No abstract

The study examined the effect of exercise and hypoxia on the mobilization and egress of innate lymphocytes (ILCs) and adaptive T cell populations in the blood. The ILCs have emerged as a critical population of cells in immune regulation at mucosal surfaces in animals and humans. Eleven healthy male subjects performed (i) 45 min of exercise at 50% O 2 peak on a cycle ergometer under normoxia and (ii) hypoxia, or (iii) while resting in hypoxia. Blood samples were obtained pre-exercise, immediately post-exercise and 60 min post-exercise and were analyzed by flow cytometry to examine the type 1 and type 3 ILCs and CD4 + and CD8 + naive and memory cell populations. There was a significant increase in the number of type 1 (NK cells) and type 3 ILC22 cells in the blood in response to exercise under normal oxygen conditions followed by a significant egress of these cells following the cessation of exercise. Exercise performed under hypoxic conditions abrogated the mobilization response of NK cells and ILC22 cells. Type 3 LTi cells were mobilized into the blood only under hypoxic rest conditions. No significant changes were observed when we analysed total CD4 + and CD8 + T cell populations or the naive and memory subsets. This study highlights that distinct innate populations are mobilised under different environmental conditions and types of stress.

The EGFR/RAS/MEK/ERK signalling pathway (ERK/MAPK) is hyper-activated in most colorectal cancers (CRCs). A current limitation of inhibitors of this pathway is that they primarily induce cytostatic effects in CRC cells. Nevertheless, these drugs do induce expression of pro-apoptotic factors, suggesting they may prime CRC cells to undergo apoptosis. As histone deacetylase inhibitors (HDACi) induce expression of multiple pro-apoptotic proteins, we examined whether they could synergize with ERK/MAPK inhibitors to trigger CRC apoptosis. Combined MEK/ERK and HDAC inhibition synergistically induced apoptosis in CRC cell lines and patient-derived tumour organoids in vitro, and attenuated Apc-initiated adenoma formation in vivo. Mechanistically this effect was mediated through induction of the BH3-only pro-apoptotic proteins BIM and BMF. Importantly, we demonstrate that this treatment paradigm can be tailored to specific MAPK genotypes in CRCs, by combining HDACi with EGFR, KRASG12C or BRAFV600 inhibitors in KRAS/BRAFWT; KRASG12C, BRAFV600E CRC cell lines respectively. These findings identify a novel ERK/MAPK genotype-targeted treatment paradigm for colorectal cancer.