Autocrine 17-β-Estradiol/Estrogen Receptor-α Loop Determines the Response to Immune Checkpoint Inhibitors in Non–Small Cell Lung Cancer

Author:

Anobile Dario P.1ORCID,Salaroglio Iris C.1ORCID,Tabbò Fabrizio2ORCID,La Vecchia Sofia1ORCID,Akman Muhlis1ORCID,Napoli Francesca3ORCID,Bungaro Maristella2ORCID,Benso Federica3ORCID,Aldieri Elisabetta1ORCID,Bironzo Paolo2ORCID,Kopecka Joanna1ORCID,Passiglia Francesco2ORCID,Righi Luisella3ORCID,Novello Silvia2ORCID,Scagliotti Giorgio V.2ORCID,Riganti Chiara14ORCID

Affiliation:

1. 1Department of Oncology, University of Torino, Torino, Italy.

2. 2Thoracic Oncology Unit, Department of Oncology at San Luigi Gonzaga Hospital, University of Torino, Torino, Italy.

3. 3Pathology Unit, Department of Oncology at San Luigi Gonzaga Hospital, University of Torino, Torino, Italy.

4. 4Molecular Biotechnology Center “Guido Tarone”, University of Torino, Torino, Italy.

Abstract

Abstract Purpose: The response to immune checkpoint inhibitors (ICI) often differs between genders in non–small cell lung cancer (NSCLC), but metanalyses results are controversial, and no clear mechanisms are defined. We aim at clarifying the molecular circuitries explaining the differential gender-related response to anti–PD-1/anti–PD-L1 agents in NSCLC. Experimental Design: We prospectively analyzed a cohort of patients with NSCLC treated with ICI as a first-line approach, and we identified the molecular mechanisms determining the differential efficacy of ICI in 29 NSCLC cell lines of both genders, recapitulating patients’ phenotype. We validated new immunotherapy strategies in mice bearing NSCLC patient-derived xenografts and human reconstituted immune system (“immune-PDXs”). Results: In patients, we found that estrogen receptor α (ERα) was a predictive factor of response to pembrolizumab, stronger than gender and PD-L1 levels, and was directly correlated with PD-L1 expression, particularly in female patients. ERα transcriptionally upregulated CD274/PD-L1 gene, more in females than in males. This axis was activated by 17-β-estradiol, autocrinely produced by intratumor aromatase, and by the EGFR-downstream effectors Akt and ERK1/2 that activated ERα. The efficacy of pembrolizumab in immune-PDXs was significantly improved by the aromatase inhibitor letrozole, which reduced PD-L1 and increased the percentage of antitumor CD8+T-lymphocytes, NK cells, and Vγ9Vδ2 T-lymphocytes, producing durable control and even tumor regression after continuous administration, with maximal benefit in 17-β-estradiol/ERα highfemale immune-xenografts. Conclusions: Our work unveils that 17-β-estradiol/ERα status predicts the response to pembrolizumab in patients with NSCLC. Second, we propose aromatase inhibitors as new gender-tailored immune-adjuvants in NSCLC. See related commentary by Valencia et al., p. 3832

Funder

Fondazione AIRC per la ricerca sul cancro ETS

Cassa di Risparmio di Torino

Compagnia di San Paolo

European Cooperation in Science and Technology

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

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