Immuno, Volume 1, Issue 2 (June 2021) – 3 articles

The development of tumors requires an initiator event, usually exposure to DNA damaging agents that cause genetic alterations such as gene mutations or chromosomal abnormalities, leading to deregulated cell proliferation. Although the mere stochastic accumulation of further mutations may cause tumor progression, it is now clear that an inflammatory microenvironment has a major tumor-promoting influence on initiated cells, in particular when a chronic inflammatory reaction already existed before the initiated tumor cell was formed. Moreover, inflammatory cells become mobilized in response to signals emanating from tumor cells. In both cases, the microenvironment provides signals that initiated tumor cells perceive by membrane receptors and transduce via downstream kinase cascades to modulate multiple cellular processes and respond with changes in cell gene expression, metabolism, and morphology. Cytokines, chemokines, and growth factors are examples of major signals secreted by immune cells, fibroblast, and endothelial cells and mediate an intricate cell-cell crosstalk in an inflammatory microenvironment, which contributes to increased cancer cell survival, phenotypic plasticity and adaptation to surrounding tissue conditions. Eventually, consequent changes in extracellular matrix stiffness and architecture, coupled with additional genetic alterations, further fortify the malignant progression of tumor cells, priming them for invasion and metastasis. Here, we provide an overview of the current knowledge on the composition of the inflammatory tumor microenvironment, with an emphasis on the major signals and signal-transducing events mediating different aspects of stromal cell-tumor cell communication that ultimately lead to malignant progression. Full article

Like in other neurodegenerative diseases, protein aggregation, mitochondrial dysfunction, oxidative stress and neuroinflammation are hallmarks of Parkinson’s disease (PD). Differentiating characteristics of PD include the central role of α-synuclein in the aggregation pathology, a distinct vulnerability of the striato-nigral system with the related motor symptoms, as well as specific mitochondrial deficits. Which molecular alterations cause neurodegeneration and drive PD pathogenesis is poorly understood. Here, we summarize evidence of the involvement of three interdependent factors in PD and suggest that their interplay is likely a trigger and/or aggravator of PD-related neurodegeneration: hypoxia, acidification and inflammation. We aim to integrate the existing knowledge on the well-established role of inflammation and immunity, the emerging interest in the contribution of hypoxic insults and the rather neglected effects of brain acidification in PD pathogenesis. Their tight association as an important aspect of the disease merits detailed investigation. Consequences of related injuries are discussed in the context of aging and the interaction of different brain cell types, in particular with regard to potential consequences on the vulnerability of dopaminergic neurons in the substantia nigra. A special focus is put on the identification of current knowledge gaps and we emphasize the importance of related insights from other research fields, such as cancer research and immunometabolism, for neurodegeneration research. The highlighted interplay of hypoxia, acidification and inflammation is likely also of relevance for other neurodegenerative diseases, despite disease-specific biochemical and metabolic alterations. Full article

Serum lactate dehydrogenase (LDH) levels are inversely related with response to immune checkpoint inhibitors (ICIs) in patients with metastatic melanoma. LDH is a key regulator of glycolysis, a pathway known to be upregulated in malignant tumors and to negatively affect antitumor immunity. We hypothesized that LDH isotype distribution in peripheral blood better reflects tumor glycolytic activity than total LDH levels and might therefore contribute to immunotherapy response prediction. LDH isotyping was performed in blood of 40 patients with metastatic melanoma and elevated LDH levels, of which 22 were treated with ipilimumab plus nivolumab. LDH-1 levels were decreased in 57.5% of patients. The percentage of LDH-2, -3 and -4, on the other hand, was elevated in 35%, 67.5% and 37.5% of patients, respectively. There was no difference in LDH isotype distribution between patients with versus patients without clinical benefit of ICIs, except for a numerically lower percentage of LDH-1 in patients without clinical benefit (median 13.3% vs. 17.6%, p = 0.1295). The percentage of LDH-1 correlated with total LDH levels and tumor burden and is therefore not likely to have strong, independent predictive value for response to ICIs. In conclusion, LDH isotyping does not contribute to ICI response prediction in melanoma patients with elevated LDH levels. Full article