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      Cell death-based treatment of lung adenocarcinoma

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          Abstract

          The most common type of lung cancer is adenocarcinoma (ADC), comprising around 40% of all lung cancer cases. In spite of achievements in understanding the pathogenesis of this disease and the development of new approaches in its treatment, unfortunately, lung ADC is still one of the most aggressive and rapidly fatal tumor types with overall survival less than 5 years. Lung ADC is often diagnosed at advanced stages involving disseminated metastatic tumors. This is particularly important for the successful development of new approaches in cancer therapy. The high resistance of lung ADC to conventional radiotherapies and chemotherapies represents a major challenge for treatment effectiveness. Here we discuss recent advances in understanding the molecular pathways driving tumor progression and related targeted therapies in lung ADCs. In addition, the cell death mechanisms induced by different treatment strategies and their contribution to therapy resistance are analyzed. The focus is on approaches to overcoming drug resistance in order to improve future treatment decisions.

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          The blockade of immune checkpoints in cancer immunotherapy.

          Drew M Pardoll (2012)
          Among the most promising approaches to activating therapeutic antitumour immunity is the blockade of immune checkpoints. Immune checkpoints refer to a plethora of inhibitory pathways hardwired into the immune system that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. It is now clear that tumours co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumour antigens. Because many of the immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies or modulated by recombinant forms of ligands or receptors. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibodies were the first of this class of immunotherapeutics to achieve US Food and Drug Administration (FDA) approval. Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.
          Article 0 comments Cited 5137 times – based on 0 reviews     Review now
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            PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors.

            Michael Curran, Welby Montalvo, Hideo Yagita … (2010)
            Vaccination with irradiated B16 melanoma cells expressing either GM-CSF (Gvax) or Flt3-ligand (Fvax) combined with antibody blockade of the negative T-cell costimulatory receptor cytotoxic T-lymphocyte antigen-4 (CTLA-4) promotes rejection of preimplanted tumors. Despite CTLA-4 blockade, T-cell proliferation and cytokine production can be inhibited by the interaction of programmed death-1 (PD-1) with its ligands PD-L1 and PD-L2 or by the interaction of PD-L1 with B7-1. Here, we show that the combination of CTLA-4 and PD-1 blockade is more than twice as effective as either alone in promoting the rejection of B16 melanomas in conjunction with Fvax. Adding alphaPD-L1 to this regimen results in rejection of 65% of preimplanted tumors vs. 10% with CTLA-4 blockade alone. Combination PD-1 and CTLA-4 blockade increases effector T-cell (Teff) infiltration, resulting in highly advantageous Teff-to-regulatory T-cell ratios with the tumor. The fraction of tumor-infiltrating Teffs expressing CTLA-4 and PD-1 increases, reflecting the proliferation and accumulation of cells that would otherwise be anergized. Combination blockade also synergistically increases Teff-to-myeloid-derived suppressor cell ratios within B16 melanomas. IFN-gamma production increases in both the tumor and vaccine draining lymph nodes, as does the frequency of IFN-gamma/TNF-alpha double-producing CD8(+) T cells within the tumor. These results suggest that combination blockade of the PD-1/PD-L1- and CTLA-4-negative costimulatory pathways allows tumor-specific T cells that would otherwise be inactivated to continue to expand and carry out effector functions, thereby shifting the tumor microenvironment from suppressive to inflammatory.
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              Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK.

              Alice Shaw, Beow Yeap, Mari Mino-Kenudson … (2009)
              The EML4-ALK fusion oncogene represents a novel molecular target in a small subset of non-small-cell lung cancers (NSCLC). To aid in identification and treatment of these patients, we examined the clinical characteristics and treatment outcomes of patients who had NSCLC with and without EML4-ALK. Patients with NSCLC were selected for genetic screening on the basis of two or more of the following characteristics: female sex, Asian ethnicity, never/light smoking history, and adenocarcinoma histology. EML4-ALK was identified by using fluorescent in situ hybridization for ALK rearrangements and was confirmed by immunohistochemistry for ALK expression. EGFR and KRAS mutations were determined by DNA sequencing. Of 141 tumors screened, 19 (13%) were EML4-ALK mutant, 31 (22%) were EGFR mutant, and 91 (65%) were wild type (WT/WT) for both ALK and EGFR. Compared with the EGFR mutant and WT/WT cohorts, patients with EML4-ALK mutant tumors were significantly younger (P < .001 and P = .005) and were more likely to be men (P = .036 and P = .039). Patients with EML4-ALK-positive tumors, like patients who harbored EGFR mutations, also were more likely to be never/light smokers compared with patients in the WT/WT cohort (P < .001). Eighteen of the 19 EML4-ALK tumors were adenocarcinomas, predominantly the signet ring cell subtype. Among patients with metastatic disease, EML4-ALK positivity was associated with resistance to EGFR tyrosine kinase inhibitors (TKIs). Patients in the EML4-ALK cohort and the WT/WT cohort showed similar response rates to platinum-based combination chemotherapy and no difference in overall survival. EML4-ALK defines a molecular subset of NSCLC with distinct clinical characteristics. Patients who harbor this mutation do not benefit from EGFR TKIs and should be directed to trials of ALK-targeted agents.
              Article 0 comments Cited 536 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Boris Zhivotovsky: +46 8 5248 7588 , Boris.Zhivotovsky@ki.se
                Journal
                Journal ID (nlm-ta): Cell Death Dis
                Journal ID (iso-abbrev): Cell Death Dis
                Title: Cell Death & Disease
                Publisher: Nature Publishing Group UK (London )
                ISSN (Electronic): 2041-4889
                Publication date (Electronic): 25 January 2018
                Publication date PMC-release: 25 January 2018
                Publication date Collection: February 2018
                Volume: 9
                Issue: 2
                Electronic Location Identifier: 117
                Affiliations
                [1 ]ISNI 0000 0001 2342 9668, GRID grid.14476.30, Faculty of Medicine, , MV Lomonosov Moscow State University, ; 119991 Moscow, Russia
                [2 ]ISNI 0000 0004 1937 0626, GRID grid.4714.6, Institute of Environmental Medicine, Division of Toxicology, , Karolinska Institutet, ; Box 210, Stockholm, SE-171 77 Sweden
                Article
                Publisher ID: 63
                DOI: 10.1038/s41419-017-0063-y
                PMC ID: 5833343
                PubMed ID: 29371589
                SO-VID: caf0e226-cd0b-43c2-bd30-35a02973c3c3
                Copyright © © The Author(s) 2018
                License:

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                Date received : 27 July 2017
                Date revision received : 18 August 2017
                Date accepted : 13 September 2017
                Categories
                Subject: Review Article
                Custom metadata
                issue-copyright-statement © The Author(s) 2018

                ScienceOpen disciplines: Cell biology
                Data availability:
                ScienceOpen disciplines: Cell biology

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