Circulating Low Density Neutrophils Are Associated with Resistance to First Line Anti-PD1/PDL1 Immunotherapy in Non-Small Cell Lung Cancer
by
, , , , , , , , , and
Hugo Arasanz
1,2,*
,
Ana Isabel Bocanegra
1
,
Idoia Morilla
2,3,
Joaquín Fernández-Irigoyen
4,
Maite Martínez-Aguillo
2,3,
Lucía Teijeira
2,3,
Maider Garnica
1,
Ester Blanco
1,5,
Luisa Chocarro
1,
Karina Ausin
4,
Miren Zuazo
1,
Gonzalo Fernández-Hinojal
6,
Miriam Echaide
1,
Leticia Fernández-Rubio
1,
Sergio Piñeiro-Hermida
1,
Pablo Ramos
1,
Laura Mezquita
7,8,
David Escors
1,*,†,
Ruth Vera
2,3,† and
Grazyna Kochan
1,† 1
Oncoimmunology Group, Navarrabiomed, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Irunlarrea St., 3, 31008 Pamplona, Spain
2
Medical Oncology Department, Hospital Universitario de Navarra, Instituto de Investigación Sanitaria de Navarra (IdiSNA), 31008 Pamplona, Spain
3
Oncobiona Group, Navarrabiomed, Instituto de Investigación Sanitaria de Navarra (IdiSNA), 31008 Pamplona, Spain
4
Clinical Neuroproteomics Unit, Proteomics Platform, Proteored-ISCIII, Navarrabiomed, Instituto de Investigación Sanitaria de Navarra (IdiSNA), 31008 Pamplona, Spain
5
Gene Therapy and Regulation of Gene Expression, Centro de Investigación Médica Aplicada (CIMA), Instituto de Investigación Sanitaria de Navarra (IdiSNA), 31008 Pamplona, Spain
6
Medical Oncology Department, Hospital Clínico San Carlos, 28040 Madrid, Spain
7
Medical Oncology Department, Hospital Clínic i Provincial de Barcelona, IDIBAPS, 08036 Barcelona, Spain
8
Medical Oncology Department, Laboratory of Translational Genomics and Targeted Therapies in Solid Tumors, IDIBAPS, 08036 Barcelona, Spain
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Cancers 2022, 14(16), 3846; https://doi.org/10.3390/cancers14163846
Submission received: 25 June 2022
/
Revised: 5 August 2022
/
Accepted: 7 August 2022
/
Published: 9 August 2022
(This article belongs to the Special Issue Treatment Modalities for Non-small Cell Lung Cancer—A Clinical Survey)
Simple Summary
Immunotherapy has been positioned as frontline therapy for advanced non-small cell lung cancer (NSCLC), alone when PD-L1 tumor expression is high, or combined with chemotherapy otherwise. However, 50% of the patients do not respond to the treatment and the mechanisms of resistance are not well defined. Moreover, it is not clear whether chemo-immunotherapy could be advantageous in high PD-L1 tumor expression. We have found that baseline circulating low-density neutrophils (LDN) identify a subset of patients intrinsically refractory to immunotherapy. Interestingly, responses can be achieved with CT+IT, detecting a progressive depletion of LDN. Besides the potential role as predictive biomarker we observed that resistance was mediated by soluble molecules related with the HGF/c-MET pathway. Our findings establish circulating myeloid cells as one of the main mediators of resistance to immunotherapy in NSCLC, and give a rationale for potential drug combinations that might improve the outcomes.
Abstract
Single-agent immunotherapy has been widely accepted as frontline treatment for advanced non-small cell lung cancer (NSCLC) with high tumor PD-L1 expression, but most patients do not respond and the mechanisms of resistance are not well known. Several works have highlighted the immunosuppressive activities of myeloid subpopulations, including low-density neutrophils (LDNs), although the context in which these cells play their role is not well defined. We prospectively monitored LDNs in peripheral blood from patients with NSCLC treated with anti-PD-1 immune checkpoint inhibitors (ICIs) as frontline therapy, in a cohort of patients treated with anti-PD1 immunotherapy combined with chemotherapy (CT+IT), and correlated values with outcomes. We explored the underlying mechanisms through ex vivo experiments. Elevated baseline LDNs predict primary resistance to ICI monotherapy in patients with NSCLC, and are not associated with response to CT+IT. Circulating LDNs mediate resistance in NSCLC receiving ICI as frontline therapy through humoral immunosuppression. A depletion of this population with CT+IT might overcome resistance, suggesting that patients with high PD-L1 tumor expression and high baseline LDNs might benefit from this combination. The activation of the HGF/c-MET pathway in patients with elevated LDNs revealed by quantitative proteomics supports potential drug combinations targeting this pathway.
Keywords:
lung cancer; NSCLC; immunotherapy; neutrophils; LDN; biomarkers; PD-1; immune checkpoint inhibitors
