癌症的一个标志是肿瘤细胞能够逃避免疫毁灭的能力。肿瘤细胞中的体细胞突变会阻止免疫毁灭，这一点已经得到了广泛的研究。然而，据我们所知，以往并没有研究肿瘤浸润免疫（TII）细胞中的体细胞突变。这是可以理解的，因为正常造血过程会阻止免疫细胞中体细胞突变的积累。然而，克隆性造血确实会导致免疫细胞中体细胞突变的积累。这些突变不能“推动”肿瘤生长，但它们可能通过抑制有效的抗肿瘤免疫反应来“促进”肿瘤生长。为了鉴定潜在的免疫抑制性克隆性造血（CH）突变在TII细胞中的情况，我们分析了乳腺癌患者的肿瘤和正常血液样本的全外显子和RNA测序数据以及单细胞RNA测序数据。我们选取了那些满足以下条件的突变：体细胞突变、存在于TII细胞中、克隆扩张、潜在致病性、在TII细胞中表达、不太可能是乘客突变和与免疫应答相关的基因。我们在TII细胞中鉴定到了八个潜在的免疫抑制性CH突变。这项工作是确定免疫抑制性CH突变在TII细胞中是否会影响实体肿瘤进展的第一步。随后的实验验证可能代表着癌症发病机制的新范式。© 2023. Springer Nature Limited.

A hallmark of cancer is a tumor cell's ability to evade immune destruction. Somatic mutations in tumor cells that prevent immune destruction have been extensively studied. However, somatic mutations in tumor infiltrating immune (TII) cells, to our knowledge, have not been previously studied. Understandably so since normal hematopoiesis prevents the accumulation of somatic mutations in immune cells. However, clonal hematopoiesis does result in the accumulation of somatic mutations in immune cells. These mutations cannot "drive" tumor growth, however, they may "facilitate" it by inhibiting an effective anti-tumor immune response. To identify potential immunosuppressive clonal hematopoietic (CH) mutations in TII cells, we analyzed exome and RNA sequencing data from matched tumor and normal blood samples, and single-cell RNA sequencing data, from breast cancer patients. We selected mutations that were somatic, present in TII cells, clonally expanded, potentially pathogenic, expressed in TII cells, unlikely to be a passenger mutation, and in immune response associated genes. We identified eight potential immunosuppressive CH mutations in TII cells. This work is a first step towards determining if immunosuppressive CH mutations in TII cells can affect the progression of solid tumors. Subsequent experimental confirmation could represent a new paradigm in the etiology of cancer.© 2023. Springer Nature Limited.