Mechanisms of immune evasion and current status of checkpoint inhibitors in non-small cell lung cancer

Angel Qin, David G Coffey, Edus H Warren, Nithya Ramnath, Angel Qin, David G Coffey, Edus H Warren, Nithya Ramnath

Abstract

In the past several years, immunotherapy has emerged as a viable treatment option for patients with advanced non-small cell lung cancer (NSCLC) without actionable driver mutations that have progressed on standard chemotherapy. We are also beginning to understand the methods of immune evasion employed by NSCLC which likely contribute to the 20% response rate to immunotherapy. It is also yet unclear what tumor or patient factors predict response to immunotherapy. The objectives of this review are (1) review the immunogenicity of NSCLC (2) describe the mechanisms of immune evasion (3) summarize efforts to target the anti-program death-1 (PD-1) and anti-program death-ligand 1(PD-L1) pathway (4) outline determinants of response to PD-1/PD-L1 therapy and (5) discuss potential future areas for research.

Keywords: Determinants of response; PD-1; PD-L1; immune evasion; non-small cell lung cancer.

© 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Figures

Figure 1
Figure 1
Top panel (A) depicts the active antitumor immune response and the interactions within the tumor microenvironment that lead to tumor cell apoptosis. Tumor antigen presentation by APCs stimulates activation of CD8+ CTLs through interaction of MHCI/TCR and B7/CD28; in turn, this leads to activation of pathways involved in CTL proliferation and IL‐2 production. The APCs also stimulate proliferation of T helper (Th) cells that secrete activating cytokines such as TNFα and IL‐2 which further promote CTL activation and proliferation. CTLs ultimately secrete cytotoxic granules that result in tumor cell death. As a countermeasure, the tumor cells secrete cytokines such as TGFβ and IL‐10 that stimulate FOXP3+ Treg proliferation. Tregs play a crucial role in dampening the immune response through inhibition of CTLs and Th cells. Bottom panel (B) depicts breakdown of the immune response through various evasive mechanisms employed by tumor cells that lead to tumor progression. Alterations of the MHCI and downregulation of TAP1 by tobacco smoke hinder APC function. FOXP3+ Tregs bind to activating cytokines such as IL‐2, thereby limiting CTL proliferation and activation. An increased density of FOXP3+ Treg cells and decreased CTLs is thought to contribute to tumor cell proliferation. APC, antigen presenting cells; CTL, cytotoxic T lymphocyte; TNF, tumor necrosis factor.

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