures. Multivariate regression against spatially counted tumor-infiltrating lymphocytes in breast, endometrial, and ovarian cancers suggested that IGR burden is a more influential covariate than other genetic aberrations in these cancers. In the MEDI4736 trial evaluating durvalumab in esophageal adenocarcinoma, IGR burden correlated with patient benefits. In the IMVigor210 trial evaluating atezolizumab in urothelial carcinoma, IGR burden increased with platinum exposure and predicted patient benefit among TMB-low, platinum-exposed tumors. Altogether, we have demonstrated that IGR burden correlates with T-cell inflammation and predicts ICB benefit in TMB-low, IGR-dominant tumors, and in platinum-exposed tumors.