| Summary: | <p>Colorectal cancer (CRC) is the third most commonly diagnosed cancer and ranks second as the leading cause of cancer deaths worldwide. Notably, it was predicted that a positive annual decline of 2 % in global incidence rates would eventually still lead to a rise in the projected burden of CRC. Therefore, it is pertinent to push the forefront of cancer treatments to reduce the predicted increase in the future CRC incidence and mortality burden.</p>
<p>Immunotherapy represents a paradigm shift in cancer treatment and has quickly established itself as a robust pillar of therapy for multiple cancers. However, immunotherapy has shown disparate results in the treatment of CRC, and its efficacy in the broader population of CRC patients remains limited. Particularly, no immune-checkpoint blockade targeting PD-L1 has yet to be approved for CRC. As such, more research is warranted to identify strategies to expand the benefits of immunotherapy to a wider CRC patient population.</p>
<p>To date, many studies have highlighted that PD-L1 expression level has a strong association with positive clinical response to anti-PD-L1 therapies. As such, we reasoned that one encumbering factor to the mixed clinical responses in CRC is the infrequent expression of PD-L1 in CRC cells. Using a range of <em>in vitro</em> culture techniques and multi omics approaches, we found that myeloid cells have a profound impact on CRC PD-L1 expression. Mechanistically, myeloid cells forced CRC cells to switch to oxidative phosphorylation (OXPHOS) as its default metabolic state. Here, we uncovered a direct link of OXPHOS regulating cellular protein III translation, which has not been reported previously. Along with this observation, we also discovered that glycolytic switch to OXPHOS in CRC cells lead to a downregulation of EGFR phosphorylation that reduces PD-L1 glycosylation and by extension its stability. Coupling together, this led to a significant suppression of CRC PD-L1. Furthermore, we found that polarization of monocytes to macrophages further downregulated PD-L1, which strongly suggests a long-term PD-L1 suppression by tumour-associated macrophages, as observed clinically. Lastly, we saw a reversal of PD-L1 suppression when transition to OXPHOS was inhibited pharmacologically. Concomitantly, this pharmacological approach also suggests a change in macrophage polarization trajectory towards an anti-tumorigenic phenotype. Collectively, our findings open up a potential druggable avenue to reinvigorate PD-L1 level in CRC via OXPHOS inhibition and explore the possibility of synergizing with PD-L1 blockade.</p>
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