Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Department of Clinical Cancer Prevention-Research, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Cancer Immunol Res. 2017 Apr;5(4):319-329. doi: 10.1158/2326-6066.CIR-16-0141. Epub 2017 Mar 2.
Immunotherapies targeting immune checkpoints have proven efficacious in reducing the burden of lung cancer in patients; however, the antigenic targets of these reinvigorated T cells remain poorly defined. Lung cancer tumors contain tumor-associated macrophages (TAM) and neutrophils, which release the serine proteases neutrophil elastase (NE) and proteinase 3 (P3) into the tumor microenvironment. NE and P3 shape the antitumor adaptive immune response in breast cancer and melanoma. In this report, we demonstrate that lung cancer cells cross-presented the tumor-associated antigen PR1, derived from NE and P3. Additionally, NE and P3 enhanced the expression of human leukocyte antigen (HLA) class I molecules on lung cancer cells and induced unique, endogenous peptides in the immunopeptidome, as detected with mass spectrometry sequencing. Lung cancer patient tissues with high intratumoral TAMs were enriched for MHC class I genes and T-cell markers, and patients with high TAM and cytotoxic T lymphocyte (CTL) infiltration had improved overall survival. We confirmed the immunogenicity of unique, endogenous peptides with cytotoxicity assays against lung cancer cell lines, using CTLs from healthy donors that had been expanded against select peptides. Finally, CTLs specific for serine proteases-induced endogenous peptides were detected in lung cancer patients using peptide/HLA-A2 tetramers and were elevated in tumor-infiltrating lymphocytes. Thus, serine proteases in the tumor microenvironment of lung cancers promote the presentation of HLA class I immunogenic peptides that are expressed by lung cancer cells, thereby increasing the antigen repertoire that can be targeted in lung cancer. .
免疫检查点靶向免疫疗法已被证明能有效减轻肺癌患者的负担；然而，这些重新激活的 T 细胞的抗原靶点仍未得到明确界定。肺癌肿瘤中含有肿瘤相关巨噬细胞（TAM）和中性粒细胞，它们将丝氨酸蛋白酶中性粒细胞弹性蛋白酶（NE）和蛋白酶 3（P3）释放到肿瘤微环境中。NE 和 P3 塑造了乳腺癌和黑色素瘤中的抗肿瘤适应性免疫反应。在本报告中，我们证明肺癌细胞交叉呈递来源于 NE 和 P3 的肿瘤相关抗原 PR1。此外，NE 和 P3 增强了肺癌细胞上人类白细胞抗原（HLA）I 类分子的表达，并在免疫肽组中诱导了独特的内源性肽，通过质谱测序检测到。肿瘤内富含 TAMs 的肺癌患者组织中 MHC I 类基因和 T 细胞标记物丰富，且 TAM 和细胞毒性 T 淋巴细胞（CTL）浸润高的患者总生存率提高。我们使用针对选定肽进行扩增的健康供体 CTL，通过针对肺癌细胞系的细胞毒性测定，证实了独特的内源性肽的免疫原性。最后，使用肽/HLA-A2 四聚体在肺癌患者中检测到针对丝氨酸蛋白酶诱导的内源性肽的 CTL，并在肿瘤浸润淋巴细胞中升高。因此，肺癌肿瘤微环境中的丝氨酸蛋白酶促进了由肺癌细胞表达的 HLA I 类免疫原性肽的呈递，从而增加了可在肺癌中靶向的抗原谱。
