Influencing the exposome, patient macroenvironment, tumor microenvironment through-line to improve clinical outcomes

Previous studies have identified an association between a tumor microenvironment characterized by a predominance of T helper cell type 2 (Th2) system cells (Th2 cells, M2 macrophages, innate lymphoid cells type 2), regulatory T cells, and myeloid derived suppressor cells with poorer cancer prognosis. In contrast, a tumor microenvironment characterized by Th1 system cells (Th1 cells, M1 macrophages, natural killer cells, CD8+ cells, innate lymphoid cells type 1) is associated with a more favorable prognosis. T2-high asthma, a quintessential Th2-dominance-based disease, is associated epidemiologically with more than double the incidence of lung, breast, prostate, and colon cancers, suggesting a connection between the Th2 immune dominant patient macroenvironment and the Th2 immune dominant tumor microenvironment. Stress, air pollution, toxicants, sleep disruption, obesity, and many other influences from the exposome are known to drive the patient into Th2 dominance. Thus, the authors hypothesize that there is a through-line connecting the exposome, patient macroenvironment, and tumor microenvironment. With this context in mind, specific defects in the tricarboxylic acid (TCA) cycle produce oncometabolites that drive oncogenic development in tissues. However these same TCA cycle defects drive macrophages to the M1 phenotype, which activates the Th1 system. Th1 system cells are responsible for clearance of oncogenically transformed cells. This should represent a check against the oncogenic influence of the oncometabolites created by the TCA cycle breaks. The authors hypothesize that, in Th2 dominant patients, the TCA cycle breaks fail to shift macrophages to the M1 phenotype, the Th1 system fails to upregulate, and the normal check against oncogenic development fails to occur. If confirmed by subsequent studies, this model may help explain the more than doubled incidence of common cancers in asthma and potentially other Th2 atopic diseases. The authors discuss clinical implications and approaches for operationalizing existing knowledge of the exposome and its impact on patient immunology.