Targeting the Complement Pathway as a Therapeutic Strategy in Lung Cancer

Abstract

Lung cancer is the leading cause of cancer death in men and women. Lung adenocarcinoma (LUAD), represents approximately 40% of all lung cancer cases. Advances in recent years, such as the identification of oncogenes and the use of immunotherapies, have changed the treatment of LUAD. Yet survival rates still remain low. Additionally, there is still a gap in understanding the molecular and cellular interactions between cancer cells and the immune tumor microenvironment (TME). Defining how cancer cells with distinct oncogenic drivers interact with the TME and new strategies for enhancing anti-tumor immunity are greatly needed. The complement cascade, a central part of the innate immune system, plays an important role in regulation of adaptive immunity. Initially it was proposed that complement activation on the surface of cancer cells would inhibit cancer progression via membrane attack complex (MAC)-dependent killing. However, data from several groups have shown that complement activation promotes cancer progression, probably through the actions of anaphylatoxins (C3a and C5a) on the TME and engagement of immunoevasive pathways. While originally shown to be produced in the liver, recent studies show localized complement production in numerous cell types including immune cells and tumor cells. These results suggest that complement inhibitory drugs may represent a powerful new approach for treatment of NSCLC, and numerous new anti-complement drugs are in clinical development. However, the mechanisms by which complement is activated and affects tumor progression are not well understood. Furthermore, the role of local complement production vs. systemic activation has not been carefully examined. This review will focus on our current understanding of complement action in LUAD, and describe gaps in our knowledge critical for advancing complement therapy into the clinic.

STRIP2, a member of the striatin‐interacting phosphatase and kinase complex, is implicated in lung adenocarcinoma cell growth and migration

“…Although bronchoscopy and computed tomography are often used to diagnose lung cancer and LUAD, these methods have certain limitations . The low detection rate of LUAD in early stage is the main barrier to the recovery of patients . Although cancer treatment has made some progress, especially in immunotherapy and molecular‐targeted therapy, the prognosis of patients with LUAD is still poor, and its 5‐year relative survival rate is no more than 1% .…”

Transcriptomic learning for digital pathology

“…Similarly, another four genes, NKG7 , ARHGAP9 , C1QA and CD53 were accurately predicted among 15/28 datasets ( R ranging from 0.38 to 0.46 for the various cancer types). CQ1 (A and B) are proteins of the complement known to be involved in T-cell activation following antigen presentation by antigen presenting cells (APC) 36 , whereas CD53 37 and NKG7 38 are known to be expressed by T and NK cells respectively.…”

Protein profiling reveals the characteristic changes of complement cascade pathway in the tissues of gastric signet ring cell carcinoma

“…Although the implications of complement cascade are incomplete and naive, its importance in host immune system has attracted studies related to a wide range of diseases. As pointed out by Kleczko et al 45 , therapies targeting complement cascade had already been experimented against immune system related diseases like rheumatoid arthritis and age-related macular degeneration. Judged by the quantitative proteomes profiled by the present study, it was assumed that the evading of complement induced cell death by up-tuning the complement negative regulators was an significant characteristic of SRCC, and targeting the CRPs might be an effective approach to inhibit SRCC.…”