# Effects of Complement on the Tumor Microenvironment in Lung Cancer

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2023 · $394,879

## Abstract

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 complemen...

## Key facts

- **NIH application ID:** 10521237
- **Project number:** 5R01CA236222-05
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** RAPHAEL A. NEMENOFF
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $394,879
- **Award type:** 5
- **Project period:** 2018-12-11 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10521237

## Citation

> US National Institutes of Health, RePORTER application 10521237, Effects of Complement on the Tumor Microenvironment in Lung Cancer (5R01CA236222-05). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10521237. Licensed CC0.

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