A smoky immune response in lung cancer patients

Science Spotlight

A smoky immune response in lung cancer patients

From the Houghton lab, Clinical Research Division

Nov. 20, 2017

Chronic Obstructive Pulmonary Disease (COPD), a chronic lung disease characterized by emphysema and/or chronic bronchitis is the third leading cause of death worldwide. More than 20 million Americans suffer from COPD. Among smokers, 20% will develop COPD (read the article). Individuals with COPD have a greater risk of developing Non-Small Cell Lung Cancer (NSCLC). Few immunology studies have investigated the link between these two diseases. In a recent study published in The American Journal of Respiratory and Critical Care Medicine, Dr. McGarry Houghton and lead authors Drs. Nicholas Mark and Julia Kargl (Clinical Research Division) addressed this question by analyzing the immune cell content from NSCLC patients with or without COPD.

The cell composition of lung and tumor tissues obtained from lung tumor resection was assessed by flow cytometry and T cell receptor sequencing. In a first cohort composed of 73 patients, 89% were former or current smokers and among those 61.1% had COPD. Patients with COPD presented increased percentages of CD3+, CD4+ and CD8+ T lymphocytes relative to the smoker individuals without COPD. Ex vivo T cell activation also showed increased differentiation of CD4+ T lymphocytes into Th1 cells. These increases were more significant during the earlier stages of the disease. The non-tumoral tissues (lung parenchyma) of the same group of smokers also presented an increase in T lymphocytes, observed in patients with or without COPD. Increased Th1 differentiation correlated between tumor and lung tissues but was higher in patients with COPD at earlier stages.

As explained by Dr. Mark, “Increased interferon gamma production/Th1 differentiation is seen in many autoimmune inflammatory diseases, such as rheumatoid arthritis, multiple sclerosis, type 1 diabetes, Crohn’s disease, and others. For some of these inflammatory conditions, the degree of IFN-gamma/Th1 mediated inflammation corresponds to disease severity or the rate of disease progression, with greater Th1 differentiation connoting a worse prognosis. Furthermore, since Virchow, we have understood that cancer is more likely to arise at sites of chronic inflammation (2). For example, in the lung, chronic inflammatory conditions such as asbestosis or silicosis are associated with substantial increases in the risk of developing NSCLC or mesothelioma.”

The figure represents in A, the immune phenotyping of resected human lung tissue using flow cytometry demonstrates increased Th1 differentiation; in B, the Comparison of paired lung and tumor samples from the same patient, demonstrate a correlation between lung and tumor Th1 differentiation; in C, the heatmap/correlogram showing that for all cell types, Th1 is the most strongly correlated between paired lung and tumor samples; in D, patients with COPD have prolonged progression free survival after immune checkpoint inhibitor treatment; in E, smoking status also affects progression-free survival.

A. Immune phenotyping of resected human lung tissue using flow cytometry demonstrates increased Th1 differentiation. B. Comparison of paired lung and tumor samples from the same patient, demonstrate a correlation between lung and tumor Th1 differentiation. C. Heatmap/correlogram showing that for all cell types, Th1 is the most strongly correlated between paired lung and tumor samples. D. Patients with COPD have prolonged progression free survival after immune checkpoint inhibitor treatment. E. Smoking status also affects progression-free survival.

Figure provided by Dr. Nicholas Mark

This increase in Th1 differentiation was not observed among the smokers; however, the fraction of CD4+ Th17 lymphocytes was higher. After cessation of smoking, Th17 levels returned to normal. These findings were confirmed in a murine cigarette exposure model. These data suggest a temporal relationship between smoking habits and Th17 differentiation. Targeting of IL-17 as a treatment for COPD and lung cancer was proposed in previous studies, however in light of these results, anti-IL-17 therapy would probably be irrelevant in former smokers.

These results raise the question of whether Th1 increase influences the response to immune checkpoint inhibitors (ICI). To address this interrogation, a second cohort of patients with advanced stage NSCLC who received anti-PD-1 or PD-L1 therapy was examined retrospectively. In many types of cancer, the PD-1 receptor when engaged by its PD-L1 ligand is responsible for suppression of immune responses to tumors. Greater progression-free survival following anti-PD-1 or anti-PD-L1 therapy was observed in COPD patients (153 days) relative to NSCLC patients without COPD (54 days), but the overall survival was similar between these two groups. Surprisingly, current smokers also had increased progression-free survival relative to former or never-smoker patients. Overall, these results suggest that COPD and smoking status influence the response to ICI treatment and progression-free survival in NSCLC patients.

Dr. Mark further explained, “Paradoxically, in the immunotherapy era the presence of more Th1 inflammation within the tumor microenvironment may actually be of benefit to patients. We believe that the improved progression free survival in patients with both NSCLC and COPD is due to increased Th1 differentiation. Conceivably, the presence of more Th1 cells in an inflamed tissue could “prime” the immune system for cell mediated attack on tumor cells. It may be that tumors that arise in the context of inflammation are more likely to utilize immune checkpoint expression as an immune evasion strategy. This may be why checkpoint blockade appears to be more effective therapeutically.”

When asked about the implications of the study, Dr. Mark answered: “Unfortunately, other than our work on immune checkpoint inhibitors in COPD, we know little about the effect of inflammatory diseases on the efficacy of immunotherapy in cancer. This is because patients with concomitant autoimmune diseases have been excluded from most immune checkpoint inhibitor trials due to concerns that immune checkpoint inhibition could exacerbate their underlying disease. There are, however, some tantalizing clues that enhanced Th1 inflammation may be associated with improved response to ICIs. For example, patients with melanoma who develop vitiligo (which is also a Th1 mediated autoimmune disease) may be more likely to respond to immune checkpoint inhibition.”

 

Funding for this study was provided by the National Institute of Health / National Cancer Institute, the FHCRC Seattle Translational Tumor Research (STTR) and European FP7-PEOPLE.

 

Mark NM, Kargl J, Busch SE, Yang GHY, Metz HE, Zhang H, Hubbard JJ, Pipavath SNJ, Madtes DK, Houghton AM. 2017. COPD Alters Immune Cell Composition and Immune Checkpoint Inhibitor Efficacy in NSCLC. The American Journal of Respiratory and Critical Care Medicine.