Lung cancer is the leading cause of cancer death in both men and women, and overall survival has not significantly improved over the last 25 years for the majority of patients. Evasion from immune attack is a hallmark of cancer and is mediated by interactions between cancer cells and the tumor microenvironment (TME). Established tumors, including lung cancer, adopt a variety of strategies to block immune attack, and targeting these pathways has shown promise as a therapeutic approach. While less studied, it is also likely that immunoevasion is critical for tumor initiation. The complement system is a component of the innate immune system, which interfaces with the adaptive immune system. Complement activation occurs through three major pathways: the classical, the alternative and the lectin pathway. All of these trigger a series of proteolytic cascades that converge in the covalent fixation of C3b to the surface of target cells. Deposited C3b leads to formation of the C5 convertase, which cleaves C5 to produce C5a and ultimately the formation of C5b- 9, designated the membrane attack complex (MAC), which can cause lysis of target cells. C3a and C5a (anaphylatoxins), byproducts of complement activation, are inflammatory mediators that bind to receptors on multiple cells of the TME. Initially it was proposed that activation of complement initiated by antibody binding to cancer cells would inhibit cancer by MAC-dependent killing of cancer cells. However, recent studies by our group and others have shown that anaphylatoxins (C3a/C5a), promote cancer progression by acting on the TME to engage immunoevasive pathways. Using a novel orthotopic immunocompetent model of non-small cell lung cancer (NSCLC), we have shown that complement is activated in lung tumors, and inhibiting complement either genetically or pharmacologically blocks tumor progression. However, how complement is activated and how it regulates tumor progression are not well understood. This project will answer these questions using relevant models of lung cancer initiation and progression with distinct oncogenic drivers. The central premise of this application is that activation of complement directly contributes to lung cancer initiation and progression through direct effects on innate immune cells leading to immunosuppression. The MPI project is a collaboration between investigators with experience in the biology of lung cancer (Nemenoff) and complement biology (Thurman). We will employ an innovative panel of genetic mouse models, as well as novel methodologies to assess the role of complement in altering the TME.
Three specific aims are proposed.
Aim 1 will identify mechanisms of complement activation in established lung tumors.
Aim 2 will examine the molecular and cellular mechanisms mediated by anaphlyatoxins.
Aim 3 will define the role of complement in tumor initiation. Completion of this project will provide preclinical data for future clinical trials using pharmacological complement modulators which have been developed for other diseases.

Public Health Relevance

This project will examine the role of the complement system, a part of the innate immune system which regulates adaptive immune responses, in mediating lung cancer progression and metastasis. Published data from our group and others support a role for complement activation in the tumor microenvironment in lung tumors leading to generation of inflammatory mediators (anaphylatoxins) which control immunosuppressive pathways. Studies will employ both genetic and pharmacological approaches to define the mechanisms of complement activation and downstream regulation..

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA236222-03
Application #
10053335
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Kuo, Lillian S
Project Start
2018-12-11
Project End
2023-11-30
Budget Start
2020-12-01
Budget End
2021-11-30
Support Year
3
Fiscal Year
2021
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045