Department of Hematology, Zhongshan Hospital, Fudan University, Shanghai, China.
Cancer Med. 2023 Dec;12(24):21651-21665. doi: 10.1002/cam4.6721. Epub 2023 Nov 15.
Intratumor heterogeneity (ITH) is an important factor for clinical outcomes in patients with multiple myeloma (MM). High ITH has been proven to be a key reason for tumor immune escape and treatment resistance. Neoantigens are thought to be associated with ITH, but the specific correlation and functional basis for this remains unclear.
We study this question through the whole-exome sequencing (WES) data from 43 high ITH newly diagnosed MM patients in our center. Mutant allele tumor heterogeneity (MATH) was conducted to quantify ITH. The cutoff value for high intratumor heterogeneity was determined by comparing MATH of different kinds of tumors. NeoPredPipe was performed to predict neoantigens and binding affinity.
Compared to other tumors, MM has a relatively low tumor mutation burden but a high ITH. Patients with high MATH had significantly shorter progression-free survival times than those with low MATH (p = 0.001). In high ITH samples, there is a decrease in strong-binding neoantigens (p = 0.019). The loss of strong-binding neoantigens is a key factor for insensitivity to therapy (p = 0.015). Loss of heterozygosity in HLA was not observed. In addition, patients with fewer neoantigens loss had higher rates of disease remission (p = 0.047). CD8 + T cells (p = 0.012) and NK cells (p = 0.011) decreased significantly in patients with high neoantigens loss rate. A prediction model based on neoantigens was built to evaluate the strength of immune escape.
The loss of strong-binding neoantigens explains why tumors with high ITH have a higher degree of immune escape and may be feasible for deciding the clinical treatment of MM.
肿瘤内异质性（ITH）是多发性骨髓瘤（MM）患者临床结局的一个重要因素。已证实高 ITH 是肿瘤免疫逃逸和治疗耐药的关键原因。新抗原被认为与 ITH 相关，但具体的相关性和功能基础尚不清楚。
我们通过中心 43 例高 ITH 初诊 MM 患者的全外显子组测序（WES）数据研究这个问题。采用突变等位基因肿瘤异质性（MATH）来量化 ITH。通过比较不同肿瘤的 MATH 值来确定高 ITH 的截断值。采用 NeoPredPipe 预测新抗原和结合亲和力。
与其他肿瘤相比，MM 的肿瘤突变负担相对较低，但 ITH 较高。MATH 较高的患者无进展生存期明显短于 MATH 较低的患者（p=0.001）。在高 ITH 样本中，强结合新抗原减少（p=0.019）。强结合新抗原的丢失是对治疗不敏感的关键因素（p=0.015）。未观察到 HLA 杂合性丢失。此外，新抗原丢失较少的患者缓解率更高（p=0.047）。高新抗原丢失率患者的 CD8+T 细胞（p=0.012）和 NK 细胞（p=0.011）显著减少。建立了一个基于新抗原的预测模型来评估免疫逃逸的强度。
强结合新抗原的丢失解释了为什么高 ITH 肿瘤具有更高程度的免疫逃逸，这可能有助于决定 MM 的临床治疗。
