COPD and squamous cell lung cancer: Aberrant inflammation and immunity is the common link

Cigarette smoking has reached epidemic proportions within many regions of the world and remains the highest risk factor for Chronic Obstructive Pulmonary Disease (COPD) and lung cancer. Squamous cell lung cancer (SCC) is commonly detected in heavy smokers, where risk of developing lung cancer is not solely defined by tobacco consumption. Although therapies that target common driver mutations in adenocarcinomas are showing some promise, they are proving ineffective in smoking-related SCC. Since COPD is characterised by an excessive inflammatory and oxidative stress response, this review details how aberrant innate, adaptive and systemic inflammatory processes can contribute to lung cancer susceptibility in COPD. Activated leukocytes release increasing levels of proteases and free radicals as COPD progresses and tertiary lymphoid aggregates accumulate with increasing severity. Reactive oxygen species promote formation of reactive carbonyls that are not only tumorigenic through initiating DNA damage, but can directly alter the function of regulatory proteins involved in host immunity and tumor suppressor functions. Systemic inflammation is also markedly increased during infective exacerbations in COPD and the interplay between tumor-promoting Serum Amyloid A (SAA) and Interleukin-17A are discussed. SAA is also an endogenous allosteric modifier of the FPR2 receptor expressed on immune and epithelial cells, and the therapeutic potential of targeting this receptor is proposed as a novel strategy for COPD-lung cancer overlap.