Development of an Immune-Related Risk Signature for Predicting Prognosis in Lung Squamous Cell Carcinoma

Active, but dysfunctional, immune responses in patients with cancer have been studied in several tumour types, but owing to the heterogeneity of cancer theories of common reaction mechanisms seem to be obsolete. In this Review of published clinical studies of patients with cancer, expression and interplay of the following cytokines are examined: interleukin 2, interleukin 6, interleukin 8, interleukin 10, interleukin 12, interleukin 18, tumour necrosis factor α (TNFα), transforming growth factor β (TGFβ), interferon-γ, HLA-DR, macrophage migration inhibitory factor (MIF), and C-X-C motif chemokine receptor 4 (CXCR4). Clinical data were analysed in a non-quantitative descriptive manner and interpreted with regard to experimentally established physiological cytokine interactions. The clinical cytokine pattern that emerged suggests that simultaneous immunostimulation and immunosuppression occur in patients with cancer, with increased concentrations of the cytokines MIF, TNFα, interleukin 6, interleukin 8, interleukin 10, interleukin 18, and TGFβ. This specific cytokine pattern seems to have a prognostic effect, since high interleukin 6 or interleukin 10 serum concentrations are associated with negative prognoses in independent cancer types. Although immunostimulatory cytokines are involved in local cancer-associated inflammation, cancer cells seem to be protected from immunological eradication by cytokine-mediated local immunosuppression and a resulting defect of the interleukin 12-interferon-γ-HLA-DR axis. Cytokines produced by tumours might have a pivotal role in this defect. A working hypothesis is that the cancer-specific and histology-independent uniform cytokine cascade is one of the manifestations of the underlying paraneoplastic systemic disease, and this hypothesis links the stage of cancer with both the functional status of the immune system and the patient's prognosis. Neutralisation of this cytokine pattern could offer novel and so far unexploited treatment approaches for cancer. Copyright © 2013 Elsevier Ltd. All rights reserved.

A malignant tumor is not merely an accumulation of neoplastic cells, but constitutes a microenvironment containing endothelial cells, fibroblasts, structural components, and infiltrating immune cells that impact tumor development, invasion, metastasis, and outcome. Hence, the evolution of cancers reflects intricate cellular and molecular interactions between tumor cells and constituents of the tumor microenvironment. Recent studies have shed new light on this complex interaction between tumor and host immune cells and the resulting immune response. The composition of the immune microenvironment differs across patients as well as in cancers of the same type, including various populations of T cells, B cells, dendritic cells, natural killer cells, myeloid-derived suppressor cells, neutrophils, and macrophages. The type, density, location, and organization of immune cells within solid tumors define the immune contexture, which has proved to be a major determinant of tumor characteristics and patient outcome. Lung cancer consists mostly of non-small cell lung cancer (85%); it is our most deadly malignant disease, with the 5-year survival rate being merely 15%. This review focuses on the immune contexture; the tumor-suppressing roles of tumor-infiltrating lymphocytes; and the relevance of this immune contexture for cancer diagnostics, prognostication, and treatment allocation, with an emphasis on non-small cell lung cancer.

Background TP53 mutation is the most common mutation in hepatocellular carcinoma (HCC), and it affects the progression and prognosis of HCC. We investigated how TP53 mutation regulates the HCC immunophenotype and thus affects the prognosis of HCC. Methods We investigated TP53 mutation status and RNA expression in different populations and platforms and developed an immune prognostic model (IPM) based on immune-related genes that were differentially expressed between TP53WT and TP53MUT HCC samples. Then, the influence of the IPM on the immune microenvironment in HCC was comprehensively analysed. Findings TP53 mutation resulted in the downregulation of the immune response in HCC. Thirty-seven of the 312 immune response-related genes were differentially expressed based on TP53 mutation status. An IPM was established and validated based on 865 patients with HCC to differentiate patients with a low or high risk of poor survival. A nomogram was also established for clinical application. Functional enrichment analysis showed that the humoral immune response and immune system diseases pathway represented the major function and pathway, respectively, related to the IPM genes. Moreover, we found that the patients in the high-risk group had higher fractions of T cells follicular helper, T cells regulatory (Tregs) and macrophages M0 and presented higher expression of CTLA-4, PD-1 and TIM-3 than the low-risk group. Interpretation TP53 mutation is strongly related to the immune microenvironment in HCC. Our IPM, which is sensitive to TP53 mutation status, may have important implications for identifying subgroups of HCC patients with low or high risk of unfavourable survival. Fund This work was supported by the International Science and Technology Cooperation Projects (2016YFE0107100), the Capital Special Research Project for Health Development (2014-2-4012), the Beijing Natural Science Foundation (L172055 and 7192158), the National Ten Thousand Talent Program, the Fundamental Research Funds for the Central Universities (3332018032), and the CAMS Innovation Fund for Medical Science (CIFMS) (2017-I2M-4-003 and 2018-I2M-3-001).