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Anti–PD-1 Immunotherapy Helps With Coexisting Chronic Inflammation From COPD, NSCLC

David Bai, PharmD
A recent study determined that patients with chronic obstructive pulmonary disease (COPD) and non-small cell lung cancer (NSCLC) had similar tumor microenvironment, but higher tumor infiltrating lymphocytes (TIL) exhaustion, than patients without COPD. The use of an anti-programmed cell death-1 (PD-1) antibody, nivolumab, was also demonstrated to be effective in this population.
 
A recent study determined that patients with chronic obstructive pulmonary disease (COPD) and non-small cell lung cancer (NSCLC) had similar tumor microenvironment, but higher tumor infiltrating lymphocytes (TIL) exhaustion, than patients without COPD. The use of an anti-programmed cell death-1 (PD-1) antibody, nivolumab, was also demonstrated to be effective in this population. The immune system plays a 2-sided role in lung cancer: it helps control tumor burden, but likewise causes inflammation, which increases the risk of cancer. On one hand, a lack of immune response from cumulative immune checkpoint regulators, such as PD-1, cause tumor progression. On the other hand, lung cancer has also been linked to inflammation from COPD, a comorbidity associated with a worsened survival in early-stage NSCLC. Because of the unknown mechanisms that COPD exerts on the immune system in patients with lung cancer, researchers performed immunohistochemistry to investigate the effect that COPD has on the immune system and to determine the effectiveness of an immunomodulator (anti–PD-1) in patients with COPD.

Four hundred and thirty-five NSCLC patients with or without COPD were used to study the immune composition of the tumor microenvironment. After profiling the tumors and separating the patients by COPD status, investigators found no immune cell density differences in neutrophils, macrophages, mature dendritic cells, and CD8 T cells in relation to COPD. However, investigators observed that the CD8 and dendritic cells were not associated with improved survival in patients with COPD stage II to III, as was seen in patients without COPD. Immune cells, particularly CD8 T cells in tumor nests (CD8Tu), seem to have an impaired protective ability when COPD is present.

After witnessing a change in the functionality of the immune cells, investigators delved deeper to see if the functions of TIL were also altered in patients with COPD. In patients with NSCLC and COPD, the percentage of forced expiratory volume in 1 second, marking airflow obstruction severity, were found to be inversely correlated to the proportion of CD8 TILs expressing PD-1 and co-expressing PD-1/ T-cell immunoglobulin and mucin domain–containing molecule-3 (TIM-3), representing TIL exhaustion.

In addition, the frequency of TIM-3, PD-1, and TIM-3/PD-1 were all revealed to be higher in patients with COPD than in patients without COPD. TIL exhaustion that was observed in patients with COPD was also determined to be only in patients with a high CD8Tu. In patients with COPD and classified into the high CD8Tu group, the frequencies of CD8 TILs expressing TIM-3 and PD-1/TIM-3 were significantly higher.

Interestingly, a high CD8Tu with PD-L1 expression greater than 5%, led to a reduced overall survival (OS) only in patients with COPD. In this cohort of patients, the use of an anti–PD-1, nivolumab, significantly increased progression-free survival (PFS). Heavy smokers with smoke exposure greater than 30 pack-years and COPD also had better PFS and OS.   

Patients with COPD and lung cancer present with similar tumor microenvironment but higher TIL exhaustion than other patients with lung cancer. Results from this study indicate that patients with lung cancer and COPD are highly susceptible to PD-1 checkpoint inhibitors and have longer PFS and OS. Larger population models will be needed to verify these results and determine if COPD severity has any impact on anti–PD-1 efficacy.

Reference

Biton J, Ouakrim H, Dechartres A et al. Impaired tumor-infiltrating T cells in patients with chronic obstructive pulmonary disease impact lung cancer response to PD-1 blockade. Am J Respir Crit Care Med. 2018;198(7):928-940. doi: 10.1164/rccm.201706-1110OC.

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