Highlights on immune checkpoint inhibitors in non–small cell lung cancer

Abstract

The treatment of advanced or refractory non-small cell lung cancer has been historically difficult owing to the lack of studies on effective systemic cure. The progress in lung cancer treatment has plateaued, necessitating new options for additional benefits. Immune checkpoint proteins are co-inhibitory factors that can diminish the antigen-specific immune responses by attenuating the regulatory role of cytotoxic T-lymphocyte-associated protein 4, programmed cell death-1, lymphocyte-activation gene 3, and T-cell immunoglobulin mucin-3. The therapeutic strategies targeting immune checkpoints mainly focus on the monoclonal antibody of these regulatory factors, which may facilitate clinical decision making. An enhanced understanding of the drug-resistance mechanisms and the therapeutic efficacy regulation will provide opportunities to improve the clinical outcomes of non-small cell lung cancer patients. Preclinical and clinical trials on these key immune-regulatory agents, which has heralded a new era in immuno-oncology in non-small cell lung cancer treatment, are currently in development. KeywordsNon-small cell lung cancer, immune checkpoint, cytotoxic T-lymphocyte-associated protein 4, programmed cell death-1, programmed cell death ligand-1, tumor immunotherapy Date

Interaction between epidermal growth factor receptor and interleukin‐6 receptor in NSCLC progression

“…[21][22][23][24] IL-6, an important signal stimulating factor in lung cancer immunization, is closely related to the occurrence and poor prognosis of lung cancer. 25 In the current study, we found that the expression of IL-6 and GP130 was significantly high (Table 1) and was associated with poor prognosis in NSCLC ( Figure 2). The IL-6 expression has also been associated with NSCLC tumor size.…”

Immunohistochemical and Image Analysis-Based Study Shows That Several Immune Checkpoints are Co-expressed in Non–Small Cell Lung Carcinoma Tumors

“…It is clear that in NCLC, several immune checkpoint pathways are expressed simultaneously and are correlated as a major mechanism of immune resistance against T cell response. 23,24 Indeed, we showed that MCs can express more than one checkpoint marker at the same time; in this regard, using sequential staining of our markers, we observed 11 simultaneous or unique expression patterns of PD-L1, B7-H3, B7-H4, and IDO-1 by MCs. Furthermore, we identified that PD-L1 þ B7-H3 þ IDO-1 was the most common combination simultaneously expressed by MCs in ADCs and PD-L1 þ B7-H3, and B7-H3 þ B7-H4 were the most common combinations in SCCs, suggesting that lung tumors can use preferentially more than one pathway to evade the immune system.…”

β-Adrenergic Signaling in Mice Housed at Standard Temperatures Suppresses an Effector Phenotype in CD8+ T Cells and Undermines Checkpoint Inhibitor Therapy

“…Consistent with previously published work by Ngiow et al (30), we observed that a decreased frequency of PD-1 + CD8 + TILs corresponded with an increased efficacy of anti-PD-1 therapy. However, to date, definitive data regarding PD-1 expression on CD8 + TILs and how this impacts responses to anti-PD-1 is debatable (6). Moreover, our data regarding PD-1 expression on CD8 + TILs is observational and warrants further investigation to more definitively evaluate if low PD-1 expression on CD8 + TILs in our model is directly linked to increased anti-PD-1 efficacy.…”

“…However, despite remarkable and durable responses, long term control of tumors is achieved in only a fraction of patients. Extensive pre-clinical and clinical studies to identify the differences between responders and nonresponders demonstrate a lack of anti-tumor T cell activity within the tumor microenvironment (TME) of non-responders (3–6). Multiple lines of evidence indicate that checkpoint inhibitors are more effective in combination with treatments that generate a robust CD8 + T cell infiltrate, including radiation (7), chemotherapy (8), and immune activating agents (9).…”

“…Additionally, clinical studies indicate that the immunoscore, a measurement of the functional orientation, density, and location of specific immune cell subsets in the TME, has significant prognostic value (5,10,11). However, understanding underlying mechanisms that could be targeted to improve T cell infiltration remains a challenge (3,6). …”