Review
Lung cancer: potential targets for immunotherapy

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Summary

Lung cancer is the most common cause of cancer-related mortality worldwide and a therapeutic challenge. Recent success with antibodies blocking immune checkpoints in non-small-cell lung cancers (NSCLC) highlights the potential of immunotherapy for lung cancer treatment, and the need for trials of combination regimens of immunotherapy plus chemotherapy that lead to immunogenic cell death. Here, we review the development of immunogenic cytotoxic compounds, vaccines, and antibodies in NSCLC, in view of their integration into personalised oncology.

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 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.

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