Increasing membrane polyunsaturated fatty acids sensitizes non-small cell lung cancer to anti-PD-1/PD-L1 immunotherapy

Immune checkpoints inhibitors (ICIs) as anti-PD-1/anti-PD-L1 have been approved as first-line treatment in patients with non-small cell lung cancer (NSCLC), but only 25 % of patients achieve durable response. We previously unveiled that estrogen receptor alpha transcriptionally up-regulates PD-L1 and aromatase inhibitors such as letrozole increase the efficacy of pembrolizumab. Here we investigated if letrozole may have additional immune-sensitizing mechanisms. We found that higher the level of PD-L1 in NSCLC, higher the activation of SREBP1c that transcriptionally increases fatty acid synthase and stearoyl-CoA desaturase enzymes, increasing the amount of polyunsaturated fatty acids (PUFAs). Letrozole further up-regulated SREBP1c-mediated transcription of lipogenic genes, and increased the amount of PUFAs, thereby leading to greater membrane fluidity and reduced binding between PD-L1 and PD-1. The same effects were observed upon supplementation with w3-PUFA docosahexaenoic acid (DHA) that enhanced the efficacy of pembrolizumab in humanized NSCLC immunexenografts. We suggest that PUFA enrichment in membrane phospholipids improves the efficacy of ICIs. We propose to repurpose letrozole or DHA as new immune-sensitizing agents in NSCLC.