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Review
. 2019 Aug 1;25(15):4592-4602.
doi: 10.1158/1078-0432.CCR-18-1538. Epub 2019 Mar 1.

Immunotherapy in Non-Small Cell Lung Cancer: Facts and Hopes

Deborah B Doroshow  1   2 , Miguel F Sanmamed  3   4   5   6 , Katherine Hastings  2 , Katerina Politi  1   2   7 , David L Rimm  1   2   7 , Lieping Chen  3 , Ignacio Melero  4   5   6 , Kurt A Schalper  1   2   7 , Roy S Herbst  8   2
Affiliations
Review

Immunotherapy in Non-Small Cell Lung Cancer: Facts and Hopes

Deborah B Doroshow et al. Clin Cancer Res. .

Abstract

Immune-checkpoint inhibitors (ICI), particularly inhibitors of the PD-1 axis, have altered the management of non-small cell lung cancer (NSCLC) over the last 10 years. First demonstrated to improve outcomes in second-line or later therapy of advanced disease, ICIs were shown to improve overall survival compared with chemotherapy in first-line therapy for patients whose tumors express PD-L1 on at least 50% of cells. More recently, combining ICIs with chemotherapy has been shown to improve survival in patients with both squamous and nonsquamous NSCLC, regardless of PD-L1 expression. However, PD-L1 and, more recently, tumor mutational burden have not proven to be straightforward indicative biomarkers. We describe the advances to date in utilizing these biomarkers, as well as novel markers of tumor inflammation, to ascertain which patients are most likely to benefit from ICIs. Ongoing translational work promises to improve the proportion of patients who benefit from these agents.

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Figures

Figure 1:
Figure 1:
Tumor Immune Microenvironment (TIME) classification. Four different molecular groups according to B7–H1 (PD-L1) expression (y-axis) and the presence of TILs (x-axis) in tumor biopsies: (1) B7–H1-negative tumors without TILs, considered immunologically ignorant because immune cells do not accumulate at the tumor site; (2) PD-L1-positive tumors with TILs, considered a paradigm of adaptive resistance of tumors mediated by the PD-1 pathway, (3) PD-L1-negative tumors with TILs, characterized by tolerance because TILs are present, but do not produce IFN-γ to induce PD-L1 expression in the tumor microenvironment, and (4) PD-L1-positive tumors without TILs, which result intrinsic induction of PD-L1 expression in tumor cells through a variety of oncogenic pathways. Abbreviations: PD-1, programmed death-1; B7–H1, B7-homolog 1; TCR, T cell receptor; TIL, tumor infiltrating lymphocyte.
Fig 2.
Fig 2.. Immune-scape mechanisms in NSCLC and new Immune Target opportunities.
Different immune-scape mechanism developed by lung tumors (brown) and available immunotherapies targeting these mechanisms (green) to stimulate an antitumor immune response. 1) antigen uptake and processing by antigen-presenting cells (APC); 2) migration of APCs to lymphoid organs; 3) antigen presentation, activation and co-stimulatory and co-inhibitory regulation of naïve T cells to become effector T cells in lymphoid organs; 4) exit of effector T cells into peripheral blood and trafficking to tumor tissues; 5) tumor antigen recognition and tumor lysis. Targets include IL-8,1,2 VISTA/PD-1H,3 B7–H4,4 B7–H3,5 IDO-1,4 LAG-3,6 HLA class I,7 and tumor-specific neoantigens.8 Abbreviations: IL-8, interleukin-8; VISTA, V-domain Ig suppressor of T cell activation; PD-1H, programmed death-1 homolog; B7–H4, B7-homolog 4; B7–H3, B7-homolog 3; IDO-1, indoleamine 2,3-dioxygenase-1; LAG-3, lymphocyte-activation gene 3; HLA, human leukocyte antigen.
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