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      Improved Prognostic Prediction in Never-Smoker Lung Cancer Patients by Integration of a Systemic Inflammation Marker with Tumor Immune Contexture Analysis

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          Abstract

          Almost 25% of lung cancers (LCs) occur in never-smokers. LC inflammatory profile, based on plasma C-reactive protein levels (CRP), predicts mortality, independently by smoking-status. We hypothesized that: CRP could be associated with tumor immune contexture (TIC) in never-smokers and both these two parameters may improve their prognosis. Sixty-eight never-smokers LC patients with high or low CRP were selected. The programmed cell death protein 1 (PD-1) and its ligand (PD-L1), the human leukocyte antigens (HLA-DR and HLA-I), CD8, CD4, CD3, CD33, CD163, and CD68 were evaluated by immunohistochemistry on surgical samples given TIC evaluation. The classification model based on TIC scores was generated by Classification and Regression Tree analysis. Tumor mutational burden was evaluated by targeted next-generation sequencing. Exclusively high CRP (H-CRP) subset showed PD-L1 expression in 35% of LC as well as lower HLA-I and HLA-DR in their stromal cells. CD3, CD4, CD8, HLA-I, HLA-DR tumor cells staining were associated with a “low inflammatory profile” subset. CRP and LC immune profiles drive clinical outcome: 5-year survival 88% against 8% was associated with low and high-risk profiles ( p < 0.0001). Clinical outcome prediction in never-smoker LC patients may be improved by both CRP and tumor immune contexture evaluation.

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          Most cited references15

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          EGFR mutation correlates with uninflamed phenotype and weak immunogenicity, causing impaired response to PD-1 blockade in non-small cell lung cancer.

          Patients with EGFR mutations showed unfavorable response to programmed cell death-1 (PD-1) blockade immunotherapy in non-small cell lung cancer (NSCLC). Yet the underlying association between EGFR mutation and immune resistance remains largely unclear. We performed an integrated analysis of PD-ligand 1(PD-L1)/CD8 expression and mutation profile based on the repository database and resected early-stage NSCLC in Guangdong Lung Cancer Institute (GLCI). Meanwhile, 2 pool-analyses were set to clarify the correlation between EGFR mutation and PD-L1 expression, and the association of EGFR status with response to anti-PD-1/L1 therapy. Pool-analysis of 15 public studies suggested that patients with EGFR mutations had decreased PD-L1 expression (odds ratio: 1.79, 95% CI: 1.10-2.93; P = 0.02). Analysis of The Cancer Genome Atlas (TCGA) and the GCLI cohort confirmed the inverse correlation between EGFR mutation and PD-L1 expression. Furthermore, patients with EGFR mutation showed a lack of T-cell infiltration and shrinking proportion of PD-L1+/CD8+ TIL (P = 0.034). Importantly, patients with EGFR mutations, especially the sensitive subtype, showed a significantly decreased mutation burden, based on analysis of the discovery and validation sets. Finally, a pool-analysis of 4 randomized control trials confirmed that patients with EGFR mutation did not benefit from PD-1/L1 inhibitors (Hazard ratio [HR] = 1.09, P = 0.51) while patients with EGFR wild-type did (HR = 0.73, P < 0.00001). This study provided evidence of a correlation between EGFR mutations and an uninflamed tumor microenvironment with immunological tolerance and weak immunogenicity, which caused an inferior response to PD-1 blockade in NSCLCs.
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            Multi-institutional Oncogenic Driver Mutation Analysis in Lung Adenocarcinoma: The Lung Cancer Mutation Consortium Experience.

            Molecular genetic analyses of lung adenocarcinoma have recently become standard of care for treatment selection. The Lung Cancer Mutation Consortium was formed to enable collaborative multi-institutional analyses of 10 potential oncogenic driver mutations. Technical aspects of testing and clinicopathologic correlations are presented.
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              Increased levels of circulating interleukin 6, interleukin 8, C-reactive protein, and risk of lung cancer.

              Previous studies that were based primarily on small numbers of patients suggested that certain circulating proinflammatory cytokines may be associated with lung cancer; however, large independent studies are lacking. Associations between serum interleukin 6 (IL-6) and interleukin 8 (IL-8) levels and lung cancer were analyzed among 270 case patients and 296 control subjects participating in the National Cancer Institute-Maryland (NCI-MD) case-control study. Results were validated in 532 case patients and 595 control subjects in a nested case-control study within the prospective Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Association with C-reactive protein (CRP), a systemic inflammation biomarker, was also analyzed. Associations between biomarkers and lung cancer were estimated using logistic regression models adjusted for smoking, stage, histology, age, and sex. The 10-year standardized absolute risks of lung cancer were estimated using a weighted Cox regression model. Serum IL-6 and IL-8 levels in the highest quartile were associated with lung cancer in the NCI-MD study (IL-6, odds ratio [OR] = 3.29, 95% confidence interval [CI] = 1.88 to 5.77; IL-8, OR = 2.06, 95% CI = 1.19 to 3.57) and with lung cancer risk in the PLCO study (IL-6, OR = 1.48, 95% CI = 1.04 to 2.10; IL-8, OR = 1.57, 95% CI = 1.10 to 2.24), compared with the lowest quartile. In the PLCO study, increased IL-6 levels were only associated with lung cancer diagnosed within 2 years of blood collection, whereas increased IL-8 levels were associated with lung cancer diagnosed more than 2 years after blood collection (OR = 1.57, 95% CI = 1.15 to 2.13). The 10-year standardized absolute risks of lung cancer in the PLCO study were highest among current smokers with high IL-8 and CRP levels (absolute risk = 8.01%, 95% CI = 5.77% to 11.05%). Although increased levels of both serum IL-6 and IL-8 are associated with lung cancer, only IL-8 levels are associated with lung cancer risk several years before diagnosis. Combination of IL-8 and CRP are more robust biomarkers than either marker alone in predicting subsequent lung cancer.
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                Author and article information

                Journal
                Cancers (Basel)
                Cancers (Basel)
                cancers
                Cancers
                MDPI
                2072-6694
                07 July 2020
                July 2020
                : 12
                : 7
                : 1828
                Affiliations
                [1 ]Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, via Venezian 1, 20133 Milan, Italy; giovanni.centonze@ 123456istitutotumori.mi.it (G.C.); adele.busico@ 123456istitutotumori.mi.it (A.B.); giovanna.garzone@ 123456istitutotumori.mi.it (G.G.); laura.cattaneo@ 123456istitutotumori.mi.it (L.C.); elena.tamborini@ 123456istitutotumori.mi.it (E.T.); federica.perrone@ 123456istitutotumori.mi.it (F.P.); giancarlo.pruneri@ 123456istitutotumori.mi.it (G.P.)
                [2 ]Tumour Genomics Unit, Department of Research, Fondazione IRCCS Istituto Nazionale Tumori, via Venezian 1, 20133 Milan, Italy; mattia.boeri@ 123456istitutotumori.mi.it (M.B.); gabriella.sozzi@ 123456istitutotumori.mi.it (G.S.)
                [3 ]Division of Biostatistics, Epidemiology and Public Health, Department of Statistics and Quantitative Methods, University of Milano-Bicocca, 20126 Milan, Italy; anna.cantarutti@ 123456unimib.it (A.C.); giovanni.corrao@ 123456unimib.it (G.C.)
                [4 ]Thoracic Surgery Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale Tumori, via Venezian 1, 20133 Milan, Italy; paola.suatoni@ 123456istitutotumori.mi.it (P.S.); ugo.pastorino@ 123456istitutotumori.mi.it (U.P.)
                [5 ]Pathology Unit, Clinical Department of Medical, Surgical and Health Sciences, University of Trieste, Ospedale di Cattinara, Strada di Fiume 447, 34149 Trieste, Italy; alessandro.mangogna@ 123456studenti.units.it
                [6 ]Human Tumors Immunobiology Unit, Department of Research, Fondazione IRCCS Istituto Nazionale Tumori, via Venezian 1, 20133 Milan, Italy; andrea.anichini@ 123456istitutotumori.mi.it
                Author notes
                [* ]Correspondence: massimo.milione@ 123456istitutotumori.mi.it ; Tel.: +39-02-2390-3460
                [†]

                These authors contributed equally.

                Author information
                https://orcid.org/0000-0001-7106-3138
                https://orcid.org/0000-0002-3700-780X
                https://orcid.org/0000-0003-2864-7941
                https://orcid.org/0000-0002-5808-0387
                https://orcid.org/0000-0001-7910-1274
                Article
                cancers-12-01828
                10.3390/cancers12071828
                7408913
                32646072
                d6459936-6954-4778-840f-335fc331b8d3
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 28 May 2020
                : 06 July 2020
                Categories
                Article

                never-smokers,inflammation,immune profile
                never-smokers, inflammation, immune profile

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