References for this Review were identified through searches of PubMed for articles published from January, 2000, to April, 2013, by use of the terms “immunotherapy”, “cancer vaccine”, “checkpoint inhibitor”, and “lung cancer”. Relevant articles published since 2000 were also identified through searches of the authors' files. Relevant references cited in selected articles were reviewed. Only articles published in English were included.
ReviewLung cancer: potential targets for immunotherapy
Introduction
In 1878, malignant lung tumours represented only 1% of all cancers seen at autopsy; nowadays, they are the leading cause of cancer mortality, with 1·37 million deaths globally each year.1 Adjuvant chemotherapy increases 5-year survival by only 5%, and surgery remains the best option for achieving long-term remission.2 New therapeutic strategies are therefore eagerly awaited. Targeted therapies based on molecular changes in subgroups of lung cancer have already provided some clinical benefit in patients with mutated epidermal growth factor receptor (EGFR) or echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) rearrangement. Immunotherapy that aims to stimulate the immune system is another option for treating cancer, and there has been renewed interest in this approach since 2011, when the US Food and Drug Administration approved ipilimumab for metastatic melanoma3 and sipuleucel-T vaccine for asymptomatic, metastatic, castrate-resistant prostate cancer.4
Section snippets
Molecular and cellular basis of cancer immunotherapy
The immune system consists of an integrated network of cells (eg, lymphocytes, macrophages, dendritic cells, and natural killer cells) that communicate through cell-to-cell contact or through membrane microparticles and various soluble mediators (eg, cytokines and chemokines). Innate immunity, mediated by macrophages, neutrophils, and natural killer cells, usually operates very early during the course of an immune response and involves a limited set of receptors. By contrast, adaptive immunity
Immunosurveillance against NSCLC
Until recently, immuno-oncology has mainly focused on melanoma and renal-cell carcinoma, with NSCLC regarded as non-immunogenic or immunoresistant.6 However, several lines of evidence argue against these assumptions. First, the incidence of NSCLC is higher in recipients of solid organ transplants who are given prolonged immunosuppression7, 8 and in patients with HIV infection.9 Second, a recent meta-analysis of 12 randomised, controlled immunotherapy trials of monoclonal antibody therapy and
Immunoescape and immunosubversion in NSCLC
Chronic lung inflammation (due to chronic bronchitis, or asbestos or tobacco smoke exposure) increases the risk of lung cancer.27 In these conditions, microenvironmental cues recruit myeloid cells that become proinflammatory components of mucosa. For example, smoking increases production of TNFα, interleukin 1, interleukin 6, and interleukin 8 by macrophages, and decreases the release of the anti-inflammatory interleukin 10.28, 29 Proinflammatory cytokines can act as growth factors for tumour
Immunotherapeutic approaches in lung cancer
The immune system can be activated or reactivated to combat cancer via several methods (Figure 1, Figure 2). Some approaches target tumour-specific antigens (using antibody-dependent cell-mediated cytotoxicity, adoptive T-cell transfer, or cancer vaccines), whereas others rely on global activation—ie, preferential stimulation of specific immune cells (T cells or natural killer cells) or reverse immunosuppression to invigorate the endogenous antitumour immune response.
Therapeutic combinations
The tumour microenvironment, and the immune system in particular, has a crucial role in modulating tumour progression and response to therapy. At the same time, therapy affects tumour composition and effector memory T-cell responses. Indicators of an ongoing immune response, such as the composition of tumour-infiltrating lymphocytes, and polymorphisms in genes encoding immune receptors (NKp30, TLR4, P2RX7), are associated with therapeutic outcome.86, 87 Therefore, several anticancer agents,
New prospects
Several approaches with high immunomodulatory potential are being developed in NSCLC or other malignancies.
Conclusions
Despite much effort aimed at developing a vaccine for NSCLC, very few immunisation approaches have led to enough of a clinical benefit to prompt randomised phase 2 or phase 3 trials. This limited success could stem from the fact that tumour-related immunosuppressive cues counteract T-cell activity (as exemplified with the clinical benefit obtained by blocking PD-L1 or PD-1). Further, tumour-rejection antigens resulting from neomutations in high-avidity T-cell receptor triggering (as described
Search strategy and selection criteria
References (125)
- et al.
Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing
Cell
(2012) - et al.
Genomic landscape of non-small cell lung cancer in smokers and never-smokers
Cell
(2012) - et al.
The role of inflammation in the pathogenesis of non-small cell lung cancer
J Thorac Oncol
(2010) - et al.
Epidemiologic perspective on immune-surveillance in cancer
Curr Opin Immunol
(2011) - et al.
Increased IL-17-producing cells correlate with poor survival and lymphangiogenesis in NSCLC patients
Lung Cancer
(2010) - et al.
Tumor-infiltrating Foxp3+ regulatory T cells are correlated with cyclooxygenase-2 expression and are associated with recurrence in resected non-small cell lung cancer
J Thorac Oncol
(2010) - et al.
Adjuvant immunotherapy for non-small cell lung cancer
Cancer Treat Rev
(2012) - et al.
Immunotherapies for non-small-cell lung cancer and mesothelioma
Lancet Oncol
(2012) - et al.
Therapeutic vaccination with TG4010 and first-line chemotherapy in advanced non-small-cell lung cancer: a controlled phase 2B trial
Lancet Oncol
(2011) - et al.
Immunization of NSCLC patients with antigen-pulsed immature autologous dendritic cells
Lung Cancer
(2007)
A CCR4 antagonist combined with vaccines induces antigen-specific CD8+ T cells and tumor immunity against self antigens
Blood
A phase II study of Tg4010 (Mva-Muc1-Il2) in association with chemotherapy in patients with stage III/IV Non-small cell lung cancer
J Thorac Oncol
TLR4 signaling promotes immune escape of human lung cancer cells by inducing immunosuppressive cytokines and apoptosis resistance
Mol Immunol
Anticancer chemotherapy-induced intratumoral recruitment and differentiation of antigen-presenting cells
Immunity
Combining radiotherapy and immunotherapy: a revived partnership
Int J Radiat Oncol Biol Phys
Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas
Int J Radiat Oncol Biol Phys
A short history of lung cancer
Toxicol Sci
Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group
J Clin Oncol
Improved survival with ipilimumab in patients with metastatic melanoma
N Engl J Med
Sipuleucel-T immunotherapy for castration-resistant prostate cancer
N Engl J Med
Neutralizing tumor-promoting chronic inflammation: a magic bullet?
Science
Immunotherapy for lung cancer
J Thorac Oncol
Incidence and risk factors for the development of lung tumors after liver transplantation
Transpl Int
Spectrum of cancer risk among US solid organ transplant recipients
JAMA
Tumor-induced CD8+ T-cell dysfunction in lung cancer patients
Clin Dev Immunol
Strengths and weaknesses of immunotherapy for advanced non-small-cell lung cancer: a meta-analysis of 12 randomized controlled trials
PLoS One
Antitumor cytotoxic T-lymphocyte response in human lung carcinoma: identification of a tumor-associated antigen
Immunol Rev
Characterization of preexisting MAGE-A3-specific CD4+ T cells in cancer patients and healthy individuals and their activation by protein vaccination
J Immunol
Predominant infiltration of macrophages and CD8(+) T Cells in cancer nests is a significant predictor of survival in stage IV nonsmall cell lung cancer
Cancer
Clinical impact of immune microenvironment in stage I lung adenocarcinoma: tumor interleukin-12 receptor beta2 (IL-12Rbeta2), IL-7R, and stromal FoxP3/CD3 ratio are independent predictors of recurrence
J Clin Oncol
Long-term survival for patients with non-small-cell lung cancer with intratumoral lymphoid structures
J Clin Oncol
Expression of multiple epigenetically regulated cancer/germline genes in nonsmall cell lung cancer
Int J Cancer
Simultaneous cellular and humoral immune response against mutated p53 in a patient with lung cancer
J Immunol
The peptide recognized by HLA-A68.2-restricted, squamous cell carcinoma of the lung-specific cytotoxic T lymphocytes is derived from a mutated elongation factor 2 gene
Cancer Res
High frequency of cytolytic T lymphocytes directed against a tumor-specific mutated antigen detectable with HLA tetramers in the blood of a lung carcinoma patient with long survival
Cancer Res
A point mutation in the alpha-actinin-4 gene generates an antigenic peptide recognized by autologous cytolytic T lymphocytes on a human lung carcinoma
Cancer Res
A point mutation in the NFYC gene generates an antigenic peptide recognized by autologous cytolytic T lymphocytes on a human squamous cell lung carcinoma
Int J Cancer
Presence of serum anti-p53 antibodies is associated with pleural effusion and poor prognosis in lung cancer patients
Clin Cancer Res
Serum anti-p53 antibodies and prognosis of patients with small-cell lung cancer
J Natl Cancer Inst
Characteristics and clinical impacts of the immune environments in colorectal and renal cell carcinoma lung metastases: influence of tumor origin
Clin Cancer Res
Better understanding tumor-host interaction in head and neck cancer to improve the design and development of immunotherapeutic strategies
Head Neck
The soluble alpha chain of interleukin-15 receptor: a proinflammatory molecule associated with tumor progression in head and neck cancer
Cancer Res
Interleukin-8/CXCL8 is a growth factor for human lung cancer cells
Br J Cancer
Correlation between interleukin 6 production and tumor proliferation in non-small cell lung cancer
Cancer Immunol Immunother
Epithelial-mesenchymal transition induced by TNF-alpha requires NF-kappaB-mediated transcriptional upregulation of Twist1
Cancer Res
Expression of IL-32 in human lung cancer is related to the histotype and metastatic phenotype
Am J Respir Crit Care Med
Myeloid suppressor cells and immune modulation in lung cancer
Immunotherapy
Haplotype loss of HLA class I antigen as an escape mechanism from immune attack in lung cancer
Cancer Res
Matrix architecture defines the preferential localization and migration of T cells into the stroma of human lung tumors
J Clin Invest
NK cells infiltrating a MHC class I-deficient lung adenocarcinoma display impaired cytotoxic activity toward autologous tumor cells associated with altered NK cell-triggering receptors
J Immunol
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2020, International ImmunopharmacologyCitation Excerpt :In addition to the recognition of tumor-expressed oncogenic proteins, studies on multiple cancer cell-extrinsic regulators in the tumor microenvironment (TME) have reinvigorated enthusiasm in anticancer research [17,18]. Concurrently, quite a few patients with lung cancer have benefited immensely from immune checkpoint inhibitors (ICIs), which target the immune cells that make up the major components of the TME [19–21]. T cell Immunoreceptor with Ig and ITIM domains (TIGIT) is becoming a hotspot of research focus within the immune checkpoint family because of its role in T cell exhaustion when binding to CD155 [22].
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