Supplementary Figure S16 from Autocrine 17-β-estradiol/estrogen receptor-α loop determines the response to immune-checkpoint inhibitors in non-small cell lung cancer

Molecular circuitries linking ERα and PD-L1. ERα, activated by the binding of 17-β-estradiol and by the phosphorylation on Ser118 via the EGFR/Akt and EGFR/ERK1/2 axes, upregulates PD-L1 and predicts a better response to pembrolizumab. However, lowering the synthesis of 17-β-estradiol with letrozole or the activity of ERα with fulvestrant sensitizes non-small cell lung cancer to pembrolizumab, relieving the PD-L1-dependent immune-suppression, allowing the expansion and activity of anti-tumor infiltrating lymphocytes, such as CD8+T-cells, NK cells and Vγ9Vδ2+T cells. We suggest the existence of four possible scenarios, depending on sex, EGFR activity, 17-β-estradiol/ERα and PD-L1 status, with a differential sensitivity to pembrolizumab and aromatase inhibitors:1) male patients with low 17-β-estradiol synthesis, low EGFR signaling, low ERα amount/activity and low PD-L1 amount; 2) male patients with high EGFR signaling, high ERα amount/activity but low 17-β-estradiol synthesis, with intermediate PD-L1 amount; 3) female patients with low EGFR signaling, low ERα amount/activity but high 17-β-estradiol synthesis, with intermediate PD-L1 amount; 4) female patients with high EGFR signaling, high ERα amount/activity, high 17-β-estradiol synthesis and high PD-L1 amount. The efficacy of pembrolizumab and the additional benefit of aromatase inhibitors increased progressively from scenario 1 to 4.