<p>M2 macrophage infiltration into tumor islets leads to poor prognosis in non-small-cell lung cancer</p>

Abstract

These authors contributed equally to this workBackground: Lung cancer is the leading cause of cancer-related death worldwide. Although the macrophages can affect the development of tumor, the contribution of macrophages to the prognosis of non-small-cell lung cancer (NSCLC) is still controversial. Moreover, anti-PD-1 therapy can redirect macrophages from an M2 to an M1 phenotype, suggesting that tumor PD-L1 may affect the prognostic role of macrophages. Therefore, in this study, we aimed to display a macrophage landscape to clarify the function of macrophages, considering the localization and polarization of the macrophages, and evaluate the effect of M2 macrophages and tumor PD-L1 in combination on the prognosis of NSCLC. Methods: We performed multiplex quantitative immunofluorescence staining of pan-cytokeratin (CK), CD68, CD163, PD-L1, and DAPI on one tissue specimen simultaneously from 137 NSCLC patients. Results: M2 macrophages, involved marginM2 (M2 macrophages in tumor stroma), and centralM2 (M2 macrophages infiltrating into tumor islets) increased as the tumor stage increased. More macrophages were found in lung squamous cell carcinoma (LUSC) patients, patients with wild-type EGFR, and smokers than in patients with lung adenocarcinoma (LUAD), patients with EGFR mutations, and non-smokers. Infiltration of centralM2 was an independent prognostic factor of poor overall survival (OS) and disease-free survival (DFS) for NSCLC patients (P<0.05), which was superior to total macrophages and total M2 macrophages. Moreover, patients with centralM2 less PD-L1 − tumors showed the best OS and DFS, while the patients with centralM2 more PD-L1 + tumors showed the worst OS and DFS, and the two groups with centralM2 less PD-L1 + and centralM2 more PD-L1 − were in the middle (P=0.002, 0.034, respectively). Conclusion: Tumor islet-infiltrating M2 macrophages influence the prognosis of NSCLC patients. The analysis of M2 macrophages and tumor PD-L1 in combination may enhance the accuracy of prognostic prediction. This study provides a new understanding of macrophages in the development of NSCLC through the analysis of macrophage landscape.

Functional and mechanistic advantage of the use of a bifunctional anti-PD-L1/IL-15 superagonist

“…Regardless, the reduction in intratumoral T reg , M2-like macrophages and M-MDSC could support N-809 efficacy, as the presence of these cell populations is associated with worse effector responses and prognosis. [48][49][50] ConClusIons For the first time, we demonstrate that a bifunctional molecule targeting PD-L1 and IL-15 induces significant tumor control in multiple murine carcinoma models resistant to N-803 or αPD-L1 monotherapy. N-809 functions by increasing intratumoral NK and CD8 + T cells, most likely through migration of peripherally activated cells into the TME, not in situ proliferation.…”

Macrophage and Tumor Cell Cross-Talk Is Fundamental for Lung Tumor Progression: We Need to Talk

“…Currently, there is no consensus in the literature on whether the high density of macrophages is detrimental or beneficial in lung cancer, while few recent reports demonstrated the correlation between prognosis and patient survival with the density of particular phenotype of macrophages. The prolonged patient survival correlated with a high density of M1 macrophages, while poor prognosis correlated with a high density of M2 macrophages in tumor islets (14)(15)(16)(17)(18)(19). Evidences suggest that cytokines secreted by TAMs induce hyperproliferative, anti-apoptotic, and metastatic responses in lung cancer, offering a potential immunotherapeutic option for its treatment (20)(21)(22).…”

NK cells and CTLs are required to clear solid tumor in a novel model of patient-derived-xenograft

“…Immune suppressive cells, e.g., myeloid derived suppressor cells (MDSC) (20), M2 macrophages (21,22), and regulatory T cells (Tregs) (23), inhibit CTL-and NK cell-effector function in solid tumors (24) via the expression of inhibitory ligands, suppressive cytokines, and tumor-promoting factors (25). Indeed, the abundance of MDSC and Tregs in solid tumors positively correlate with advanced disease and increased tumor burden (26)(27)(28), and are independent predictors of poor outcome (29-32). Concurrently, pharmacological targeting of MDSC and Tregs in animal models and clinics significantly improves anti-tumor immunity enabling tumor control (33,34).…”