Treatment rationale and protocol design: an investigator-initiated phase II study of combination treatment of nivolumab and TM5614, a PAI-1 inhibitor for previously treated patients with non-small cell lung cancer.

Background: There is no established standard 3rd line treatment for patients with advanced non-small cell lung cancer (NSCLC). Although cytotoxic chemotherapeutic agents that are not used as 1st or 2nd line treatment are administrated as 3rd line treatment, their anti-tumor efficacy is insufficient. Anti-programmed death ligand-1 (PD-L1)/programmed death-1 (PD1) treatment is more effective and less toxic than chemotherapy in anti-PD-L1/PD-1 treatment-naïve patients with NSCLC. Therefore, anti-PD-L1/PD-1 therapy is considered an appropriate 3rd line treatment. However, the anti-tumor efficacy is limited in patients previously treated with anti-PD-L1/PD-1 antibody. Today, new drugs are needed to increase the efficacy of anti-PD-L1/PD-1 antibodies. Methods: This open-label, single-arm, investigator-initiated phase II study is designed to evaluate combination treatment of nivolumab and TM5614, a plasminogen activator inhibitor (PAI-1) inhibitor as 3rd or more line treatment in NSCLC patients who underwent standard treatment. The primary endpoint is the objective response rate and the secondary endpoints are progression-free survival (PFS), overall survival (OS), duration of response (DOR) and safety. Recruitment began in September 2023 and is expected to continue for approximately three years. Discussion: Currently, there is no standard 3rd line treatment for advanced NSCLC, and we hope that the findings of this study will facilitate more effective treatments in this setting. Ethics and dissemination: the study protocol conformed to the ethical principles outlined in the Declaration of Helsinki. All patients will provide written informed consent prior to enrollment. Results will be published in a peer-reviewed publication. Trial Registration: This study is registered to Japan Registry of Clinical Trials with number: jRCT2061230039 (19/July/2023).

The Tumor Immune Microenvironment Is Associated With Recurrence in Early-Stage Lung Adenocarcinoma.

Introduction: Immune checkpoint inhibitors have recently been approved for the treatment of early-stage NSCLC in the perioperative setting on the basis of phase 3 trials. However, the characteristics of such patients who are susceptible to recurrence after adjuvant chemotherapy or who are likely to benefit from postoperative immunotherapy have remained unclear. Methods: This biomarker study (WJOG12219LTR) was designed to evaluate cancer stem cell markers (CD44 and CD133), programmed death-ligand 1 (PD-L1) expression on tumor cells, CD8 expression on tumor-infiltrating lymphocytes, and tumor mutation burden in completely resected stage II to IIIA NSCLC with the use of archived DNA and tissue samples from the prospective WJOG4107 trial. Tumors were classified as inflamed or noninflamed on the basis of the PD-L1 tumor proportion score and CD8+ tumor-infiltrating lymphocyte density. The association between each potential biomarker and relapse-free survival (RFS) during adjuvant chemotherapy was assessed by Kaplan-Meier analysis. Results: A total of 117 patients were included in this study. The median RFS was not reached (95% confidence intervals [CI]: 22.4 mo-not reached; n = 39) and 23.7 months (95% CI: 14.5-43.6; n = 41) in patients with inflamed or noninflamed adenocarcinoma, respectively (log-rank p = 0.02, hazard ratio of 0.52 [95% CI: 0.29-0.93]). Analysis of the combination of tumor inflammation category and TP53 mutation status revealed that inflamed tumors without TP53 mutations were associated with the longest RFS. Conclusions: PD-L1 expression on tumor cells, CD8+ T cell infiltration, and TP53 mutation status may help identify patients with early-stage NSCLC susceptible to recurrence after adjuvant chemotherapy.

Efficacy and Safety of Re-administration of Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor (EGFR-TKI) After EGFR-TKI-Induced Interstitial Lung Disease (CS-Lung-005).

PURPOSE: This study investigated the safety and efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) re-administration after recovery from EGFR-TKI-induced interstitial lung disease (ILD). METHODS: This multicenter retrospective study collected data from consecutive advanced NSCLC patients who underwent EGFR-TKI re-administration after recovery from EGFR-TKI-induced ILD. RESULTS: Fifty-eight patients were registered. The grades of initial TKI-induced ILD were grade 1 to 4. TKIs used for re-administration were erlotinib for 15 patients, osimertinib for 15, gefitinib for 14, afatinib for 13 patients, and dacomitinib for 1 patient. ILD recurred in 13 patients (22.4%), comprising 3 patients with grade 1, 6 patients with grade 2, and 4 patients with grade 3. No significant associations were found between ILD recurrence and age, smoking history, performance status, time from initial ILD to TKI re-administration, or concomitant corticosteroid use. However, the incidence of ILD recurrence was high in cases of repeated use of gefitinib or erlotinib or first time use of osimertinib at TKI re-administration. The ILD recurrence rate was lowest in patients treated with first time use of gefitinib (8%) or erlotinib (8%), followed by patients treated with repeated use of osimertinib (9%). The response rate, median progression-free survival by TKI re-administration, and median overall survival were 55%, 9.6 and 84.8 months, respectively. CONCLUSION: This study showed that EGFR-TKI re-administration is a feasible and effective treatment for patients who recovered from EGFR-TKI-induced ILD. Our results indicate that re-administration of EGFR-TKI is an important option for long-term prognosis after recovery from EGFR-TKI-induced ILD.

NOTCH1 and CREBBP co-mutations negatively affect the benefit of adjuvant therapy in completely resected EGFR-mutated NSCLC: translational research of phase III IMPACT study.

The phase III IMPACT study (UMIN000044738) compared adjuvant gefitinib with cisplatin plus vinorelbine (cis/vin) in completely resected epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). Although the primary endpoint of disease-free survival (DFS) was not met, we searched for molecular predictors of adjuvant gefitinib efficacy. Of 234 patients enrolled in the IMPACT study, 202 patients were analyzed for 409 cancer-related gene mutations and tumor mutation burden using resected lung cancer specimens. Frequent somatic mutations included tumor protein p53 (TP53; 58.4%), CUB and Sushi multiple domains 3 (CSMD3; 11.8%), and NOTCH1 (9.9%). Multivariate analysis showed that NOTCH1 co-mutation was a significant poor prognostic factor for overall survival (OS) in the gefitinib group and cAMP response element binding protein (CREBBP) co-mutation for DFS and OS in the cis/vin group. In patients with NOTCH1 co-mutations, gefitinib group had a shorter OS than cis/vin group (Hazard ratio 5.49, 95% CI 1.07-28.00), with a significant interaction (P for interaction = 0.039). In patients with CREBBP co-mutations, the gefitinib group had a longer DFS than the cis/vin group, with a significant interaction (P for interaction = 0.058). In completely resected EGFR-mutated NSCLC, NOTCH1 and CREBBP mutations might predict poor outcome in patients treated with gefitinib and cis/vin, respectively.

Lack of Association of Plasma Levels of Soluble Programmed Cell Death Protein 1, Programmed Death-Ligand 1, and CTLA-4 With Survival for Stage II to IIIA NSCLC After Complete Resection and Adjuvant Chemotherapy.

Introduction: Perioperative treatment in NSCLC has gained marked attention with the introduction of immune checkpoint inhibitors. Such a paradigm shift has given us additional opportunities to evaluate potential biomarkers in patients with these curable disease stages. Methods: This study (WJOG12319LTR) was designed as a biomarker study to evaluate whether soluble immune markers were prognostic or predictive on relapse-free survival in patients with stage II to IIIA NSCLC who underwent complete resection and adjuvant chemotherapy with cisplatin plus S-1, which is an oral fluoropyrimidine formulation that consists of tegafur, gimeracil, and oteracil, or S-1 alone in the previous WJOG4107 study. Archived plasma samples were assayed for soluble (s) forms of programmed cell death protein 1 (sPD-1), programmed death-ligand 1(sPD-L1), and CTLA-4 (sCTLA-4) with the highly sensitive HISCL system. Using time-dependent receiver operating characteristic curve analysis, the area under the curves were derived and optimal cutoff values were determined. Using the cutoff values, whether the marker was prognostic or predictive was assessed by survival analysis. Results: A total of 150 patients were included in the study. The time-dependent receiver operating characteristics analysis revealed that the area under the curves for sPD-1, sPD-L1, and sCTLA-4 were 0.54, 0.51, and 0.58, respectively. The survival analysis did not reject that hazard ratios were 1 in terms of the soluble immune marker and the treatment-marker interaction for all three markers. Conclusions: There was no proof that circulating concentrations of sPD-1, sPD-L1, and sCTLA-4 were prognostic or predictive factors of the outcome for adjuvant chemotherapy after complete resection in patients with NSCLC.

Pre-Existing Interstitial Lung Abnormalities Are Independent Risk Factors for Interstitial Lung Disease during Durvalumab Treatment after Chemoradiotherapy in Patients with Locally Advanced Non-Small-Cell Lung Cancer.

Introduction/Background: Chemoradiotherapy (CRT) followed by durvalumab, an immune checkpoint inhibitor, is the standard treatment for locally advanced non-small-cell lung cancer (NSCLC). Interstitial lung disease (ILD) is a life-threatening toxicity caused by these treatments; however, risk factors for the ILD have not yet been established. Interstitial lung abnormalities (ILAs) are computed tomography (CT) findings which manifest as minor interstitial shadows. We aimed to investigate whether ILAs could be risk factors for grade-two or higher ILD during durvalumab therapy. Patients and Methods: Patients with NSCLC who received durvalumab after CRT from July 2018 to June 2021 were retrospectively enrolled. We obtained patient characteristics, laboratory data, radiotherapeutic parameters, and chest CT findings before durvalumab therapy. Results: A total of 148 patients were enrolled. The prevalence of ILAs before durvalumab treatment was 37.8%. Among 148 patients, 63.5% developed ILD during durvalumab therapy. The proportion of patients with grade-two or higher ILD was 33.8%. The univariate logistic regression analysis revealed that older age, high dose-volume histogram parameters, and the presence of ILAs were significant risk factors for grade-two or higher ILD. The multivariate analysis showed that ILAs were independent risk factors for grade-two or higher ILD (odds ratio, 3.70; 95% confidence interval, 1.69−7.72; p < 0.001). Conclusions: We showed that pre-existing ILAs are risk factors for ILD during durvalumab treatment after CRT. We should pay attention to the development of grade-two or higher ILD during durvalumab treatment in patients with ILAs.

Efficacy of Chemoimmunotherapy in NSCLC Patients With Brain Metastasis With or Without Prior Brain Radiotherapy.

BACKGROUND/AIM: Many patients with advanced lung cancer develop brain metastasis (BM); however, few reports confirming the efficacy of immune checkpoint inhibitors (ICIs) plus chemotherapy in non-small cell lung cancer (NSCLC) patients with symptomatic BM have been published. Therefore, we retrospectively evaluated the effects of chemoimmunotherapy in NSCLC patients who did or did not receive prior brain radiotherapy. PATIENTS AND METHODS: A total of 103 patients with advanced NSCLC who received ICIs plus chemotherapy at our hospital from January 2019 to July 2021 were retrospectively enrolled. RESULTS: Patients with BM tended to have shorter progression-free survival (PFS) and overall survival (OS) compared with patients without BM. The maximum size of BM and the proportion of patients with symptomatic BM were greater among patients who received brain radiotherapy before chemoimmunotherapy. However, patients who received prior brain radiotherapy had better PFS and OS compared with patients who did not receive prior brain radiotherapy. CONCLUSION: Patients who received prior brain radiotherapy experienced a superior therapeutic benefit of ICIs plus chemotherapy, including those with larger and more symptomatic BM.

Characteristic computed tomography features in mesenchymal-epithelial transition exon14 skipping-positive non-small cell lung cancer.

BACKGROUND: Mesenchymal-epithelial transition exon14 (METex14) skipping is one of the therapeutic driver oncogene mutations in non-small cell lung cancer (NSCLC), and can be treated with tepotinib and capmatinib. There is only one report on computed tomography (CT) findings of METex14 skipping-positive NSCLC, which shows that the primary tumor tends to have a large mass in the upper lobe, and extrathoracic metastases are common. This study examined the CT findings of METex14 skipping-positive NSCLC, focusing on the features of the margins and internal structures. METHODS: We consecutively included patients with METex14 skipping-positive NSCLC who were diagnosed between January 2018 and December 2020 at four independent institutions. We retrospectively reviewed the patient demographics and CT findings for tumor margins (invasion into surrounding tissue, lobulation, pleural indentation, spicula, and ground-glass opacity) and internal structures (air bronchograms, cavitation and internal low-density area). RESULTS: Fifteen patients with METex14 skipping-positive NSCLC were identified. Almost half of the patients were men (7/15; 46.7%), and their median age was 75.0 years. More than half were either current or former smokers (9/15; 60.0%). A vast majority of histological subtypes were adenocarcinoma (10/15; 66.7%), followed by pleomorphic carcinoma (3/15; 20.0%) and squamous cell carcinoma (2/15; 13.3%). With regard to CT findings, most primary tumors presented as masses larger than 30 mm (12/15; 80.0%) and were located in the upper lobes (12/15; 80.0%). Invasion into surrounding tissue and presence of internal low-density areas were observed in 60.0% (9/15) and 66.7% (10/15) of the primary tumors, respectively. Additionally, their frequencies increased to 72.7% (8/11) and 90.9% (10/11) in stage III/IV cases, respectively. In lymph node metastasis, internal low-density areas were observed in 8/10 cases (80.0%). Although these two CT features were rarely observed in distant metastases at diagnosis, they became apparent with progression of the metastatic tumor size. CONCLUSIONS: METex14 skipping-positive NSCLC tumors tend to invade surrounding tissue and possess internal low-density areas. These CT findings might be characteristic of METex14 skipping-positive NSCLC.

Gemcitabine maintenance therapy after gemcitabine and platinum drug chemotherapy for naive stage IIIB/IV squamous cell lung cancer: a phase II study.

Platinum doublet is the standard chemotherapy regimen for unresectable nonsmall-cell lung cancer (NSCLC) without a driver mutation. However, for squamous cell lung cancer, the most effective cytotoxic regimen is not yet established. Combination therapy of gemcitabine with a platinum agent is a highly effective treatment among the platinum doublet regimens and is promising as a treatment for advanced squamous cell lung carcinoma. In this study, we prospectively evaluated the efficacy of gemcitabine + platinum combination therapy followed by maintenance gemcitabine monotherapy in untreated advanced squamous cell lung cancer. Patients with squamous cell lung cancer received four cycles of gemcitabine + platinum combination therapy every 3 or 4 weeks. After the induction therapy, gemcitabine maintenance therapy was administered every 3 or 4 weeks until disease progression or unacceptable toxicity. Of 18 patients enrolled, the median progression-free survival was 3.9 months. Only six patients received maintenance chemotherapy with gemcitabine. The median survival time of all enrolled patients was 18.1 months. Cytopenia of any grade occurred in at least 70% of the enrolled patients. However, severe adverse events were observed in only a few cases. Gemcitabine maintenance therapy after gemcitabine plus platinum agents is a suggested treatment for unresectable squamous cell lung cancer. While the overall toxicity profile of this therapy is acceptable, attention should be paid to bone marrow suppression.

Coexistence of Emphysema With Non-small-cell Lung Cancer Predicts the Therapeutic Efficacy of Immune Checkpoint Inhibitors.

BACKGROUND/AIM: Chronic obstructive pulmonary disease coexisting with non-small-cell lung cancer (NSCLC) was reported to be associated with a longer progression-free survival (PFS) in patients treated with immune checkpoint inhibitors (ICIs). In the present study, we investigated the impact of emphysematous change on the treatment response to ICIs in patients with NSCLC. PATIENTS AND METHODS: A total of 153 patients with advanced NSCLC who received ICIs (nivolumab, pembrolizumab, or atezolizumab) at our hospital from January 2016 to May 2019 were retrospectively enrolled. RESULTS: According to the Goddard scoring system, 71 (46.4%) patients were classified as having emphysema and 82 (53.6%) as having no emphysema. Multivariate analysis showed that a good performance status and coexisting emphysema (hazard ratio=0.49; 95% confidence intervaI=0.28-0.84; p=0.010) were independent predictors of a better PFS. CONCLUSION: Recognizing emphysema coexisting with NSCLC may help predict the therapeutic efficacy of ICIs in such patients.

First-line immune checkpoint therapy in metastatic squamous cell lung cancer harboring both EGFR mutation and high expression of PD-L1: A case report.

A 90-year-old female was admitted to our hospital with a history of a dry cough. Chest computed tomography (CT) scan showed a tumor shadow, and CT-guided lung biopsy revealed squamous cell carcinoma harboring an EGFR mutation. In addition, programmed death-ligand 1 (PD-L1) was highly expressed with a tumor proportion score (TPS) of >75%. Pembrolizumab therapy in the first-line setting was not effective, and the patient died at six months from the first visit. Squamous cell lung cancers (SCLCs) with both EGFR mutation and high expression of PD-L1 are very rare.

Carboplatin Plus Nab-paclitaxel in Performance Status 2 Patients With Advanced Non-small-cell Lung Cancer.

BACKGROUND/AIM: This phase I/II study aimed at assessing the efficacy of combination therapy with carboplatin (CBDCA) on day 1 and nab-paclitaxel (Nab-PTX) on days 1 and 8 of a 21-day cycle in performance status (PS) 2 patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: PS 2 patients with NSCLC were enrolled into a phase I study using a 3 + 3 design. Once the recommended phase II dose (RP2D) was established, the patients were enrolled into phase II. RESULTS: Based on the phase I findings, the RP2D was determined as CBDCA area under the curve 6 mg/ml/min and Nab-PTX 100 mg/m2 In the phase II part, 27 patients were evaluable. The overall response rate was 44%. The median progression-free survival and overall survival were 5.2 months and 14.0 months, respectively. There was no treatment-related death. CONCLUSION: CBDCA plus Nab-PTX therapy is a promising treatment strategy for PS 2 patients with NSCLC.

Krebs von den Lungen-6 (KL-6) is a prognostic biomarker in patients with surgically resected nonsmall cell lung cancer.

By immunizing mice with a lung adenocarcinoma cell line, we previously established a murine IgG1 monoclonal antibody that recognizes a sialylated sugar chain designated Krebs von den Lungen-6 (KL-6). KL-6 is a high-molecular-weight glycoprotein classified as a human MUC1 mucin. The aim of this study was to determine whether KL-6 expression in tumors correlates with circulating KL-6 levels and whether circulating KL-6 has any prognostic value in patients with surgically resected non-small cell lung cancer (NSCLC). Immunohistochemical analysis of KL-6 expression was performed on 103 NSCLC tissues, and its associations with serum KL-6 levels and survival were examined. We also evaluated whether KL-6 expression patterns and/or serum KL-6 levels could predict prognosis in these NSCLC patients. Immunohistochemical analysis of KL-6 in NSCLC tissues showed that a depolarized KL-6 expression pattern was associated with a high level of circulating KL-6 and a poor prognosis in NSCLC patients who underwent curative surgery. Furthermore, a high circulating KL-6 level was associated with both poorer progression-free survival (PFS) and overall survival (OS), and multivariate analyses confirmed its independent prognostic value for both PFS and OS (p = 0.041 and 0.023, respectively). Our data suggest that preoperative serum KL-6 level reflects KL-6 expression patterns in NSCLC tissue, and can serve as a useful prognostic biomarker in NSCLC patients who undergo curative surgery.

[A case of primary small intestinal malignant lymphoma found based on multiple pulmonary nodules with cavitation].

A 72-year-old man complained of dyspnea and epigastric pain. He was admitted to our hospital with progressive dyspnea and abnormal chest radiograph findings. Chest CT scan on admission showed multiple nodular shadows with and without air-bronchograms, vessels or cavitation. Transbronchial and percutaneous lung biopsy specimens demonstrated poorly differentiated carcinoma. Pulmonary metastases were suspected, but their primary origin was unknown. Chest and abdominal CT scans on the 18th hospital day showed a giant tumor of the small intestine and rapid progression of the pulmonary tumor, forming cavitation. The patient's condition worsened, and he died on the 51st hospital day. At autopsy, a final diagnosis of T-cell lymphoma of the small intestine and pulmonary metastases was obtained. This is a rare case which was found primarily based on the characteristic radiologic features of pulmonary metastases.

[A case of tumor microembolism diagnosed by perfusion scan and transbronchial lung biopsy].

A 70-year-old woman with breast cancer treated with hormonal therapy had progressive shortness of breath for one month. Chest radiograph and computed tomography showed mild interstitial changes, but could not account for her respiratory failure. Lymphangitic carcinomatosis, drug-induced pneumonitis, idiopathic interstitial pneumonitis, opportunistic infection, and pulmonary edema were considered in the differential diagnosis of the CT findings. A perfusion scan revealed numerous small subsegmental perfusion defects in both lung fields. Bronchoalveolar lavage fluid (BALF) contained some cancer cells, suggesting lymphangitic carcinomatosis. Transbronchial biopsy (TBLB) specimen showed tumor emboli in small pulmonary arteries. Immunohistochemical findings of TBLB specimen were consistent with breast cancer cells. A diagnosis of tumor microembolism caused by breast cancer metastasis was made. Antemortem diagnosis of tumor microembolism is very difficult. Here, we report a case of tumor microembolism diagnosed by perfusion scan and TBLB.

[A case of hearing loss and diffuse alveolar hemorrhage associated with microscopic polyangitis].

We report a rare case of bilateral hearing loss and diffuse alveolar hemorrhage associated with microscopic polyangitis (MPA). A 75-year-old woman complained of hearing loss. Two months later, she was admitted due to rapidly progressing dyspnea. Chest radiography and CT scan showed diffuse bilateral consolidations. Mechanical ventilation was required for respiratory insufficiency. Laboratory data demonstrated anemia and renal failure. Steroid pulse therapy and antibiotics were initiated. On day 2, bronchoalveolar lavage showed fresh blood-like fluid, which suggested diffuse alveolar hemorrhage (DAH). Serum level of myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA) was elevated. Therefore, DAH and rapidly progressive glomerulonephritis associated with MPA were diagnosed. Treatment was also performed with cyclophosphamide pulse therapy and plasmapheresis. Her pulmonary lesion improved dramatically. We emphasize the effectiveness of bronchoalveolar lavage for prompt and accurate diagnoses. Moreover, this case report also suggests that early cyclophosphamide therapy and plasmapheresis may be an effective treatment for MPA with diffuse alveolar hemorrhage. In contrast, hearing loss did not improve after therapy. Some cases reported hearing loss as a rare symptom of MPA. We also suspect that hearing loss may be a complication of MPA. We reported this case because there has been no description of hearing loss accompanying DAH associated with MPA.

Suppressor of cytokine signaling 1 inhibits pulmonary inflammation and fibrosis.

BACKGROUND: Suppressor of cytokine signaling (SOCS) proteins are inhibitors of cytokine signaling. Our previous study suggested that SOCS1 regulates collagen synthesis by lung fibroblasts, suggesting a role of SOCS1 in the pathophysiology of pulmonary fibrosis. OBJECTIVES: We sought to investigate the role of SOCS1 in pulmonary inflammation and fibrosis in vivo. METHODS: SOCS1-haplodeficient mice treated with bleomycin (BLM) were evaluated for pulmonary inflammation and fibrosis compared with wild-type mice. The human study group was composed of 18 patients with interstitial lung disease. Lung specimens obtained by means of open lung biopsy were investigated to determine whether the severity of fibrosis was associated with decreased SOCS1 expression. Finally, we further analyzed the effect of exogenous SOCS1 on BLM-induced lung injury based on adenoviral SOCS1 gene transfer to the lung. RESULTS: SOCS1-haplodeficient mice treated with BLM showed markedly enhanced pulmonary inflammation and fibrosis compared with wild-type mice. Using human lung specimens, we found that SOCS1 mRNA levels inversely correlated with duration of the disease. SOCS1 expression was significantly less in lung tissue from patients with idiopathic pulmonary fibrosis (IPF) compared with that in non-IPF patients. Moreover, SOCS1 expression was significantly less in severe fibrotic lesions (lower lobe) than in less fibrotic lesions (upper lobe). Adenoviral SOCS1 gene transfer to murine lungs significantly decreased lymphocytic inflammation, pulmonary fibrosis, and mortality because of BLM-induced lung injury. Exogenous SOCS1 inhibited expression of various cytokines, including TNF-alpha, which might play a key role. CONCLUSIONS: These results suggest that SOCS1 might act as a suppressor for pulmonary fibrosis. SOCS1 might be a target of IPF treatment.

Overproduction of collagen and diminished SOCS1 expression are causally linked in fibroblasts from idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and often fatal pulmonary disorder, and its pathology is characterized by parenchymal fibrosis. To investigate the characteristics of fibroblasts in IPF, we obtained eight fibroblast cell lines from lungs with IPF and eight lines from normal lungs. We found that the fibroblasts from IPF spontaneously produced higher amounts of type I collagen and had lower expression levels of SOCS1 than fibroblasts from normal lung. By using mouse fibroblasts, we demonstrated the causal relationship between them: the deficiency of SOCS1 in fibroblasts resulted in increased collagen production, whereas overexpression of SOCS1 suppressed collagen production. IFN-gamma suppressed spontaneous collagen production even in SOCS1-deficient fibroblasts, indicating that IFN-gamma inhibition is SOCS1-independent. In contrast, IFN-gamma suppressed the increase of collagen production induced by IL-4 in wild type fibroblasts but not SOCS1-deficient fibroblasts, suggesting IFN-gamma acted exclusively via SOCS1 in this case. Following IFN-gamma stimulation, the amount of SOCS1 mRNA expressed by IPF fibroblasts was comparable to that of normal fibroblasts. Thus, the extent of SOCS1 increase after stimulation by IFN-gamma was significantly higher in IPF fibroblasts. The extent to which IFN-gamma inhibited collagen production was also larger in IPF fibroblasts than in normal fibroblasts. These results suggest that the exaggerated production of collagen observed in fibroblasts from IPF is causally related to the diminished expression of SOCS1, and IPF fibroblasts are more susceptible to IFN-gamma because of decreased expression of SOCS1.