Tumor-Induced CD8+ T-Cell Dysfunction in Lung Cancer Patients

Abstract

Lung cancer is the leading cause of cancer deaths worldwide and one of the most common types of cancers. The limited success of chemotherapy and radiotherapy regimes have highlighted the need to develop new therapies like antitumor immunotherapy. CD8+ T-cells represent a major arm of the cell-mediated anti-tumor response and a promising target for developing T-cell-based immunotherapies against lung cancer. Lung tumors, however, have been considered to possess poor immunogenicity; even so, lung tumor-specific CD8+ T-cell clones can be established that possess cytotoxicity against autologous tumor cells. This paper will focus on the alterations induced in CD8+ T-cells by lung cancer. Although memory CD8+ T-cells infiltrate lung tumors, in both tumor-infiltrating lymphocytes (TILs) and malignant pleural effusions, these cells are dysfunctional and the effector subset is reduced. We propose that chronic presence of lung tumors induces dysfunctions in CD8+ T-cells and sensitizes them to activation-induced cell death, which may be associated with the poor clinical responses observed in immunotherapeutic trials. Getting a deeper knowledge of the evasion mechanisms lung cancer induce in CD8+ T-cells should lead to further understanding of lung cancer biology, overcome tumor evasion mechanisms, and design improved immunotherapeutic treatments for lung cancer.

The Non–Small Cell Lung Cancer Immune Contexture. A Major Determinant of Tumor Characteristics and Patient Outcome

“…Although it is difficult to provide proper proof of immunosurveillance in humans (21), a large body of evidence supports the idea that developing cancers are not ignored by the immune system. Evidence for immunosurveillance of lung cancer can be found in patients with HIV infection who have an increased frequency of virally induced malignancies (22,23), and in immunosuppressed organ transplant recipients who have a higher risk of developing NSCLC (24). Further support of immunosurveillance in NSCLC can be found in studies that have demonstrated the ability of the immune system to spontaneously recognize tumor-associated antigens (TAAs) (25).…”

“…It has been demonstrated that many effector immune cells are anergic and have reduced functions in the lung tumor microenvironment (23,31). In addition, lung tumor cells may induce a loss or down-regulation of HLA class I molecules during tumor progression, modulating the susceptibility of tumor cells to lysis by cytotoxic CD8…”

Targeting miR-23a in CD8+ cytotoxic T lymphocytes prevents tumor-dependent immunosuppression

“…This apparent discrepancy between the in vitro and in vivo functionality of CTLs in ACT is largely attributed to the presence of immunosuppressive barriers within the tumor microenvironment, which are co-opted by tumors to evade the host immune system (8)(9)(10)(11). Of these, TGF-β is a key cytokine during tumor pathogenesis secreted and upregulated by a wide variety of tumors, including melanoma and lung cancer (12)(13)(14)(15).…”

Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer

“…However, as our collective understanding of cancer immunology has evolved, more promising forms of immunotherapy have emerged. In particular, strategies targeting negative regulators (i.e., checkpoints) of the immune system have demonstrated significant antitumor activity across a range of solid tumors, including non‐small cell lung cancer (NSCLC)—a malignancy long considered poorly immunogenic . In recent years, checkpoint inhibitors targeting the programmed cell death protein‐1 (PD‐1)/programmed cell death ligand‐1 (PD‐L1) axis have shown significant antitumor activity in NSCLC .…”