Mixed Response to Cancer Immunotherapy is Driven by Intratumor Heterogeneity and Differential Interlesion Immune Infiltration.
Mixed Response to Cancer Immunotherapy is Driven by Intratumor Heterogeneity and Differential Interlesion Immune Infiltration.
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DOI：
10.1158/2767-9764.crc-22-0050
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发表时间：
2022-07
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一些患者对免疫治疗的反应喜忧参半，其生物学机制和临床影响尚不清楚。我们从同一患者的淋巴结(LN)转移灶中获得了两个肿瘤样本。两种肿瘤的全外显子组测序和肿瘤浸润性淋巴细胞(TIL)的单细胞测序显示，肿瘤克隆性和TIL的特征有显著差异，尤其是耗尽的T细胞克隆型，尽管肿瘤细胞和T细胞克隆之间的密切关系被观察到是重叠的耗尽的T细胞克隆对重叠的新抗原的反应。为了模拟临床环境，我们从同一肿瘤细胞系中产生了几个克隆的小鼠模型。同样，不同的肿瘤克隆具有不同的TIL，其中一个对程序化细胞死亡蛋白1(PD-1)的阻断有反应，而在这个模型中另一个不起作用。我们进一步进行了队列研究(n=503)，用PD-1阻滞剂单一疗法治疗，以调查混合反应的结果。在我们的队列中，对PD-1阻断有混合反应的患者预后较差。特别是，在仅有LN转移的患者中，肿瘤和T细胞克隆在原发灶和LN灶之间都有显著差异，患者对抗PD-1单抗有肿瘤反应，随后出现疾病进展。我们的结果强调，即使在同一患者中，肿瘤间的异质性也会改变TIL的特征，导致对免疫治疗的混合反应和显著的结果差异。一些患者对免疫治疗的反应喜忧参半，但其生物学机制和临床意义尚不清楚。我们的临床和小鼠研究结果强调，即使在同一患者中，肿瘤间的异质性也会改变TIL的特征，导致对免疫治疗的混合反应和显著的结果差异。
Some patients experience mixed response to immunotherapy, whose biological mechanisms and clinical impact have been obscure. We obtained two tumor samples from lymph node (LN) metastatic lesions in a same patient. Whole exome sequencing for the both tumors and single-cell sequencing for the both tumor-infiltrating lymphocytes (TIL) demonstrated a significant difference in tumor clonality and TILs’ characteristics, especially exhausted T-cell clonotypes, although a close relationship between the tumor cell and T-cell clones were observed as a response of an overlapped exhausted T-cell clone to an overlapped neoantigen. To mimic the clinical setting, we generated a mouse model of several clones from a same tumor cell line. Similarly, differential tumor clones harbored distinct TILs, and one responded to programmed cell death protein 1 (PD-1) blockade but the other did not in this model. We further conducted cohort study (n = 503) treated with PD-1 blockade monotherapies to investigate the outcome of mixed response. Patients with mixed responses to PD-1 blockade had a poor prognosis in our cohort. Particularly, there were significant differences in both tumor and T-cell clones between the primary and LN lesions in a patient who experienced tumor response to anti–PD-1 mAb followed by disease progression in only LN metastasis. Our results underscore that intertumoral heterogeneity alters characteristics of TILs even in the same patient, leading to mixed response to immunotherapy and significant difference in the outcome. Several patients experience mixed responses to immunotherapies, but the biological mechanisms and clinical significance remain unclear. Our results from clinical and mouse studies underscore that intertumoral heterogeneity alters characteristics of TILs even in the same patient, leading to mixed response to immunotherapy and significant difference in the outcome.