On Respiratory Health: Are Allergies Protecting You from Lung Cancer?

Over the past five years, there has been a flurry of confusing reports suggesting that allergies can either increase or reduce the risks of lung cancer. This article is intended to clarify this respiratory health issue by describing the underlying mechanism.

A unifying theory is now emerging in the scientific community based on the effect of certain immune and inflammatory cells on tumor growth. In fact, a relationship between cancer and inflammation was first proposed in 30 BC by Aulus Cornelius Celsus, a roman encyclopedist who defined inflammation based on these four criteria:

1. dolor (pain)
2. calor (heat)
3. rubor (redness)
4. tumor (swelling)

What is Inside a Tumor?

Nearly 50% of the cells forming a tumor are non-malignant. They include pericytes, lymphocytes, fibroblasts, natural killer cells, neutrophils and macrophages. The last two cell types have been implicated in tumor growth and pulmonary metastasis. Within the tumor, the secretion of various cytokines maintains a cross-talk between the resident and inflammatory cells, which stimulates cell proliferation and migration.

How Important are these Inflammatory Responses in Lung Cancer?

Neutrophils constitute an important line of defense against infection, as they produce an arsenal of molecules and enzymes with bacterial killing activity. However, excess accumulation of neutrophil elastase (NE) resulting from chronic inflammation is responsible for the lung damage reported in patients with chronic obstructive pulmonary disease (COPD), emphysema and cystic fibrosis. This scientific breakthrough led to the development of a synthetic NE inhibitor: ONO-5046/Sivelestat (ONO Pharmaceuticals).

More recently, NE was also shown to activate epidermal growth factor receptors (EGFRs) which promote the proliferation of resident cells by the release of growth factors (TGF, PDGF, VEGF). The tremendous implications of this finding for lung cancer were demonstrated by a clinical study showing that ONO-5046 completely inhibited pulmonary metastasis. Therefore, the scientific community is now well aware of the pivotal role of neutrophils in lung cancer.

Neutrophil Elastase Inhibitors Prevent Pulmonary Metastasis

Are Asthmatics and COPD Patients More Likely to Develop Lung Cancer?

Since most patients exhibit chronic inflammatory responses to lung infection, the persistent agglomerates of inflammatory cells could set the stage for tumor growth. In 2009, the Environment and Genetics in Lung cancer Etiology (EAGLE) conducted a survey using 4,220 subjects, including healthy subjects, asthmatics and COPD patients. Surprisingly, this study reported opposite effects in their respiratory health and between the two diseases on the incidence of lung cancer. While COPD patients were more at risk, asthma appeared protective, compared to the healthy subjects. This discrepancy may reflect the distinct types of airway inflammation reported for these two diseases. Asthmatic lungs recruit T helper 2 lymphocytes (Th2), mast cells and eosinophils. In contrast, T helper 1 lymphocytes (Th1), neutrophils and macrophages predominate in the lungs of COPD and cystic fibrosis patients. This study suggests that neutrophilic inflammation predisposes to the development of lung cancer.

Neutrophil-Dominant Airway Inflammation Predisposes COPD Patients to the Development of Lung Cancer

Can Inflammatory Responses to Allergen Protect us Against Lung Cancer?

It is important to understand that we all react to the inhalation of allergens by the initiation of an inflammatory response. The sentinel dendritic cells embedded in the airway wall capture an allergen, which triggers their migration to the lymph nodes. Upon arrival, they secrete cytokines which initiate the differentiation of naïve lymphocytes into Th1 or Th2 cells. These cells will direct airway responses toward a Th1-neutrophilic, or a Th2-eosinophilic, type of inflammatory response. In the case of allergic reactions, the Th1/Th2 balance is tilted in favor of Th2 cell-mediated responses, as in the case of allergic asthma. Consequently, individuals constantly challenged by common airborne allergens (house dust mites, pet dander or endotoxin) may suppress tumor growth by keeping low levels of neutrophils in their lungs.

Therapies Including Neutrophil Elastase Inhibitors Could Reduce Lung Damage and the Incidence of Cancer in Patients with COPD or Cystic Fibrosis

Cancer Immunotherapy. Another area of intensive research is the development of therapies aiming to enhance cancer cell recognition and destruction by boosting the activities of natural killer (NK) cells. For instance, Gefitinib is a selective inhibitor of EGFRs on cancer cells which enhances NC cell targeting. This drug is prescribed for advanced stage lung cancer in 64 countries including the US. Also, over 100 vaccine therapies for lung cancer are currently tested in clinical trials to stimulate dendritic cell-mediated NK cell activation, while reducing immunosuppression by regulatory T-cells. For example, Medarex is currently conducting a Clinical Trial Phase II for Ipilumumab, an anti-CTLA-4 antibody which selectively blocks the activity of regulatory T-cells. These success stories are emerging from the recent acknowledgement that cancer is, above all, the result of a deregulated inflammatory response.

Good health is man's most precious possession and this includes our respiratory health. The importance of it in our personal life can't be minimized.

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