Background

Natural killer (NK) cells are non-antigen specific innate immune cells that can be redirected to targets of interest using multiple strategies, although none are currently FDA-approved. We sought to evaluate NK cell infiltration into tumors to develop an improved understanding of which histologies may be most amenable to NK cell-based therapies currently in the developmental pipeline.

Methods

DNA (targeted/whole-exome) and RNA (whole-transcriptome) sequencing was performed from tumors from 45 cancer types (N = 90,916 for all cancers and N = 3365 for prostate cancer) submitted to Caris Life Sciences. NK cell fractions and immune deconvolution were inferred from RNA-seq data using quanTIseq. Real-world overall survival (OS) and treatment status was determined and Kaplan–Meier estimates were calculated. Statistical significance was determined using X² and Mann–Whitney U tests, with corrections for multiple comparisons where appropriate.

Results

In both a pan-tumor and prostate cancer (PCa) -specific setting, we demonstrated that NK cells represent a substantial proportion of the total cellular infiltrate (median range 2–9% for all tumors). Higher NK cell infiltration was associated with improved OS in 28 of 45 cancer types, including (PCa). NK cell infiltration was negatively correlated with common driver mutations and androgen receptor variants (AR-V7) in primary prostate biopsies, while positively correlated with negative immune regulators. Higher levels of NK cell infiltration were associated with patterns consistent with a compensatory anti-inflammatory response.

Conclusions

Using the largest available dataset to date, we demonstrated that NK cells infiltrate a broad range of tumors, including both primary and metastatic PCa. NK cell infiltration is associated with improved PCa patient outcomes. This study demonstrates that NK cells are capable of trafficking to both primary and metastatic PCa and are a viable option for immunotherapy approaches moving forward. Future development of strategies to enhance tumor-infiltrating NK cell-mediated cytolytic activity and activation while limiting inhibitory pathways will be key.

中文翻译：

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前列腺癌中的自然杀伤细胞浸润可预测患者预后的改善

背景

自然杀伤 (NK) 细胞是非抗原特异性的先天免疫细胞，可以使用多种策略将其重定向到感兴趣的靶点，尽管目前还没有一种策略获得 FDA 批准。我们试图评估 NK 细胞浸润到肿瘤中的情况，以更好地了解哪些组织学最适合目前正在开发的基于 NK 细胞的疗法。

方法

 对提交给 Caris Life Sciences 的 45 种癌症类型的肿瘤（所有癌症N = 90,916， 前列腺癌N = 3365 ）进行 DNA（靶向/全外显子组）和 RNA（全转录组）测序。使用 quanTIseq 从 RNA-seq 数据推断 NK 细胞分数和免疫解卷积。确定真实世界的总生存期 (OS) 和治疗状态，并计算 Kaplan-Meier 估计值。^{使用 X 2}和 Mann-Whitney U检验确定统计显着性，并在适当时对多重比较进行修正。

结果

在泛肿瘤和前列腺癌 (PCa) 特异性环境中，我们证明 NK 细胞占总细胞浸润的很大一部分（所有肿瘤的中位范围为 2-9%）。在 45 种癌症类型中，有 28 种癌症类型（包括 PCa）中，较高的 NK 细胞浸润与 OS 改善相关。NK细胞浸润与原发性前列腺活检中的常见驱动突变和雄激素受体变异（ AR-V7 ）呈负相关，而与负免疫调节剂呈正相关。较高水平的 NK 细胞浸润与代偿性抗炎反应的模式相关。

结论

使用迄今为止最大的可用数据集，我们证明 NK 细胞可以浸润多种肿瘤，包括原发性和转移性前列腺癌。NK 细胞浸润与 PCa 患者预后的改善相关。这项研究表明 NK 细胞能够运输至原发性和转移性 PCa，并且是未来免疫治疗方法的可行选择。未来开发增强肿瘤浸润 NK 细胞介导的细胞溶解活性和激活同时限制抑制途径的策略将是关键。