Antipodoplanin antibody enhances the antitumor effects of CTLA-4 blockade against malignant mesothelioma by natural killer cells.

Combination immunotherapy with multiple immune checkpoint inhibitors (ICIs) has been approved for various types of malignancies, including malignant pleural mesothelioma (MPM). Podoplanin (PDPN), a transmembrane sialomucin-like glycoprotein, has been investigated as a diagnostic marker and therapeutic target for MPM. We previously generated and developed a PDPN-targeting Ab reagent with high Ab-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). However, the effects of anti-PDPN Abs on various tumor-infiltrating immune cells and their synergistic effects with ICIs have remained unclear. In the present study, we established a novel rat-mouse chimeric anti-mouse PDPN IgG2a mAb (PMab-1-mG2a ) and its core-fucose-deficient Ab (PMab-1-mG2a -f) to address these limitations. We identified the ADCC and CDC activity of PMab-1-mG2a -f against the PDPN-expressing mesothelioma cell line AB1-HA. The antitumor effect of monotherapy with PMab-1-mG2a -f was not sufficient to overcome tumor progression in AB1-HA-bearing immunocompetent mice. However, PMab-1-mG2a -f enhanced the antitumor effects of CTLA-4 blockade. Combination therapy with anti-PDPN Ab and anti-CTLA-4 Ab increased tumor-infiltrating natural killer (NK) cells. The depletion of NK cells inhibited the synergistic effects of PMab-1-mG2a -f and CTLA-4 blockade in vivo. These findings indicated the essential role of NK cells in novel combination immunotherapy targeting PDPN and shed light on the therapeutic strategy in advanced MPM.

Potential of fluoropyrimidine to be an immunologically optimal partner of immune checkpoint inhibitors through inducing immunogenic cell death for thoracic malignancies.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are a revolutionary paradigm in the treatment of thoracic malignancies and chemoimmunotherapy is a current standard care in this field. Chemotherapeutic agents are known to induce not only direct cytotoxic effects on tumor cells but also immune modulating effects, such as stimulating immunogenic cell death (ICD). Currently, either pemetrexed (PEM) or taxane plus platinum are combined with ICIs for patients with non-small cell lung cancer (NSCLC); however, it is still unknown whether these agents are immunologically optimal partners for ICIs. METHODS: To determine the immunologically optimal chemotherapeutic agent, we first evaluated the ability of several chemotherapeutic agents, including platinum, PEM, taxane, and 5-fluorouracil (5-FU) to induce ICD using several thoracic tumor cell lines in vitro. ICD was evaluated by the cell surface expression of calreticulin (CRT) and adenosine-triphosphate (ATP) secretion. We further performed an antitumor vaccination assay in vivo. RESULTS: 5-FU induced cell surface expression of CRT and ATP secretion most efficiently among the several chemotherapeutic agents. This effect was enhanced when it was combined with platinum. In the antitumor vaccination assay in vivo, we found that vaccination with dying-AB1-HA (a murine malignant mesothelioma cell line) cells treated with 5-FU, but neither PEM nor PTX, reduced the tumor growth of living-AB1-HA cells inoculated 1 week after vaccination by recruiting CD3+ CD8+ T cells into the tumor microenvironment. CONCLUSION: Our findings indicate that fluoropyrimidine can be an immunologically optimal partner of ICIs through the induction of ICD for thoracic malignancies.

A multicenter, open-label, phase II trial of pemetrexed plus bevacizumab in elderly patients with previously untreated advanced or recurrent nonsquamous non-small cell lung cancer.

BACKGROUND: Although the incidence of lung cancer in elderly individuals has been increasing in recent years, the number of clinical trials designed specifically for elderly patients with advanced non-small cell lung cancer (NSCLC) is still limited. To fulfill this unmet medical need, we conducted a phase II study to elucidate the efficacy of pemetrexed (PEM) plus bevacizumab (Bev) combination chemotherapy in elderly patients with nonsquamous NSCLC. METHODS: A total of 29 elderly patients (≥75 years old) with nonsquamous NSCLC were enrolled in this multicenter, open-label, phase II study, and 27 patients were finally analyzed. PEM at 500 mg/m2 on day 1 plus Bev at 15 mg/kg on day 1 were administered triweekly. The primary endpoint was the investigator-assessed objective response rate. RESULTS: The median age at initiating chemotherapy was 80 years old. Almost all patients (92.6%) had adenocarcinoma histology. The median number of cycles administered was 6, and the objective response rate was 40.7%. The median progression-free survival, overall survival and 1-year survival were 8.8 months, 27.2 months and 79%, respectively. The treatment was well-tolerated, and no treatment-related death was observed. CONCLUSION: Combination chemotherapy with PEM plus Bev in elderly patients with previously untreated advanced non-squamous NSCLC exhibited favorable antitumor activity and tolerability, suggesting that a combination of PEM plus Bev might be a promising treatment option for this population.

FoundationOne CDx detected an uncovered variant of epidermal growth factor receptor exon 19 deletion by Oncomine Dx target test in a patient with lung adenocarcinoma.

A non-smoker woman with advanced lung adenocarcinoma was referred to us. The Oncomine Dx target test (ODxTT), a next-generation sequencing (NGS)-based hot spots panel test, did not detect any driver mutations, so we treated her with chemo-immunotherapy. After second-line chemotherapy, we performed FoundationOne CDx, a NGS-based comprehensive genomic profiling (CGP) test, and identified a rare variant of epidermal growth factor receptor exon 19 deletion that had not been covered by ODxTT. This case highlights the importance of considering the indication of a CGP test for patients who are likely to harbor driver mutations, even when ODxTT fails to detect any.

A case of atopic cough with aphonia showed a prominent response to a histamine H1 receptor antagonist.

A 33-year-old woman admitted to our hospital for further examination of severe non-productive cough lasting for about two months. Her symptom did not ameliorate by treatments including long acting ß2 agonists. She had a medical history of drug allergy to non-steroidal anti-inflammatory drugs. At the initial visit, she could not speak at all and communicated with us in writing. Chest auscultation revealed no wheezes, rhonchi and other crackles. Laboratory findings showed a mild eosinophilia with normal total and specific serum immunoglobulin E. The results of an electrocardiogram, a chest X-ray and a chest CT were unremarkable. A fractional exhaled nitric oxide value was within normal limit. Based on these observations, a diagnosis of atopic cough (AC) was suspected, and we started treatment with a histamine H1 receptor antagonist (H1-RA). She had become able to speak again in association with complete disappearance of cough by eight-weeks after treatment initiation, and her symptoms did not recur even after cessation of treatment. By the confirmation of remarkable clinical improvement in response to a H1-RA, a diagnosis of AC was made. To the best of our knowledge, this is the first report of an AC patient who presented severe cough with aphonia. J. Med. Invest. 70 : 281-284, February, 2023.

Identification of fibrocyte cluster in tumors reveals the role in antitumor immunity by PD-L1 blockade.

Recent clinical trials revealed that immune checkpoint inhibitors and antiangiogenic reagent combination therapy improved the prognosis of various cancers. We investigated the roles of fibrocytes, collagen-producing monocyte-derived cells, in combination immunotherapy. Anti-VEGF (vascular endothelial growth factor) antibody increases tumor-infiltrating fibrocytes and enhances the antitumor effects of anti-PD-L1 (programmed death ligand 1) antibody in vivo. Single-cell RNA sequencing of tumor-infiltrating CD45+ cells identifies a distinct "fibrocyte cluster" from "macrophage clusters" in vivo and in lung adenocarcinoma patients. A sub-clustering analysis reveals a fibrocyte sub-cluster that highly expresses co-stimulatory molecules. CD8+ T cell-costimulatory activity of tumor-infiltrating CD45+CD34+ fibrocytes is enhanced by anti-PD-L1 antibody. Peritumoral implantation of fibrocytes enhances the antitumor effect of PD-L1 blockade in vivo; CD86-/- fibrocytes do not. Tumor-infiltrating fibrocytes acquire myofibroblast-like phenotypes through transforming growth factor ß (TGF-ß)/small mothers against decapentaplegic (SMAD) signaling. Thus, TGF-ßR/SMAD inhibitor enhances the antitumor effects of dual VEGF and PD-L1 blockade by regulating fibrocyte differentiation. Fibrocytes are highlighted as regulators of the response to programmed death 1 (PD-1)/PD-L1 blockade.

Clinical significance of fractional exhaled nitric oxide and periostin as potential markers to assess therapeutic efficacy in patients with cough variant asthma.

BACKGROUND: In Japan, cough variant asthma (CVA) is the most common etiology of chronic cough. Contrary to substantial progress in understanding the roles of various factors in classic asthma, little is known regarding the pathogenesis and development of CVA. Furthermore, few studies have explored valuable biomarkers for evaluating the therapeutic efficacy of patients with CVA. METHODS: We conducted a single-center, prospective study to investigate the clinical significance of various clinical factors as potential "therapeutic" markers for CVA. RESULTS: From December 2019 to September 2020, we enrolled 20 patients with CVA and 10 age-matched healthy control subjects. Fractional exhaled nitric oxide (FeNO) values were significantly higher in patients with CVA than those in healthy controls. All patients with CVA commenced treatment at the initial visit, which markedly alleviated symptoms 12 weeks after treatment. FeNO values and serum periostin levels were significantly decreased following treatment, and altered FeNO values correlated with improved visual analogue scale scores of symptoms. Moreover, changes in both FeNO values and serum periostin levels were significantly correlated with increased values of some pulmonary function tests while also correlating with each other. CONCLUSIONS: Our observations indicate the usefulness of FeNO and periostin as potential "therapeutic" markers for CVA. To the best of our knowledge, this is the first report demonstrating the clinical significance of these factors as potential biomarkers to assess therapeutic efficacy in patients with CVA.

Immune checkpoint inhibitor-related pneumonitis with atypical radiologic features in a patient with anti-aminoacyl-tRNA synthetase antibody.

A man with non-small-cell lung cancer who was negative for anti-nuclear antibodies was admitted for dyspnea after immune checkpoint inhibitor (ICI) administration. Computed tomography (CT) showed complexed radiologic features, including subpleural and basal predominant reticular shadow with cystic structures and peribronchovascular consolidation. Although we treated him with high-dose steroid under a diagnosis of ICI-related pneumonitis, he developed acute exacerbation of pneumonitis with progressive fibrosis and volume loss. A re-evaluation identified anti-aminoacyl-tRNA synthetase antibody in the serum collected before ICI administration. This case highlights the importance of re-evaluating pre-existing autoimmune disorders in patients who develop ICI-related pneumonitis with atypical radiologic features.

S-1 eliminates MDSCs and enhances the efficacy of PD-1 blockade via regulation of tumor-derived Bv8 and S100A8 in thoracic tumor.

Myeloid-derived suppressor cells (MDSCs) have been known to play a pivotal role in the induction of immune tolerance, which limits the benefits of immune checkpoint inhibitors (ICIs). Recent studies revealed that several chemotherapeutic agents decreased tumor-infiltrating MDSCs. Therefore, combination therapy with cytotoxic chemotherapeutic agents and ICIs was approved for first-line treatment for lung cancer. However, the impact of chemotherapeutic agents on MDSCs and an optimal partner of ICIs has not been fully investigated in thoracic tumors, including lung cancer and malignant pleural mesothelioma. In the present study, we found that treatment with 5-FU and its oral formulation, S-1, suppressed tumor progression and inhibited the accumulation of MDSCs in thoracic tumor-bearing mice. Tumor-infiltrating T cells and dendritic cells were significantly expanded in S-1-treated mice. 5-FU suppressed the ability of tumor cells to recruit MDSCs, while it did not suppress the survival and differentiation of mouse MDSCs in vitro. We also revealed that 5-FU or S-1 significantly downregulated the expression of tumor-derived Bv8 and S100A8. The knockdown of Bv8 or S100A8 in tumor cells suppressed tumor growth and MDSC recruitment in vivo. Furthermore, in comparison with pemetrexed, administration of S-1 improved the synergistic therapeutic efficacy of anti-PD-1 antibodies with or without carboplatin. Our findings revealed a novel mechanism wherein S-1 primed a favorable tumor microenvironment to provide the rationale for combination therapy with S-1 and ICIs as the optimal therapy for thoracic cancer.

Analysis of the chemotactic factors for tumor-infiltrating fibrocytes and their prognostic significances in lung cancer.

Fibrocytes, which are bone marrow-derived collagen-producing cells, have been reported to be involved in pathogenesis of pulmonary fibrosis. Our previous study reported that tumor-infiltrating fibrocytes play a role in tumor progression and drug resistance in lung cancer. The present study therefore examined chemotactic factors for fibrocytes in tissues of non-small cell lung cancer (NSCLC) and their prognostic significance. Surgically resected tumor tissues were examined for the expression of chemotactic factors, including C-X-C motif chemokine 12 (CXCL12), CCL2, platelet-derived growth factor (PDGF)-AA and PDGF-BB, as well as tumor-infiltrating fibrocytes by immunostaining. The chemotactic ability of fibrocytes in response to each factor was evaluated using a migration assay by counting the migrated cells microscopically, and expression of receptors for chemotactic factors were analyzed by flow cytometry. The expression of CXCL12, but not CCL2, PDGF-AA, or PDGF-BB, was associated with the number of tumor-infiltrating fibrocytes in lung adenocarcinoma (LUAD), but not lung squamous cell carcinoma (LUSQ). In addition, patients with an increased expression of CXCL12 in LUAD but not LUSQ showed a significantly poorer prognosis compared with those with a decreased expression. However, the expression of CCL2, PDGF-AA and PDGF-BB was not correlated with the prognosis of patients with NSCLC. The number of fibrocytes was associated with a poor prognosis in LUAD. Fibrocytes derived from the peripheral blood of healthy subjects as well as patients with lung cancer expressed higher levels of CXCR4 compared with CCR2, PDGF and receptor-α and receptor-ß. Overall, these results suggested that targeting tumor-infiltrating fibrocytes via the CXCL12/CXCR4 axis may be a useful strategy for controlling the progression of NSCLC, particularly LUAD.

Efficacy and safety of second-line chemotherapy for patients with advanced non-small cell lung cancer complicated by interstitial lung disease.

BACKGROUND: Treatment of non-small cell lung cancer (NSCLC) patients with interstitial lung disease (ILD) is limited because of the risk of its acute exacerbation (AE). Furthermore, the efficacy and safety of second-line chemotherapy for these patients is unclear. METHODS: To investigate the efficacy and safety of second-line chemotherapy for NSCLC patients with ILD, we retrospectively reviewed patients who were treated at our institute between April 2010 and December 2018. RESULTS: Thirty-five patients received two or more regimens. Thirty-four patients were male and the median age at the initiation of second-line chemotherapy was 70 years. Almost all patients had a smoking history. Fourteen patients had adenocarcinoma and 15 had squamous cell carcinoma histology. Stages III and IV were observed in 20 and 11 patients, respectively. With respect to the type of ILD, 12 patients had usual interstitial pneumonia (UIP). The overall response rate and disease control rate were 11.4 and 68.6%, respectively. The median progression-free and median overall survival were 4.1 and 6.4 months, respectively. The AE of ILD was observed in eight patients, five of whom died. UIP and low percentage vital capacity were detected as significant risk factors for the AE of ILD. CONCLUSION: Second-line chemotherapy among patients with NSCLC complicated by ILD showed a certain effectiveness, but some patients experienced the AE of ILD, which may lead to death. The risk of the AE of ILD must be considered especially for patients with UIP and low percentage VC.

The efficacy of mass screening for chronic obstructive pulmonary disease using screening questionnaires in a medical health check-up population.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a preventable and treatable disease, highlighting the need for efficient screening strategies to identify patients with COPD. However, there is little evidence regarding the efficacy of mass screening for COPD, and no epidemiological studies on COPD have been conducted in the Shikoku region of Japan. METHODS: In this cross-sectional study, we originally investigated the efficacy of mass screening for COPD among community residents in the aforementioned region using two COPD screening questionnaires. RESULTS: From July 2018 through January 2019, 688 participants were enrolled. COPD was diagnosed using the Global Initiative for the Chronic Obstructive Lung Disease criteria. Twenty-one patients were newly diagnosed with COPD and 19 (90.5%) had early stages COPD. The prevalence of COPD in this study was 3.1%. The COPD Population Screener (COPD-PS) questionnaire and the International Primary Care Airways Guidelines (IPAG) questionnaire had extremely high negative predictive values in discriminating participants with COPD from those without. The scores of both questionnaires were correlated with spirometric tests and with each other. The COPD-PS questionnaire had significantly better specificity and area under the receiver operating characteristic curve value than the IPAG questionnaire. Moreover, only the COPD-PS questionnaire was identified as an independent factor for predicting COPD diagnosis in the multivariate analysis. CONCLUSIONS: Mass screening for COPD using screening questionnaires, particularly the COPD-PS questionnaire, might be useful to identify the early stages of COPD in a medical health check-up population.

Efficacy of osimertinib in epidermal growth factor receptor-mutated non-small-cell lung cancer patients with pleural effusion.

BACKGROUND: Osimertinib is a standard first-line treatment for advanced non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. Although malignant pleural effusion (PE) is a common clinical problem in NSCLC, information about the efficacy of osimertinib in patients with PE is limited, especially regarding its efficacy in EGFR T790M-negative patients with PE remains unclear. METHODS: We retrospectively reviewed the medical records of patients with NSCLC harboring EGFR mutations who were treated with osimertinib in our institution between May 2016 and December 2020. RESULTS: A total of 63 patients with EGFR mutated NSCLC were treated with osimertinib; 33 (12 with PE) had no EGFR T790M mutation, while 30 (12 with PE) had EGFR T790M mutation. In EGFR T790M-negative NSCLC, the progression-free survival (PFS) of the patients with PE was comparable to that of the patients without PE (median PFS 19.8 vs. 19.8 months, p = 0.693). In EGFR T790M- positive NSCLC, the PFS and overall survival (OS) of the patients with PE were significantly shorter than those of the patients without PE (median PFS 16.8 vs. 8.3 months, p = 0.003; median OS 44.9 vs. 14.2 months, p = 0.007). In the multivariate analysis, the presence of PE was independently associated with shorter PFS and OS in EGFR T790M-positive NSCLC patients, but not EGFR T790M-negative patients. CONCLUSIONS: These data suggest the efficacy of osimertinib may differ between EGFR T790M-positive and -negative NSCLC patients with PE.

Radiation therapy induces an abscopal effect and upregulates programmed death-ligand 1 expression in a patient with non-small cell lung cancer.

Radiation therapy (RT) activates the antigen presentation of dendritic cells and priming of cancer-specific cytotoxic CD8+ T cells, occasionally resulting in a systemic immune response to the tumor outside of the treatment field. The phenomenon of tumor regression at the site distant from irradiated fields is known as the abscopal effect. Several case reports have indicated a potential role of RT in overcoming primary and acquired resistance against immune checkpoint inhibitors in non-small cell lung cancer (NSCLC) and melanoma patients. We herein report an NSCLC patient who developed acquired resistance to an RT-induced abscopal effect and subsequently experienced reactivation of the systemic antitumor immune response by pembrolizumab, an antiprogrammed death 1 antibody. In this case, RT not only induced an abscopal effect but also upregulated the programmed death-ligand 1 expression outside of the irradiated field when the patient developed resistance to the abscopal effect. This case can facilitate our understanding of the mechanism underlying the RT-induced systemic immune response against cancer cells and adaptive resistance mechanism of cancer cells from immune surveillance. These findings highlight the promising results of current clinical trials combining RT and immune checkpoint inhibitors. Ongoing clinical trials will further establish evidence supporting combination therapy with RT and immune checkpoint inhibitors.

A case of pulmonary pleomorphic carcinoma with preexisting interstitial pneumonia successfully treated with pembrolizumab.

Pulmonary pleomorphic carcinoma is often refractory to chemotherapy and follows an aggressive clinical course. Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced lung cancer, and a few cases with pleomorphic carcinoma have been reported to show tumor shrinkage after therapy with ICIs. When treating patients with ICIs, patient selection is essential, and monitoring and management of immune-related adverse events, including pneumonitis, are needed. We herein report a case of pulmonary pleomorphic carcinoma with preexisting interstitial pneumonia treated with pembrolizumab, antiprogrammed cell death 1 antibody. Our report highlights important considerations necessary when treating advanced pleomorphic carcinoma patients complicated with interstitial pneumonia. We also review the literature regarding the use of ICIs in such patients.

A case of chest tightness variant asthma†:†the usefulness of fractional exhaled nitric oxide as a marker for the diagnosis and clinical improvement.

A 50-year-old woman was referred to our hospital for further examination of severe constricting pain at the right-side dominant anterior chest. She had medical history of outgrown childhood asthma and allergies to several animals. Chest auscultation revealed no wheezes, rhonchi and other crackles. Laboratory findings showed an eosinophilia and an elevation of total immunoglobulin E. The results of an electrocardiogram, a chest X-ray and a chest CT were unremarkable. A fractional exhaled nitric oxide value remarkably elevated, but the abnormalities in pulmonary function test were modest. Her chest pain was ameliorated after inhaling procaterol. Based on these findings, a diagnosis of chest tightness variant asthma was formulated, and we started treatment with inhaled corticosteroid / long acting ß2 agonist. At two-weeks after treatment, her symptom markedly improved and a fractional exhaled nitric oxide value decreased, which led to a definitive diagnosis of chest tightness variant asthma. A fractional exhaled nitric oxide value further decreased to the normal range in consistent with symptom disappearance at 10-months after treatment, indicating the usefulness of fractional exhaled nitric oxide as a promising marker for the diagnosis and clinical improvement of chest tightness variant asthma. J. Med. Invest. 68 : 389-392, August, 2021.

A rare case of invasive thymoma presented a dramatic response to low-dose prednisolone as a single-drug therapy.

A 76-year-old woman with a history of angina pectoris, hypertension and dyslipidemia was pointed out an abnormal opacity in the right hilar region on routine chest X-ray. Chest computed tomography showed masses in the anterior mediastinum with the invasion of the adjacent ascending aorta, right brachiocephalic vein and right pleura. Histologic examination led to a diagnosis of Masaoka stage IVa thymoma. Three courses of chemotherapy were given, but further tumor progression was seen. Thereafter, the patient was followed without aggressive treatments. One year after the initial diagnosis, she presented with dyspnea and right chest pain. Chest CT revealed right massive pleural effusion with pleural dissemination and much further progression of existing tumors. For the purpose of symptom palliation, a low dose (5 mg / day) of prednisolone was commenced, which unexpectedly led to marked alleviation of patient's symptoms and dramatic decrease of pleural effusion. To the best of our knowledge, this is the first report of an invasive thymoma responded to low-dose corticosteroid. The present case suggests that corticosteroids, even at low doses, might be potentially effective for invasive thymoma after failure of surgery, chemotherapy and radiotherapy. J. Med. Invest. 68 : 396-399, August, 2021.

Correlation between immune-related adverse events and therapeutic effects of nivolumab in patients with malignant pleural mesothelioma.

BACKGROUND: Nivolumab is used for the treatment of malignant pleural mesothelioma (MPM). However, immune-related adverse events (irAEs) occur in patients treated with nivolumab. Several studies have reported the correlation between irAEs and therapeutic effects of immune checkpoint inhibitor, but none have reported the correlation in MPM. Here we report a retrospective study which shows the correlation between irAEs and therapeutic effects of nivolumab in patients with MPM. METHODS: This study included patients treated with nivolumab at Tokushima University Hospital from February 2009 to September 2021. We retrospectively reviewed the medical records to evaluate the several clinical factors, such as the presence or absence of irAEs, their severities, progression-free survival (PFS), overall survival (OS) or objective response to the treatment. RESULTS: Eleven patients received treatment with nivolumab. Objective response rate was 18.2% and the disease control rate was 90.9%. Median PFS was 6.8 months (95% confidence interval, 1.3 to 11.9 months) and median OS was 15.2 months (95% confidence interval, 8.9 to 21.5 months). IrAEs occurred in eight patients (72.7%), and grade ≥ 2 irAEs occurred in six patients (54.5%). PFS and OS were significantly longer in the grade ≥ 2 irAEs group than in grade < 2 irAEs group (median PFS 13.6 vs. 3.8 months, p = 0.0093; median OS not reached vs. 8.6 months, p = 0.0108). CONCLUSIONS: This is the first study to report the correlation between irAEs and therapeutic effects in patients with MPM. Because the presence of irAEs may be associated with a favorable clinical outcome, early detection and appropriate management of irAEs will increase the therapeutic benefits to patients.

Programmed death (PD)-1/PD-ligand 1 blockade mediates antiangiogenic effects by tumor-derived CXCL10/11 as a potential predictive biomarker.

Immune checkpoint inhibitor (ICI) programmed death (PD)-1/PD-ligand 1 (PD-L1) blockade has been approved for various cancers. However, the underlying antitumor mechanisms mediated by ICIs and the predictive biomarkers remain unclear. We report the effects of anti-PD-L1/PD-1 Ab in tumor angiogenesis. In syngeneic mouse models, anti-PD-L1 Ab inhibited tumor angiogenesis and induces net-like hypoxia only in ICI-sensitive cell lines. In tumor tissue and serum of ICI-sensitive cell line-bearing mice, interferon-γ (IFN-γ) inducible angiostatic chemokines CXCL10/11 were upregulated by PD-L1 blockade. In vitro, CXCL10/11 gene upregulation by IFN-γ stimulation in tumor cell lines correlated with the sensitivity of PD-L1 blockade. The CXCL10/11 receptor CXCR3-neutralizing Ab or CXCL11 silencing in tumor cells inhibited the antiangiogenic effect of PD-L1 blockade in vivo. In pretreatment serum of lung carcinoma patients receiving anti-PD-1 Ab, the concentration of CXCL10/11 significantly correlated with the clinical outcome. Our results indicate the antiangiogenic function of PD-1/PD-L1 blockade and identify tumor-derived CXCL10/11 as a potential circulating biomarker of therapeutic sensitivity.

Blockade of PD-1/PD-L1 Pathway Enhances the Antigen-Presenting Capacity of Fibrocytes.

Fibrocytes, a distinct population of collagen-producing, monocyte-derived cells, are involved in wound healing as well as fibrotic diseases. Recently, fibrocytes have been revealed to play a role in the tumor microenvironment, particularly under antiangiogenic therapy. In addition, combination cancer immunotherapy with immune checkpoint inhibitor and antiangiogenic agents have been developed for various cancers in the clinical setting, although the immunological background is not clear. In the current study, we aimed to determine the function of fibrocytes in tumor immunity induced by immune checkpoint inhibitor therapy. Human and murine fibrocytes were generated from PBMCs and lungs, respectively. The expression of costimulatory and inhibitory molecules on fibrocytes was examined by flow cytometry. The stimulation of CD8+ T cells by fibrocytes was examined in MLRs with a 3H-thymidine incorporation assay. Fibrocytes expressed CD80low and CD86high as a costimulatory molecule, and expressed PD-L1high, but not PD-L2, as a coinhibitory molecule. Without any stimulation, fibrocytes strongly enhanced the proliferation of CD8+ T cells in mice and humans. Treatment with anti-CD86 and -CD54 Abs inhibited the growth of CD8+ T cells induced by fibrocytes. Anti-PD-L1 Ab further enhanced the proliferation of CD8+ T cells, even in the OVA-specific MLR with OT-1Rag-/- mice. Importantly, fibrocytes derived from PBMCs of patients with lung adenocarcinoma or murine MC38 tumors augmented the proliferation of CD8+ T cells with PD-L1 blockade. These results suggest that fibrocytes infiltrating tumor sites may play a role in the antitumor immunity mediated by CD8+ T cells when the activity is further enhanced by PD-L1/PD-1 blockade.