School of Medical Sciences and the Kirby Institute, Faculty of Medicine, UNSW Sydney, Sydney, NSW, Australia.
Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia.
Front Immunol. 2022 May 17;13:826391. doi: 10.3389/fimmu.2022.826391. eCollection 2022.
Lung cancer is the leading cause of cancer-related death worldwide. Increasing evidence indicates a critical role for chronic inflammation in lung carcinogenesis. S100A8 is a protein with reported pro- and anti-inflammatory functions. It is highly expressed in myeloid-derived suppressor cells (MDSC) that accumulate in the tumor microenvironment and abrogate effective anti-cancer immune responses. Mechanisms of MDSC-mediated immunosuppression include production of reactive oxygen species and nitric oxide, and depletion of L-arginine required for T cell function. Although S100A8 is expressed in MDSC, its role in the lung tumor microenvironment is largely unknown. To address this, mouse recombinant S100A8 was repeatedly administered intranasally to mice bearing orthotopic lung cancers. S100A8 treatment prolonged survival from 19 days to 28 days (p < 0.001). At midpoint of survival, whole lungs and bronchoalveolar lavage fluid (BALF) were collected and relevant genes/proteins measured. We found that S100A8 significantly lowered expression of cytokine genes and proteins that promote expansion and activation of MDSC in lungs and BALF from cancer-bearing mice. Moreover, S100A8 enhanced activities of antioxidant enzymes and suppressed production of nitrite to create a lung microenvironment conducive to cytotoxic lymphocyte expansion and function. In support of this, we found decreased MDSC numbers, and increased numbers of CD4 T cells and natural killer T (NK-T) cells in lungs from cancer-bearing mice treated with S100A8. treatment of splenocytes with S100A8 protein activated NK cells. Our results indicate that treatment with S100A8 may favourably modify the lung microenvironment to promote an effective immune response in lungs, thereby representing a new strategy that could complement current immunotherapies in lung cancer.
肺癌是全球癌症相关死亡的主要原因。越来越多的证据表明，慢性炎症在肺癌发生中起着关键作用。S100A8 是一种具有报道的促炎和抗炎功能的蛋白质。它在髓系来源的抑制细胞（MDSC）中高度表达，这些细胞在肿瘤微环境中积累并消除有效的抗癌免疫反应。MDSC 介导的免疫抑制机制包括产生活性氧和一氧化氮，以及耗尽 T 细胞功能所需的 L-精氨酸。尽管 S100A8 在 MDSC 中表达，但它在肺部肿瘤微环境中的作用在很大程度上尚不清楚。为了解决这个问题，我们反复给患有原位肺癌的小鼠鼻腔内给予小鼠重组 S100A8。S100A8 治疗将生存期从 19 天延长至 28 天（p < 0.001）。在生存期的中点，收集整个肺和支气管肺泡灌洗液（BALF），并测量相关基因/蛋白。我们发现 S100A8 显著降低了来自荷瘤小鼠肺部和 BALF 中促进 MDSC 扩增和激活的细胞因子基因和蛋白的表达。此外，S100A8 增强了抗氧化酶的活性，抑制了亚硝酸盐的产生，从而创造了有利于细胞毒性淋巴细胞扩增和功能的肺部微环境。支持这一点，我们发现来自 S100A8 治疗的荷瘤小鼠肺部的 MDSC 数量减少，CD4 T 细胞和自然杀伤 T（NK-T）细胞数量增加。用 S100A8 蛋白处理脾细胞激活了 NK 细胞。我们的结果表明，S100A8 的治疗可能有利地改变肺部微环境，以促进肺部有效的免疫反应，从而代表了一种新的策略，可以补充肺癌的当前免疫疗法。
