Clinical Outcomes and Immunotherapy in Lung Cancer With Pulmonary Fibrosis

Interstitial Lung Diseases, Lung Cancer (Diagnosis), Pulmonary Fibrosis

Lung cancer, Pulmonary fibrosis, Immune checkpoint inhibitor, Tumor microenvironment, Single-cell RNA sequencing, Interstitial lung disease

This retrospective observational study evaluates immune checkpoint inhibitor (ICI)-related outcomes in lung cancer patients with concomitant pulmonary fibrosis/interstitial lung disease (ILD) and determines how fibrosis/ILD modifies immunotherapy effectiveness and safety. The study characterizes the clinical, radiographic, pathological, and molecular features of lung cancer with ILD and examines their associations with ICI response and survival. A comparator cohort of lung cancer patients without radiographic ILD from the same institution and time period is included to compare ICI effectiveness (e.g., response and survival outcomes) and pulmonary toxicity signals, including pneumonitis and acute ILD exacerbation. In a translational sub-study, archived lung tumor specimens 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 which 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 evaluates how fibrosis/ILD status and related clinical features are associated with immunotherapy use, effectiveness, and safety. 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) are identified. A comparator cohort of lung cancer patients without radiographic ILD from the same institution and time period is assembled to enable direct comparisons of immunotherapy outcomes. Baseline demographics, smoking history, comorbidities, pulmonary function and imaging features (when available), tumor histology and stage, relevant laboratory indices, and molecular testing results are collected and analyzed. Associations between these variables and ICI exposure or clinical outcomes are evaluated. Primary analyses focus on immunotherapy-related endpoints, including real-world measures of ICI effectiveness such as objective response and survival outcomes captured in routine clinical care. Safety analyses include ILD-relevant outcomes such as immune-related pneumonitis, acute exacerbation of underlying ILD, treatment interruption or discontinuation, and other clinically significant pulmonary adverse events. Comparative analyses evaluate whether patients with lung cancer and fibrosis/ILD experience different ICI effectiveness or higher pulmonary toxicity risk compared with patients without ILD. Additional analyses explore which clinical, radiographic, pathological, or molecular features within the ILD cohort are associated with favorable or unfavorable immunotherapy outcomes. To investigate potential mechanisms underlying differential immunotherapy responses in fibrosis-associated lung cancer, a translational sub-study analyzes available archived lung tumor specimens (e.g., bronchoscopic biopsy, computed tomography-guided biopsy, or surgical samples). Single-cell transcriptomics and spatial transcriptomics are performed to compare tumors arising in a fibrotic lung environment with tumors from patients without ILD. These analyses 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 are 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.

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