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.

Keywords: complement-immunological terms; immunotherapy; lung cancer; microenvironment; oncogene.

Figure 1

Common driver mutations in lung cancer. Lung cancers have historically been subdivided into either small cell lung cancer (SCLC), or non-small cell lung cancer (NSCLC). Small cell lung cancer has few oncogenic driver mutations; here are listed the most frequently identified genetic mutations in SCLC (Left). NSCLC can further be subdivided into squamous cell lung carcinoma (SCC), or lung adenocarcinoma (LUAD). Multiple oncogenic drivers have been identified in LUAD (Right); for many of these targeted therapies have been developed. For SCC (Middle), there are fewer identified oncogenic drivers, and no targeted therapies have been approved.

Figure 2

The complement pathway. A schematic of the complement signaling pathway where all 3 pathways (classical, lectin, and alternative) converge on C3. The red, bolded inhibitory signs indicate points in the complement signaling cascade where pharmacologic inhibitors can be used to alter signaling within cells, while the red, unbolded inhibitory sign indicates regulatory proteins in the complement cascade.

Figure 3

Local complement signaling in tumors. A schematic of complement signaling that occurs within tumors. Systemic complement is produced by the liver and travels via the blood to distant sites. While locally, within a tumor, tumor cells, T cells, and endothelial cells can all produce complement that acts either in an autocrine or paracrine fashion.