Clinical Outcomes and Immunotherapy in Lung Cancer With Pulmonary Fibrosis

Overview

This retrospective observational study will evaluate immune checkpoint inhibitor (ICI)-related outcomes in lung cancer patients with concomitant pulmonary fibrosis/interstitial lung disease (ILD) and determine how fibrosis/ILD modifies immunotherapy effectiveness and safety. We will characterize the clinical, radiographic, pathological, and molecular features of lung cancer with ILD and examine their associations with ICI response and survival. A comparator cohort of lung cancer patients without radiographic ILD from the same institution and time period will be used to compare ICI effectiveness (e.g., response and survival outcomes) and pulmonary toxicity signals, including pneumonitis/acute ILD exacerbation. In a translational sub-study, archived lung tumor specimens will undergo single-cell and spatial transcriptomic profiling to identify fibrosis-associated tumor-microenvironment programs that may underlie differential immunotherapy outcomes.

Lung cancer with concomitant pulmonary fibrosis/interstitial lung disease (ILD) represents a clinically challenging population in whom immune checkpoint inhibitor (ICI) treatment may be influenced by baseline lung vulnerability and a distinct tumor immune microenvironment. This single-center, retrospective observational cohort study is designed to evaluate how fibrosis/ILD status and related clinical features are associated with immunotherapy use, effectiveness, and safety. We will identify patients with pathologically confirmed lung cancer and radiographic evidence of pulmonary fibrosis/ILD diagnosed and treated at Jiangsu Province Hospital (The First Affiliated Hospital of Nanjing Medical University). A comparator cohort of lung cancer patients without radiographic ILD from the same institution and time period will be assembled to enable direct comparisons of immunotherapy outcomes. The study will characterize baseline demographics, smoking history, comorbidities, pulmonary function and imaging features (when available), tumor histology and stage, relevant laboratory indices, and molecular testing results. These variables will be examined for associations with ICI exposure and outcomes. The primary analyses will focus on immunotherapy-related endpoints, including real-world measures of ICI effectiveness (such as objective response and survival outcomes captured in routine care) and ILD-relevant safety outcomes, including immune-related pneumonitis and/or acute exacerbation of underlying ILD, treatment interruption or discontinuation, and other clinically significant pulmonary adverse events. Comparative analyses will evaluate whether patients with lung cancer and fibrosis/ILD experience different ICI effectiveness or higher pulmonary toxicity risk compared with patients without ILD, and will explore which clinical, radiographic, pathological, or molecular features within the ILD cohort are linked to better or worse immunotherapy outcomes. To investigate potential mechanisms underlying differential immunotherapy response in fibrosis-associated lung cancer, a translational sub-study will analyze available archived lung tumor specimens (e.g., bronchoscopic biopsy, CT-guided biopsy, or surgical samples). Single-cell transcriptomics and spatial transcriptomics will be performed to compare tumors arising in a fibrotic lung environment with tumors from patients without ILD. These analyses will be used to identify fibrosis-associated cellular states, immune microenvironment composition, and signaling programs that may contribute to altered immunotherapy sensitivity or toxicity. Findings from the multi-omics analyses will be integrated with clinical outcome data to generate mechanistic hypotheses and potential biomarkers relevant to immunotherapy decision-making in lung cancer patients with pulmonary fibrosis/ILD.