Sci Rep

Sci Rep. were divided into two groups according to CD47 expression (high or low), using a cutoff value of 150. High CD47 expression was associated with wood smoke exposure (71.1% vs 28.9%, em P /em ?=?.013) and presence of EGFR (+) mutations (66.7% vs 33.3%, em P /em ?=?.04). Survival analysis carried out in the whole population did not show any association of CD47 expression and survival outcome. However, in patients with EGFR (+) mutations, CD47 expression was associated with higher progression\free survival (PFS) (12.2 vs. 4.4?months, em P /em ?=?.032). When the survival analysis was performed according to CD47 levels (cut off value: 150), both, PFS and overall survival (OS) were shortened in patients with a high expression of CD47 (10.7 vs. NR, em P /em ?=?.156) and (29.2 vs. NR months em P /em ?=?.023), respectively. Conclusions CD47 overexpression is not a prognostic factor for PFS and OS in NSCLC patients. However, the presence of EGFR mutations and high expression of CD47 were associated with shortened PFS and OS. Coexpression of these markers represents a potential biomarker and characterizes a therapeutic niche for lung cancer. strong class=”kwd-title” Keywords: CD47, EGFR, immune checkpoint, lung adenocarcinoma, phagocytosis Abstract High CD47 expression was found in NSCLC patients harboring EGFR mutation and correlated with a worsened clinical outcome based on a low progression free\survival. 1.?INTRODUCTION Lung cancer (LC) remains the leading cause of cancer\related deaths worldwide, with approximately 2.5?million new cases and 1.5?million deaths per year.1 Non\Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all cases with less than 21% of overall survival (OS) rate to 5?years.2 Development of targeted therapy and immunotherapy has revolutionized NSCLC treatment. Molecular alterations of EGFR and Polyphyllin A ALK, and development of tyrosine kinase inhibitors (TKIs) have improved the response rate and OS in NSCLC patients.3, 4 However, less than 20% are candidates receive TKI\based therapy, so the prognosis for patients with advanced NSCLC remains poor.5, 6 Tumor development is a process that involves an interplay between cancer cells, normal stroma and defense system.7 The equilibrium between the immune system and tumor cells is disrupted during carcinogenesis, conferring to tumors the capacity to escape from host immune elimination through an immune editing process.7, 8 Incorporation of immune checkpoint inhibitors (ICIs) against T\lymphocyte\associated antigen 4 (CTL\4), programmed cell death 1 (PD\1) and PD\1 ligand (PDL\1), represents an option for treatment in NSCLC patients without druggable genetic alterations.8 Despite the fact that patients treated Rabbit Polyclonal to TNFAIP8L2 with ICIs show durable responses and an increase of median OS, a portion of them do not respond and others progress during treatment.9 Macrophage targeting opens Polyphyllin A new possibilities for cancer immunotherapy, and tumor\associated macrophages (TAMs) and plays a fundamental role in the maintenance of a suppressive tumor microenvironment. TAMs have emerged as potential targets Polyphyllin A of immunotherapy, because they promote activation and elimination of tumor cells Polyphyllin A through phagocytosis 10 Cluster of differentiation 47 (CD47) is a receptor ubiquitously expressed in normal cells that regulates phagocytosis.11 Inhibition of phagocytosis occurs when CD47 binds to signal regulatory protein alpha (SIRP) expressed on the macrophage surface.12, 13 CD47 overexpression is associated with growth and progression in various cancer types such as non\Hodgkin’s lymphoma, gastric, colorectal, bladder, breast cancer and NSCLC.14, 15, 16 We have previously reported that CD47 overexpression in whole\blood samples from NSCLC patients is associated with poor OS, and its expression on neutrophil surface prevents apoptosis and phagocytic clearance of these cells.14 Use of anti\CD47 antibodies for treatment of non\Hodgkin lymphoma, breast, bladder, and ovarian carcinomas has shown promising results.12, 17, 18, 19, 20 However, data regarding CD47 expression and its potential relation with clinical outcomes in lung cancer patients remain limited. In this study, we determined CD47 expression by immunohistochemistry and its relation with clinical characteristics, genetic alterations and survival outcomes. 2.?MATERIALS AND METHODS 2.1. Patients and study design This is a retrospective study; we analyzed the collected tissue biopsies, and clinical data from 169 NSCLC patients from the Instituto Nacional de Cancerologa (INCan) between March 2012 and September 2016. Patients were included according to the following criteria: 18?years of age, high stage (IIIb or IV), histology confirmation of NSCLC, Eastern Cooperative Oncology Group Performance Status (ECOG PS) 2. Patients were eligible to receive platinum\based chemotherapy or TKIs (Erlotinib or Gefitinib) according to EGFR status. Clinical and pathological characteristics were collected from medical records. All procedures complied with the ethical standards of the Institutional Review Board as well as the Ethical Committee of INCan (011/018/ICI\CV/683) and the Helsinki Declaration of 1975. 2.2. Immunohistochemistry and CD47 H\score Briefly, tissue sections of formalin\fixed paraffin\embedded (FFPE) samples (5?m) were deparaffinized, blocked for endogenous peroxidase activity with hydrogen peroxide. Antigen retrieval was performed with immune heat\DNA retriever citrate (cat # BSB 0023,.