Immunotherapy Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan;
Immunotherapy Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan.
Anticancer Res. 2022 Jul;42(7):3537-3549. doi: 10.21873/anticanres.15840.
Many reports demonstrate that a high tumor mutation burden (TMB-H) is closely associated with good prognosis of cancer. However, specific studies investigating the association of various TMB statuses with overall survival in patients with solid tumors are scarce.
In the present study, we investigated the association of TMB status with overall survival in 5,072 patients with cancer from the HOPE project and clarified the specific mechanism responsible for the good prognosis of the TMB-H group. All tumors were classified into one of four groups based on TMB: ultralow (UL), low (L), intermediate (I) and high (H).
The TMB-H group had a better prognosis than the TMB-I and TMB-L groups, but not than the TMB-UL group. Analyzing the expression of 293 immune response-associated genes, 17 genes were up-regulated in the TMB-H group compared to the TMB-I and TNB-L groups, and two genes [CD274 and interferon-γ (IFNG)] were identified as good prognostic factors. Analysis of immune cell populations inside tumors demonstrated that the frequencies of exhausted CD8 T-cells, activated effector CD8 T-cells and natural killer cells were significantly higher in the TMB-H group. The T-cell receptor repertoire numbers and the diversity evenness score (DE50) were lower in the TMB-H group than in TMB-UL group; however, no association of the DE50 value with the binding or elution affinity of epitope peptides from neoantigens was found.
One possible mechanism for the good prognosis of the TMB-UL group compared to the TMB-H group might be that the TMB-UL group features a balance between immunosuppression and immunostimulation.
许多报告表明，高肿瘤突变负担（TMB-H）与癌症的良好预后密切相关。然而，具体研究肿瘤突变负荷状态与实体瘤患者总生存的相关性的研究很少。
在本研究中，我们调查了 HOPE 项目中 5072 例癌症患者的 TMB 状态与总生存的关系，并阐明了 TMB-H 组预后良好的具体机制。所有肿瘤根据 TMB 分为 UL、L、I 和 H 四组之一。
TMB-H 组的预后优于 TMB-I 和 TMB-L 组，但与 TMB-UL 组无差异。分析 293 个免疫反应相关基因的表达，TMB-H 组有 17 个基因上调，与 TMB-I 和 TNB-L 组相比，两个基因（CD274 和干扰素-γ（IFNG））被鉴定为良好的预后因素。分析肿瘤内免疫细胞群体表明，TMB-H 组衰竭 CD8 T 细胞、激活效应 CD8 T 细胞和自然杀伤细胞的频率明显升高。T 细胞受体库数量和多样性均匀度评分（DE50）在 TMB-H 组低于 TMB-UL 组；然而，DE50 值与新抗原表位肽的结合或洗脱亲和力之间没有关联。
与 TMB-H 组相比，TMB-UL 组预后良好的一个可能机制可能是 TMB-UL 组在免疫抑制和免疫刺激之间保持平衡。
