Identification of signaling networks associated with lactate modulation of macrophages and dendritic cells

The advancement in the understanding of cancer immune evasion has
manifested the development of cancer immunotherapeutic approaches such as
checkpoint inhibitors and interleukin agonists. Although cancer
immunotherapy breakthroughs have demonstrated improved potency for cancer
treatment, only a fraction of patients effectively respond to these
treatments. Moreover, there is compelling evidence indicating that cancer
cells develop a unique microenvironment through adaptive metabolic
reprogramming, which aberrantly modulates host immunity to evade
immunosurveillance. As part of the tumor cell adaptive metabolic switch,
lactate is produced and released into the tumor environment. Recent
studies have shown that lactate significantly modulates immune functions,
especially in innate immune cells. Dendritic cells (DCs) and macrophages
(MΦs) are specialized antigen-presenting cells serving as key players in
innate immunity and anticancer-associated immune responses. Although, most
studies have shown that lactate affects immune phenotypes (e.g., surface
protein expression and cytokine production), the cell signaling network
mediated by lactate is not fully understood. In the present study, we
identified the key signaling pathways in bone marrow-derived DCs and MΦs
that are changed by cancer-relevant concentrations of lactate. First,
transcriptome analysis was used to guide notable signaling pathways
mediated by lactate. Subsequently, biomolecular techniques including
immunoblotting, flow cytometry, and immunofluorescence imaging were
performed to further investigate and confirm the changes in these key
signaling pathways. The result indicated that lactate differentially
impacted the biochemical networks of DCs and MΦs. While lactate mainly
altered STAT3, ERK, and MAPK p38 signaling cascades in DCs, the STAT1 and
GSK-3β signaling in MΦs are the major pathways significantly impacted by
lactate. This study identifies key signal transductions impacted by
lactate, which advances our understanding of the interplay between the
tumor microenvironment and innate immunity.

人们对肿瘤免疫逃逸机制认知的不断深入，推动了肿瘤免疫治疗手段的发展，例如检查点抑制剂（checkpoint inhibitors）与白细胞介素激动剂（interleukin agonists）。尽管肿瘤免疫治疗的突破性进展已证实其在癌症治疗中具备更优疗效，但仅有少数患者能对这类治疗产生有效应答。此外，已有充分证据表明，肿瘤细胞可通过适应性代谢重编程（adaptive metabolic reprogramming）构建独特的肿瘤微环境，通过异常调控宿主免疫以逃避免疫监视（immunosurveillance）。作为肿瘤细胞适应性代谢转换的一部分，乳酸被产生并释放至肿瘤微环境中。近期研究显示，乳酸可显著调控免疫功能，尤其在先天免疫细胞（innate immune cells）中。树突状细胞（Dendritic cells, DCs）与巨噬细胞（macrophages, MΦs）是一类特化的抗原呈递细胞（antigen-presenting cells），在先天免疫及抗肿瘤相关免疫应答中发挥关键作用。尽管多数研究已证实乳酸可影响免疫表型（例如表面蛋白表达与细胞因子产生），但乳酸介导的细胞信号网络仍未被完全阐明。本研究明确了受癌症相关浓度乳酸调控的骨髓来源DCs与MΦs中的关键信号通路。首先，本研究通过转录组分析（transcriptome analysis）筛选出乳酸介导的显著信号通路；随后，借助免疫印迹（immunoblotting）、流式细胞术（flow cytometry）与免疫荧光成像（immunofluorescence imaging）等分子生物学技术，进一步探究并验证了上述关键信号通路的变化。研究结果表明，乳酸对DCs与MΦs的生化网络存在差异性影响：乳酸主要改变DCs中的STAT3、ERK及MAPK p38信号级联反应，而MΦs中受乳酸显著影响的核心通路则为STAT1与GSK-3β信号通路。本研究明确了乳酸调控的关键信号转导过程，有助于深化我们对肿瘤微环境与先天免疫之间相互作用的认知。