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Review
. 2021 Jul;10(7):3369-3384.
doi: 10.21037/tlcr-20-1134.

A narrative review on tumor microenvironment in oligometastatic and oligoprogressive non-small cell lung cancer: a lot remains to be done

Lorenzo Belluomini  1 , Alessandra Dodi  1 , Alberto Caldart  1 , Dzenete Kadrija  1 , Marco Sposito  1 , Miriam Casali  1 , Giulia Sartori  1 , Miriam Grazia Ferrara  2 , Alice Avancini  3 , Emilio Bria  2 , Jessica Menis  4   5 , Michele Milella  1 , Sara Pilotto  1
Affiliations
Review

A narrative review on tumor microenvironment in oligometastatic and oligoprogressive non-small cell lung cancer: a lot remains to be done

Lorenzo Belluomini et al. Transl Lung Cancer Res. 2021 Jul.

Abstract

Objective: In this review, we aim to collect and discuss available data about the role and composition of tumor microenvironment (TME) in oligometastatic (OMD) and oligoprogressive (OPD) non-small cell lung cancer (NSCLC). Furthermore, we aim to summarize the ongoing clinical trials evaluating as exploratory objective the TME composition, through tissue and/or blood samples, in order to clarify whether TME and its components could explain, at least partially, the oligometastatic/oligoprogressive process and could unravel the existence of predictive and/or prognostic factors for local ablative therapy (LAT).

Background: OMD/OPD NSCLC represent a heterogeneous group of diseases. Several data have shown that TME plays an important role in tumor progression and therefore in treatment response. The crucial role of several types of cells and molecules such as immune cells, cytokines, integrins, protease and adhesion molecules, tumor-associated macrophages (TAMs) and mesenchymal stem cells (MSCs) has been widely established. Due to the peculiar activation of specific pathways and expression of adhesion molecules, metastatic cells seem to show a tropism for specific anatomic sites (the so-called "seed and soil" hypothesis). Based on this theory, metastases appear as a biologically driven process rather than a random release of cancer cells. Although the role and the function of TME at the time of progression in patients with NSCLC treated with tyrosine-kinase inhibitors and immune checkpoint inhibitors (ICIs) have been investigated, limited data about the role and the biological meaning of TME are available in the specific OMD/OPD setting.

Methods: Through a comprehensive PubMed and ClinicalTrials.gov search, we identified available and ongoing studies exploring the role of TME in oligometastatic/oligoprogressive NSCLC.

Conclusions: Deepening the knowledge on TME composition and function in OMD/OPD may provide innovative implications in terms of both prognosis and prediction of outcome in particular from local treatments, paving the way for future investigations of personalized approaches in both advanced and early disease settings.

Keywords: Tumor microenvironment (TME); local ablative therapy (LAT); non-small cell lung cancer (NSCLC); oligometastases; oligoprogression.

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Conflict of interest statement

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tlcr-20-1134). The series “Oligometastatic NSCLC: definition and treatment opportunities” was commissioned by the editorial office without any funding or sponsorship. EB serves as an unpaid editorial board member of Translational Lung Cancer Research from September 2019 to September 2021. MM reports honoraria or speakers’ fee from Pfizer, EUSA Pharma and Astra Zeneca, outside the submitted manuscript. SP reports honoraria or speakers’ fee from Astra-Zeneca, Eli-Lilly, BMS, Boehringer Ingelheim, MSD and Roche, outside the submitted manuscript. The authors have no other conflicts of interest to declare.

Figures

Figure 1
Figure 1
Local invasion of the stroma and composition of tumor microenvironment. HIF-1, hypoxia-inducible factor 1; TME, tumor microenvironment; MSCs, mesenchymal stem cells; VEGF, vascular endothelial growth factor; IL-6 and IL-8, interleukin-6 and interleukin-8; FGF-2, fibroblast growth factor; PDGF, platelet-derived growth factor; TAMs M2, tumor-associated macrophages M2; COX-2, cyclooxygenase-2; PDGF-β, platelet-derived growth factor beta; VEGF-α, vascular endothelial growth factor alpha; MMP-9, matrix metalloproteinase-9; uPA, urokinase-type plasminogen activator; αSMA, alpha smooth muscle actin; TGF β-1, transforming growth factor beta-1; HGF, hepatocyte growth factors; SDF1, stromal cell-derived factor 1; CXCL12, C-X-C motif chemokine 12; Tregs, regulatoryT cells.
Figure 2
Figure 2
Intravasation/extravasation of cancer cells and “seed and soil” theory. JAG-1,2, Jagged ligands 1,2; DLL, delta-like ligand; CTC, circulating tumor cell; RANK/RANK-L, receptor activator of nuclear factor kappa-B/receptor activator of nuclear factor kappa-B ligand; PECAM-1, the platelet and endothelial cell adhesion molecule-1; CDCP1, CUB domain containing protein 1; TME, tumor microenvironment; mets, metastases; ANGPTL4, angiopoietin-like factor 4; VEGF, vascular endothelial growth factor; SDF1, stromal cell-derived factor 1; CXCL12, C-X-C motif chemokine 12; IGF-1R, insulin-like growth factor receptor 1; MSp/TAMS, macrophage-stimulating protein/tumor-associated macrophages; mTOR, mammalian target of rapamycin; EGFR/ERBB2, epidermal growth factor receptor/receptor tyrosine-protein kinase erbB-2; VEGFR-2, vascular endothelial growth factor receptor 2; TILs PD-1 positive, PD-1-positive tumor infiltrating lymphocytes; VCAM-1, vascular cell adhesion molecule-1; CCR6/CCL20, chemokines.
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