The clinical significance of tertiary lymphoid structure and its relationship with peripheral blood characteristics in patients with surgically resected non-small cell lung cancer: a single-center, retrospective study.

INTRODUCTION: The presence of tertiary lymphoid structure (TLS) in tumor tissues has been reported to be a factor associated with a good prognosis in several types of cancers. However, the relationship between TLS formation and peripheral blood findings remains unclear. The purposes of the study were to evaluate the effect of the presence of TLS on survival and determine the peripheral blood characteristics associated with TLS formation in non-small cell lung cancer (NSCLC) patients. METHODS: A total of 147 consecutive NSCLC patients who underwent lung resection at Fukushima Medical University Hospital between 2013 and 2017 were enrolled. TLS expression was evaluated, and the relationships between clinical parameters and outcomes were analyzed. Peripheral blood mononuclear cells (PBMCs) were further analyzed by mass cytometry to characterize the TLS-positive microenvironment. RESULTS: Forty-six patients had high TLS expression, and the remaining 101 patients had low TLS expression. In stage II to IV patients (n = 35), disease-free survival was longer in the high TLS expression group (p = 0.027). A low neutrophil to lymphocyte ratio (NLR) < 2.75 in the peripheral blood was associated with high TLS expression (p = 0.003). Citrus analysis after mass cytometry assay showed that the number of cells expressing HLA-DR and CD9 in PBMCs was lower in the high TLS expression group. CONCLUSION: High TLS expression is associated with a good prognosis after surgery in stage II and III NSCLC patients. In the peripheral blood, a low NLR and few antigen-presenting cells indicate the presence of TLS in the tumor microenvironment.

[Resistance Mechanisms to Immune Checkpoint Inhibitor and Its Overcome with Focus on ß-Catenin in Lung Cancer].

Although the indications for immune checkpoint inhibitors are expanding rapidly, the disease will eventually progress in many patients. Elucidating and overcoming the resistant mechanisms to immune checkpoint inhibitors is a major challenge. WNT/ß-catenin pathway has long been known as one of the mechanisms involved in cell proliferation and epithelial-mesenchymal transition in cancer development. Recently, it has become clear that WNT/ß-catenin pathway also plays a role in cancer immune escape, as reported in melanoma. We have also studied WNT/ß-catenin pathway as a mechanism of immune escape in lung cancer. In this article, we review how WNT/ß-catenin pathway is involved in immune escape and resistance to immune checkpoint inhibitors, mainly in non-small cell lung cancer. In addition, we discuss how to overcome the tumor immune mechanism caused by WNT/ß-catenin pathway in the context of current combination therapies and therapies in development.

[ß-Catenin Expression in Non-Small Cell Lung Cancer and Therapeutic Effect of Immune Checkpoint Inhibitors].

Recently, ß-catenin mediated immune escape mechanism has been reported in several cancers. We investigated whether ß-catenin is associated with resistance to immune checkpoint inhibitor therapy in non-small cell lung cancer. Non-small cell lung cancer patients expressing high levels of ß-catenin showed poor progression-free survival and overall survival after single agent anti-PD-1 therapy. They had less infiltration of CD8-positive cells and antigen-presenting cells. Microarray analysis also showed low gene expression of CD8A and IFNG. siRNA knockdown of CTNNB1 in the ß-catenin-positive lung cancer cell line LK-2 tended to decrease CTNNB1 and ATF3 expression and increase CCL4 expression. The results suggest that ß- catenin suppresses tumor infiltration by antigen-presenting cells and confers resistance to immune checkpoint inhibitors in non-small cell lung cancer via downregulation of CCL4 production.

[Monitoring Tumor Infiltrating Lymphocytes by Peripheral Blood in Lung Cancer Patients].

There have been many reports on the association between tumor infiltrating lymphocytes and cancer prognosis. It is known that tumor infiltrating lymphocytes contain not only cytotoxic T lymphocytes but also bystander lymphocytes and immunosuppressive cells. In most of previous reports, tumor infiltrating lymphocytes were defined as CD3 or CD8 T cells. It is generally thought that patients with cancer rich in tumor infiltrating lymphocytes have a good prognosis. Most tumor infiltrating lymphocytes are thought to be cytotoxic T lymphocytes. It is also reported that cancer rich in tumor infiltrating lymphocytes is responsive to immune checkpoint inhibitors. In recent years, several reports revealed clonal replacement in tumor infiltrating lymphocytes after administration of immune checkpoint inhibitors. This change was also detectable in peripheral blood. From the viewpoint of lung cancer treatment, combination of immune checkpoint inhibitors and chemotherapy became the standard therapy. We need to understand the tumor immune microenvironment in order to select the best treatment regimen for each patient. However, it is often difficult to obtain an adequate amount of tissue biopsy sample in standard of care. It is hoped that we can understand the tumor immune microenvironment using the peripheral blood. Thus, studying the association between treatment response, tumor infiltrating lymphocytes, and peripheral blood is considered to be important to research and develop peripheral blood biomarkers in lung cancer.

[Fenestration, Pedicle Muscle Flap, and Omental Plombage for Pyothorax].

We sometimes encounter patients with chronic empyema of their thoracic cavity with or without air leakage. These patients suffer from mental and physical problems because of restrictions in daily life and long-term treatment. Pyothorax is divided into acute or chronic empyema. The former is treated by thoracic drainage or debridement under video-assisted thoracic surgery, while the latter is treated by managing the infection and reducing the dead space of the thoracic cavity. In this section, we describe the procedures for some treatment methods and technical skills to manage pyothorax, including fenestration, pedicle muscle flap plombage, omental plombage. The thoracic surgeon should consider the advantages and disadvantages of each method and choose an appropriate technique or possibly a combination of techniques to obtain an optimal outcome in the treatment of pyothorax. The techniques and knowledge described in this section would be useful for many thoracic surgeons' clinical work. Although the treatment methods differ between institutions, this guideline for thoracic empyema is needed to standardize treatment of this entity in the future.

Ground-glass nodule in a patient with echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK)-positive lung cancer: a case report.

BACKGROUND: Grand-glass nodule for CT image has thought to be less aggressive tumor in lung cancer. Echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK)-positive lung cancer presenting with Ground-glass nodules (GGNs) is relatively rare, and few such cases have been reported. CASE PRESENTATION: An asymptomatic 56-year-old woman exhibited a 1.1-cm GGN in the lower lobe of the left lung on computed tomography during a medical checkup. Positron emission tomography showed no difference in uptake by the nodule compared with other organs. We elected to perform surgery because the nodule included a solid component and had grown only slightly during the last 2 years according to thin-section computed tomography. Partial resection of the lower left lung was performed by video-assisted thoracic surgery. Pathological examination revealed mucus-producing high columnar epithelium forming an irregular tubular-acinar-like structure partly replacing the alveolar epithelium on hematoxylin and eosin staining. More than 50 % of the tumor demonstrated a lepidic growth pattern. The tumor was negative for epidermal growth factor receptor mutation but positive for the EML4-ALK fusion oncogene according to fluorescence in situ hybridization. CONCLUSIONS: We herein report a case of EML4-ALK-positive lung cancer presenting with a GGN along with a review of the relevant literature, including histopathological findings and imaging features. We consider that EML4-ALK-positive lung cancer is often highly progressive and that careful follow-up is therefore essential in these patients.

FDG-PET in the evaluation of response to nivolumab in recurrent non-small-cell lung cancer.

BACKGROUND: Nivolumab, an immune checkpoint inhibitor, is recently clinically applied to non-small cell lung cancer (NSCLC) treatment, and this causes T cell activation and T cell infiltration to tumor tissue through the blockade of the interaction between programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1). 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) sometimes shows false positive because of the recruitment of neutrophils, lymphocytes, and macrophages. To date, there is only one report except our case, which described the correlation between FDG-PET and nivolumab. CASE PRESENTATION: We report on a 75-year-old man on nivolumab treatment for metastatic non-small cell lung cancer. He had undergone right lower lobectomy for lung adenocarcinoma in the right S8 segment 10 months prior to recurrence. Pathological findings revealed invasive adenocarcinoma, pT1bN2M0 stage IIIA. Epidermal growth factor receptor (EGFR) mutation was positive for de novo T790M and anaplastic lymphoma kinase (ALK) rearrangement was negative. Immunohistochemistry was negative for PD-L1. He underwent chemotherapy with a combination of cisplatin and pemetrexed for four cycles but developed progressive disease involving the right hemithorax, multiple lymph nodes, and multiple osseous sites. Nivolumab was instituted as a second-line chemotherapy. After six courses of this immunotherapy, FDG-PET scan showed decreased FDG uptake in each recurrent lesion despite T lymphocyte activation by nivolumab. Serum carcinoembryonic antigen (CEA) level was also remarkably decreased. CONCLUSIONS: Nivolumab's effect on recurrent NSCLC may be monitored by PET; larger studies are needed.

[Two cases of thymic carcinoid treated with octreotide long-acting repeatable].

Thymic carcinoid is a rare disease that accounts for 3.1% of thymic tumors and 1.8-6% of all carcinoid tumors in Japan. Advanced thymic carcinoid has a 5-year survival rate of 28-31%.Compared with carcinoid tumors that arise in other organs, thyroid carcinoid tumors carry a relatively worse prognosis, and the most effective therapeutic strategy is thought to be surgical resection.However, for patients with recurrence and distant metastases, multimodal therapy including radiotherapy and/or chemotherapy is usually applied.No chemotherapy treatment regimen has been established in Japan, although the National Comprehensive Cancer Network Guidelines proposed the application of octreotide long-acting repeatable(LAR).In this report, we present two cases of thymic carcinoid that were treated with octreotide LAR and achieved long-term survival.

Multiple therapeutic peptide vaccines consisting of combined novel cancer testis antigens and anti-angiogenic peptides for patients with non-small cell lung cancer.

BACKGROUND: Vaccine treatment using multiple peptides derived from multiple proteins is considered to be a promising option for cancer immune therapy, but scientific evidence supporting the therapeutic efficacy of multiple peptides is limited. METHODS: We conducted phase I trials using a mixture of multiple therapeutic peptide vaccines to evaluate their safety, immunogenicity and clinical response in patients with advanced/recurrent NSCLC. We administered two different combinations of four HLA-A24-restricted peptides. Two were peptides derived from vascular endothelial growth factor receptor 1 (VEGFR1) and 2 (VEGFR2), and the third was a peptide derived from up-regulated lung cancer 10 (URLC10, which is also called lymphocyte antigen 6 complex locus K [LY6K]). The fourth peptide used was derived from TTK protein kinase (TTK) or cell division associated 1 (CDCA1). Vaccines were administered weekly by subcutaneous injection into the axillary region of patients with montanide ISA-51 incomplete Freund's adjuvant, until the disease was judged to have progressed or patients requested to be withdrawn from the trial. Immunological responses were primarily evaluated using an IFN-gamma ELiSPOT assay. RESULTS: Vaccinations were well tolerated with no severe treatment-associated adverse events except for the reactions that occurred at the injection sites. Peptide-specific T cell responses against at least one peptide were observed in 13 of the 15 patients enrolled. Although no patient exhibited complete or partial responses, seven patients (47%) had stable disease for at least 2 months. The median overall survival time was 398 days, and the 1- and 2-year survival rates were 58.3% and 32.8%, respectively. CONCLUSION: Peptide vaccine therapy using a mixture of four novel peptides was found to be safe, and is expected to induce strong specific T cell responses. TRIAL REGISTRATION: These studies were registered with ClinicalTrials.gov NCT00633724 and NCT00874588.

Salvage surgery for advanced non-small cell lung cancer following previous immunotherapy: a retrospective study.

BACKGROUND: The development of systemic chemotherapy including immune checkpoint inhibitors (ICIs) has provided patients with unresectable advanced non-small cell lung cancer (NSCLC) an opportunity to undergo surgical intervention after initial treatment. However, no consensus regarding the indication for salvage surgery in these patients has been reached. METHODS: We conducted a retrospective study of patients who underwent salvage surgery for advanced NSCLC (cStage IIIA-IVB) after treatment with ICIs from January 2018 to December 2022 at Aizu Medical Center and Fukushima Medical University Hospital. We evaluated the patients' clinical data, calculated disease-free survival (DFS) and overall survival (OS), and assessed the survival benefit using the Kaplan-Meier method. RESULTS: Thirteen patients underwent salvage surgery after immunotherapy. All patients achieved downstaging after initial chemotherapy. Eleven patients underwent lobectomy, and one patient underwent extirpation of intra-abdominal lymph nodes. The mean surgery time and intraoperative blood loss were 242.2 min and 415.1 g, respectively. The mean drainage period was 4.2 days (range, 2-9 days). Grade ≥ 3 postoperative complications were confirmed in three patients. The 2-year DFS rate was 71.2%, and the 2-year OS rate was 76.2%. A pathological complete response compatible with ypStage 0 was achieved in four (30.8%) patients. Patients with ypStage 0 and I achieved significantly better OS than those with ypStage ≥ II (p = 0.044), and patients without severe complications achieved significantly better DFS and OS than those with severe complications (p = 0.001 and p < 0.001, respectively). CONCLUSIONS: Salvage surgery after chemotherapy including ICIs is a feasible and effective treatment option for patients with advanced NSCLC, especially those who acquire downstaging to pathological stage 0 or I. However, severe perioperative complications might affect patient survival. A prospective study is urgently needed to evaluate the efficacy of salvage surgery.

Laparoscopic repair of an incarcerated inguinal hernia containing the sigmoid colon with a colonoscope.

Here, we report the first case of laparoscopic surgery to repair an incarcerated colonoscope in an inguinal hernia containing the sigmoid colon. After colonoscopy was performed on a 74-year-old man with positive fecal occult blood test results, the colonoscope could not be withdrawn. A bulge consistent with an incarcerated colonoscope was found on examination of the patient's left inguinal area. Computed tomography revealed and led to the diagnosis of an incarcerated colonoscope in the sigmoid colon within the inguinal hernia. After confirmation during emergency laparoscopic surgery, the incarcerated sigmoid colon was reduced, and the colonoscope was removed under radiographic and laparoscopic guidance. No ischemic changes or serosal injuries were observed, averting the need for resection. A transabdominal preperitoneal approach with a mesh was then used to repair the inguinal hernia laparoscopically. The patient's postoperative recovery was uneventful, and no recurrence was observed at the 1-year follow-up.

Development of a novel artificial intelligence algorithm to detect pulmonary nodules on chest radiography.

BACKGROUND: In this study, we aimed to develop a novel artificial intelligence (AI) algorithm to support pulmonary nodule detection, which will enable physicians to efficiently interpret chest radiographs for lung cancer diagnosis. METHODS: We analyzed chest X-ray images obtained from a health examination center in Fukushima and the National Institutes of Health (NIH) Chest X-ray 14 dataset. We categorized these data into two types: type A included both Fukushima and NIH datasets, and type B included only the Fukushima dataset. We also demonstrated pulmonary nodules in the form of a heatmap display on each chest radiograph and calculated the positive probability score as an index value. RESULTS: Our novel AI algorithms had a receiver operating characteristic (ROC) area under the curve (AUC) of 0.74, a sensitivity of 0.75, and a specificity of 0.60 for the type A dataset. For the type B dataset, the respective values were 0.79, 0.72, and 0.74. The algorithms in both the type A and B datasets were superior to the accuracy of radiologists and similar to previous studies. CONCLUSIONS: The proprietary AI algorithms had a similar accuracy for interpreting chest radiographs when compared with previous studies and radiologists. Especially, we could train a high quality AI algorithm, even with our small type B data set. However, further studies are needed to improve and further validate the accuracy of our AI algorithm.

Wnt/ß-Catenin Signaling and Resistance to Immune Checkpoint Inhibitors: From Non-Small-Cell Lung Cancer to Other Cancers.

Lung cancer is the leading cause of cancer-related deaths worldwide. The standard of care for advanced non-small-cell lung cancer (NSCLC) without driver-gene mutations is a combination of an anti-PD-1/PD-L1 antibody and chemotherapy, or an anti-PD-1/PD-L1 antibody and an anti-CTLA-4 antibody with or without chemotherapy. Although there were fewer cases of disease progression in the early stages of combination treatment than with anti-PD-1/PD-L1 antibodies alone, only approximately half of the patients had a long-term response. Therefore, it is necessary to elucidate the mechanisms of resistance to immune checkpoint inhibitors. Recent reports of such mechanisms include reduced cancer-cell immunogenicity, loss of major histocompatibility complex, dysfunctional tumor-intrinsic interferon-γ signaling, and oncogenic signaling leading to immunoediting. Among these, the Wnt/ß-catenin pathway is a notable potential mechanism of immune escape and resistance to immune checkpoint inhibitors. In this review, we will summarize findings on these resistance mechanisms in NSCLC and other cancers, focusing on Wnt/ß-catenin signaling. First, we will review the molecular biology of Wnt/ß-catenin signaling, then discuss how it can induce immunoediting and resistance to immune checkpoint inhibitors. We will also describe other various mechanisms of immune-checkpoint-inhibitor resistance. Finally, we will propose therapeutic approaches to overcome these mechanisms.

Immunolocalization of CD80 and CD86 in Non-Small Cell Lung Carcinoma: CD80 as a Potent Prognostic Factor.

It has been demonstrated that tumor cells express programed cell death protein 1 (PD-L1) to escape T lymphocytes that express programed cell protein 1 (PD-1), and PD-1/PD-L1 immune checkpoint inhibitors have been regarded in lung cancer patients. CD80 and CD86 are members of B7 superfamily which regulates T lymphocyte activation and tolerance. However, immunolocalization of CD80 and CD86 has not been examined in the lung carcinoma tissues and their clinical significance remains unknown. Therefore, to clarify clinical significance of CD80 and CD86, we immunolocalized these in 75 non-small cell lung carcinomas (NSCLC) in this study. Immunoreactivities of CD80 and CD86 were mainly detected in tumor-infiltrating macrophages. Immunohistochemical CD80 status was high in 56% of NSCLC, and it was positively associated with stage, pathological T factor, distant metastasis, histological type and PD-L1 status. Moreover, multivariate analysis turned out that the CD80 status was an independent worse prognostic factor. CD86 status was high in 53% of the cases, but it was not significantly associated with any clinicopathological parameters. These findings suggest that CD80 is a potent worse prognostic factor possibly in association with escape from immune attack in NSCLC.

[A case of long-term survival after resection of aortic arch for locally advanced non-small cell lung cancer with induction chemotherapy].

Our patient was a 57-year-old male with a history of esophageal cancer. He was referred to our hospital for squamous cell lung carcinoma(SCC). Chest computed tomography identified a mass in the left lung field, which was suspected to be invading the reconstructed gastric tube, left subclavian artery, common carotid artery, and distal aortic arch. He was diagnosed as primary pulmonary squamous cell carcinoma(SCC)because six years had already passed since a previous surgery for early esophageal cancer. He received three courses of induction chemotherapy including S-1/CDDP. We evaluated the therapy as a partial response. He underwent an extended resection of distal aortic arch and left subclavian artery with left upper lobectomy, and those vessels were reconstructed using prosthetic grafts. Pathological findings showed the tumor as a well differentiated SCC of pT4N0M0 at stage III A, with a residual tumor on the reconstructed gastric tube, even though the effect of induction chemotherapy was Ef2. He received three courses of S-1/CDDP after surgery. The patient has been well without recurrence for 31 months after surgery.

[Renal-salt wasting syndrome in a patient with CDDP containing chemotherapy for recurrent non-small-cell lung cancer].

Hyponatremia is one of the major side effects that occurs after CDDP-based cancer chemotherapy. However, RSWS has rarely been reported as a cause of hyponatremia occurring after chemotherapy containing CDDP. A 70-year-old female who had recurrent lung adenocarcinoma after surgery was treated with CDDP, pemetrexed and bevacizumab-containing chemotherapy. She suffered from acute-onset consciousness disturbance and hyponatremia on day 3 of chemotherapy. Although SIADH was considered at the time of onset, the patient was subsequently diagnosed with RSWS, based on observations of dehydration, high levels of urinary sodium excretion and evidence of renal tubule failure. She recovered from these conditions without any residual disability after infusion of hypertonic saline fluid on day 13 of chemotherapy. In this report, we have described RSWS, which is rare complication that may follow CDDP-based chemotherapy. It is important, but not very easy, to distinguish between SIADH and RSWS clinically for the selection of an appropriate treatment.

Pathological Complete Response after Immune-Checkpoint Inhibitor Followed by Salvage Surgery for Clinical Stage IV Pulmonary Adenocarcinoma with Continuous Low Neutrophil-to-Lymphocyte Ratio: A Case Report.

Immune-checkpoint inhibitors (ICIs) play a crucial role in the treatment of advanced nonsmall cell lung cancer (NSCLC); however, most patients fail this treatment after a limited period. We here report a patient with a pathological complete response after treatment with ICI for stage IV pulmonary adenocarcinoma. A 73-year-old man was referred to our hospital because of hoarseness. A roentgenogram and chest CT scan revealed a huge (78-mm diameter) pulmonary tumor in the right upper lobe and a tumor with cavitation in the left lower lobe. A CT scan also showed enlarged upper mediastinal lymph nodes (LNs). Transbronchial lung biopsy of the tumors showed adenocarcinomas in both. The tumor in the right upper lobe was considered to be the primary with mediastinal LNs metastasis and that in the left lower lobe a pulmonary metastasis. The disease was determined to be cT4N2M1a stage IVA. He was treated with first-line chemotherapy comprising cisplatin, pemetrexed, and bevacizumab for 6 cycles. However, 6 months after initial treatment, the primary and metastatic tumors enlarged, and he was treated with second-line anti-programed death 1 therapy for 7 months with a partial response. 18-fluorodeoxyglucose positron emission tomography (FDG-PET) revealed weak accumulation of FDG in the primary tumor only with no accumulation in the left pulmonary metastasis or mediastinal lymph node (LNs), despite the LNs still being enlarged. He was diagnosed as having ycT1bN0M0 stage IA2 disease and underwent right upper lobectomy. Postoperative pathological findings revealed that cancer tissues had been replaced by scar tissue and that CD4-positive T cells, rather than CD8-positive T cells, were predominant. It was also noted that he had a lower neutrophil-to-lymphocyte ratio (NLR) during immunotherapy than before immunotherapy and after surgery. He was diagnosed to be ypT0N0M0 stage 0 (Ef.3). His postoperative course was uneventful, and he remained well for 12 months after surgery with no further treatment. Neoadjuvant chemotherapy with ICIs for advanced NSCLC may be a promising modality, even for clinical stage IV disease, in the near future. Furthermore, NLR during immunotherapy may be a promising biomarker of ICIs treatment.

CTLA-4 Expression in Tumor-infiltrating Lymphocytes Is Irrelevant to PD-L1 Expression in NSCLC.

BACKGROUND/AIM: Treatments containing ipilimumab have shown a good outcome in patients with non-small cell lung cancer (NSCLC) regardless of the PD-L1 tumor proportion score (TPS). However, the association between PD-L1 TPS and the expression of CTLA-4 in tumor-infiltrating lymphocytes is unknown. PATIENTS AND METHODS: Fifty-five NSCLC patients who underwent surgery in our hospital were included in this study. We measured the proportions of CTLA-4+ regulatory T cells, and CTLA-4+ CD8 T cells, and statistically analyzed their correlations with the PD-L1 TPS. RESULTS: Statistical correlations were found neither between the proportion of CTLA-4+ regulatory T cells to CD8 T cells and the PD-L1 TPS (p=0.2859) nor between the proportion of CTLA-4+ cells in CD8 T cells and the PD-L1 TPS (p=0.1919). CONCLUSION: The proportions of CTLA-4+ regulatory T cells to CD8 T cells and CTLA-4+ cells in CD8 T cells were irrelevant to the PD-L1 TPS in NSCLC patients.

Tumor ß-catenin expression is associated with immune evasion in non-small cell lung cancer with high tumor mutation burden.

ß-catenin expression by tumor cells suppressed dendritic cell recruitment to the tumor microenvironment in a melanoma model, resulting in fewer tumor-infiltrating lymphocytes. Immunohistochemistry was used in the present study to examine the association between the expression of ß-catenin and tumor infiltrating lymphocytes and CD11c+ cells in 122 patients with non-small cell lung cancer (NSCLC), who underwent radical surgery. ß-catenin was positive in 24% of NSCLC tumors compared with 59% of squamous cell carcinomas and 11% of adenocarcinomas. There was no significant association between the expression of ß-catenin and the frequency of CD8+ cell infiltration into tumor tissues, including the stroma. Conversely, the infiltration of CD8+ cells into tumor nests was significantly lower in ß-catenin-positive cases compared with that in negative ß-catenin cases. Similarly, CD11c+ cell infiltration was significantly lower in the ß-catenin-positive group. The ß-catenin-positive group had shorter overall survival and recurrence-free survival times compared with that in the negative group. Furthermore, ß-catenin-positive NSCLC had a high tumor mutation burden, but tended to have a low expression of programmed death-ligand 1. In conclusion, the expression of ß-catenin in NSCLC was negatively associated with CD11c+ cells and cytotoxic T cell infiltration at the tumor site and had a tendency towards a poor prognosis.

Prognostic significance of OX40+ lymphocytes in tumor stroma of surgically resected small-cell lung cancer.

OX40 (CD134) is a co-stimulatory molecule mostly expressed on activated T lymphocytes. Previous reports have shown that OX40 can be an immuno-oncology target and a clinical biomarker for cancers of various organs. In this study, we collected formalin-fixed paraffin-embedded tumor samples from 124 patients with small-cell lung cancer (SCLC) who had undergone surgery. We analyzed the expression profiles of OX40 and other relevant molecules, such as CD4, CD8, and Foxp3, in tumor stroma and cancer nest using immunohistochemistry and investigated their association with survival. High infiltration of OX40+ lymphocytes (OX40high) in tumor stroma was positively associated with relapse-free survival (RFS) and overall survival (OS) compared with low infiltration of OX40+ lymphocytes (OX40low) (RFS, median, 26.0 months [95% confidence interval (CI), not reached (NR)-NR] vs 13.2 months [9.1-17.2], p = .024; OS, NR [95% CI, NR-NR] vs 29.8 months [21.3-38.2], p = .049). Multivariate analysis revealed that OX40high in tumor stroma was an independent indicator of prolonged RFS. Moreover, RFS of patients with OX40high/CD4high in tumor stroma was significantly longer than that of patients with OX40low/CD4low. The RFS of patients with tumor stroma with OX40high/CD8high was significantly longer than that of patients with tumor stroma with OX40low/CD8high, OX40high/CD8low, or OX40low/CD8low. These findings suggest that OX40+ lymphocytes in tumor stroma play a complementary role in regulating the relapse of early-stage SCLC. Reinforcing immunity by coordinating the recruitment of OX40+ lymphocytes with CD4+ and CD8+ T cells in tumor stroma may constitute a potential immunotherapeutic strategy for patients with SCLC.