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BACKGROUND

Recently, immune-checkpoint blockade has shown striking clinical results in different cancer patients. However, a significant inter-individual and inter-tumor variability exists among different cancers. The expression of the toxins granzyme A (GZMA) and perforin 1 (PRF1), secreted by effector cytotoxic T cells and natural killer (NK) cells, were recently used as a denominator of the intratumoral immune cytolytic activity (CYT). These levels are significantly elevated upon CD8+ T-cell activation as well as during a productive clinical response against immune-checkpoint blockade therapies. Still, it is not completely understood how different tumors induce and adapt to immune responses.

METHODS

Here, we calculated the CYT across different cancer types and focused on differences between primary and metastatic tumors. Using data from 10,355, primary tumor resection samples and 2,787 normal samples that we extracted from The Cancer Genome Atlas and Genotype-Tissue Expression project databases, we screened the variation of CYT across 32 different cancer types and 28 different normal tissue types. We correlated the cytolytic levels in each cancer type with the corresponding patient group's overall survival, the expression of several immune-checkpoint molecules, as well as with the load of tumor-infiltrating lymphocytes (TILs), and tumor-associated neutrophils (TANs) in these tumors.

RESULTS

We found diverse levels of CYT across different cancer types, with highest levels in kidney, lung, and cervical cancers, and lowest levels in glioma, adrenocortical carcinoma (ACC), and uveal melanoma. GZMA protein was either lowly expressed or absent in at least half of these tumors; whereas PRF1 protein was not detected in almost any of the different tumor types, analyzing tissue microarrays from 20 different tumor types. CYT was significantly higher in metastatic skin melanoma and correlated significantly to the TIL load. In TCGA-ACC, skin melanoma, and bladder cancer, CYT was associated with an improved patient outcome and high levels of both GZMA and PRF1 synergistically affected patient survival in these cancers. In bladder, breast, colon, esophageal, kidney, ovarian, pancreatic, testicular, and thyroid cancers, high CYT was accompanied by upregulation of at least one immune-checkpoint molecule, indicating that similar to melanoma and prostate cancer, immune responses in cytolytic-high tumors elicit immune suppression in the tumor microenvironment.

CONCLUSION

Overall, our data highlight the existence of diverse levels of CYT across different cancer types and suggest that along with the existence of complicated associations among various tumor-infiltrated immune cells, it is capable to promote or inhibit the establishment of a permissive tumor microenvironment, depending on the cancer type. High levels of immunosuppression seem to exist in several tumor types.

BACKGROUND

METHODS

RESULTS

CONCLUSION

背景

最近，免疫检查点阻断在不同癌症患者中显示出显著的临床效果。然而，不同癌症之间存在显著的个体间和肿瘤间差异。效应性细胞毒性T细胞和自然杀伤（NK）细胞分泌的颗粒酶A（GZMA）和穿孔素1（PRF1）毒素的表达，最近被用作肿瘤内免疫细胞溶解活性（CYT）的指标。这些水平在CD8 + T细胞激活时以及针对免疫检查点阻断疗法的有效临床反应期间显著升高。然而，目前尚不完全清楚不同肿瘤如何诱导和适应免疫反应。

方法

在这里，我们计算了不同癌症类型的CYT，并重点关注原发性肿瘤和转移性肿瘤之间的差异。利用我们从癌症基因组图谱和基因型-组织表达项目数据库中提取的10355个原发性肿瘤切除样本和2787个正常样本的数据，我们筛选了32种不同癌症类型和28种不同正常组织类型的CYT变化。我们将每种癌症类型的细胞溶解水平与相应患者组的总生存期、几种免疫检查点分子的表达以及这些肿瘤中肿瘤浸润淋巴细胞（TIL）和肿瘤相关中性粒细胞（TAN）的负荷进行了关联。

结果

我们发现不同癌症类型的CYT水平各不相同，在肾癌、肺癌和宫颈癌中水平最高，在神经胶质瘤、肾上腺皮质癌（ACC）和葡萄膜黑色素瘤中水平最低。在至少一半的这些肿瘤中，GZMA蛋白表达低或不存在；而在分析20种不同肿瘤类型的组织微阵列时，几乎在任何不同肿瘤类型中都未检测到PRF1蛋白。转移性皮肤黑色素瘤中的CYT显著更高，并且与TIL负荷显著相关。在TCGA-ACC、皮肤黑色素瘤和膀胱癌中，CYT与患者预后改善相关，并且GZMA和PRF1的高水平协同影响这些癌症患者的生存。在膀胱癌、乳腺癌、结肠癌、食管癌、肾癌、卵巢癌、胰腺癌、睾丸癌和甲状腺癌中，高CYT伴随着至少一种免疫检查点分子的上调，这表明与黑色素瘤和前列腺癌类似，细胞溶解水平高的肿瘤中的免疫反应在肿瘤微环境中引发免疫抑制。