Development of adoptive immunotherapy with KK-LC-1-specific TCR-transduced γδT cells against lung cancer cells.

The present study analyzed the antitumor effect of γδT cells transduced with the TCR of cancer-specific CTLs to establish forceful cancer-specific adoptive immunotherapy. We cloned the TCRαß genes from CTLs showing HLA-B15 restricted recognition of Kita-Kyushu lung cancer antigen-1 (KK-LC-1), a cancer/germline gene antigen, identified in a lung adenocarcinoma case (F1121). The TCRαß and CD8 genes were transduced into γδT cells induced from PBLs of healthy volunteers stimulated with zoledronate and IL-2. The KK-LC-1-specific TCRαß-CD8 γδT cells showed cytotoxic activity against the KK-LC-1 positive lung cancer cell line F1121L and produced IFN-γ against F1121L and KK-LC-1 peptide-pulsed F1121 EBV-B cells. These responses were blocked by HLA class I and HLA-B/C antibodies. An in vivo assay using NOD/SCID mice with xenotransplantation of human lung cancer cells was performed, and the TCRαß-CD8 transduced γδT cells (TCRαß-CD8 γδT cells) were intravenously injected. Growth inhibition of KK-LC-1+ , HLA-B15+ lung cancer cells was confirmed in mice with injection of the TCRαß-CD8 γδT cells from 1 wk after xenotransplantation of cancer cells but not in those treated 2 wk after xenotransplantation. The resected specimens of the tumor, 2 wk after xenotransplantation, highly expressed FasL but not programmed death ligand-1 (PD-L1) by immunohistochemical staining. FasL highly expressed cancer cells xenotransplanted 2 wk ago were resistant to TCRαß-CD8 γδT cells injection. These results suggested that apoptosis of Fas-positive TCRαß-CD8 γδT cells may be induced by a Fas-mediated signal after interacting with FasL-positive cancer cells.

Detection of circulating tumor cells with a novel microfluidic system in malignant pleural mesothelioma.

Detection of rare tumor cells circulating in the blood (CTCs) presents technical challenges. CellSearch, the only approved system for clinical use, fails to capture epithelial cell adhesion molecule-negative CTCs such as malignant pleural mesothelioma (MPM). We have developed a novel microfluidic device (CTC-chip) in which any Ab to capture CTCs is conjugated. The CTC-chip was coated with an Ab against podoplanin that is abundantly expressed on MPM. Circulating tumor cell-detection performance was evaluated in experimental models in which MPM cells were spiked in blood sampled from a healthy volunteer and in clinical samples drawn from MPM patients. The CTC-chip showed superior CTC-detection performance over CellSearch in experimental models (sensitivity, 63.3%-64.5% vs 0%-1.1%; P < .001) and in clinical samples (CTC-positivity, 68.8% vs 6.3%; P < .001). A receiver operating characteristic (ROC) analysis showed that the CTC test provided a significant diagnostic performance in discrimination of unresectable disease from resectable disease (area under the ROC curve, 0.851; P = .003). The higher CTC count (≥2 cells/mL) was significantly associated with a poor prognosis (P = .030). The novel CTC-chip enabled sensitive detection of CTCs, which provided significant diagnostic and prognostic information in MPM.

A liquid biopsy in primary lung cancer.

A tissue biopsy is the "golden standard" for molecular profiling that is essential in decision-making regarding treatment for malignant tumors, including primary lung cancer. However, tumor biopsies are associated with several limitations, including invasiveness and difficulty in achieving access. Liquid biopsies have several potential advantages over tissue biopsies, and recent advances in molecular technologies have enabled liquid biopsies to be introduced into daily clinical practice. Cell-free blood-based liquid biopsies to detect mutations in the epidermal growth factor receptor (EGFR) gene in the plasma have been approved and may be useful in selecting patients for treatment with tyrosine kinase inhibitors of EGFR. We herein describe blood-based liquid biopsies and review the current status and future perspectives of plasma genotyping in primary lung cancer.

Treatment of Non-small Cell Lung Cancer with EGFR-mutations.

The discovery of activating mutations in the epidermal growth factor receptor (EGFR) gene and development of tyrosine kinase inhibitors (TKIs) of EGFR have achieved a paradigm shift in treatment strategy of non-small cell lung cancer (NSCLC). For advanced NSCLC harboring activating EGFR mutations, an EGFR-TKI is preferably prescribed as it provides a superior survival benefit over platinum-based chemotherapy. To further improve the therapeutic outcomes, more potent EGFR-TKIs through irreversible inhibition of tyrosine kinase have been developed. In a recent clinical trial, an irreversible EGFR-TKI (osimertinib) showed a superior survival benefit with lower toxicity profile. In addition, combination treatments such as an EGFR-TKI plus platinum-based chemotherapy may achieve a long-term survival. For earlier-stage resectable NSCLC with EGFR-mutations, several clinical trials to assess the efficacy of EGFR-TKIs in pre-operative induction setting and in postoperative adjuvant setting are now ongoing. Here we review and discuss the current status and future perspectives of treatment for EGFR-mutated NSCLC.

[A Case Report of Luminal A Male Inflammatory Breast Cancer that Was Difficult to Treat Because of Trousseau Syndrome].

This report describes the case of a 67-year-old male with inflammatory breast cancer. He had noticed a left breast mass about seven years previously, but he had ignored it. He then visited our hospital 4 months previously when multiple small masses occurred in the left front chest wall. The tumor was diagnosed as skin metastasis of breast cancer by skin biopsy and he was referred to our department. The tumor cells were positive for estrogen receptor and progesterone receptor, and negative for HER2/neu, and the Ki67 expression was 10-15%. The subtype of his breast cancer was luminal A type. It had secondary inflammatory breast cancer and preceded chemotherapy. Also, as the veins in the lower extremity were filled with thrombus, we gave him an anticoagulant (Edoxaban), but due to the malignant hyper coagulable state (Trousseau syndrome) a CV port could not be implanted. 3 courses of docetaxel every 3 weeks failed to control the disease. Since an obstruction of the right iliac artery was newly observed, the anticoagulant was changed to cilostazol and rivaroxaban, but left second finger and fourth finger necrosis occurred due to peripheral circulatory failure. The condition of the disease was stabilized by FEC (5-FU, epirubicin, cyclophosphamide) therapy, but it became difficult to secure the blood vessel. Without constructing a CV port because of the thrombus, chemotherapy was changed to S-1 oral administration, and strength to the chest wall Modulated radiotherapy intensity modulated radiation therapy (IMRT) was performed. Although the tumor was reduced, the condition of the whole body gradually weakened and the patient died a year and a half after the start of the treatment. This case of inflammatory luminal in male breast cancer that caused thrombus was difficult to treat. Thrombosis in advanced cancer patients is often pointed out, but since male breast cancer patients tend to take a long time to visit the hospital after becoming aware of the mass and arrive at an advanced state, it is necessary to notify the public of the existence of male breast cancer.

Programmed death-ligand 1 (PD-L1) expression in pleomorphic carcinoma of the lung.

BACKGROUND AND OBJECTIVES: Pulmonary pleomorphic carcinoma (PPC) is a rare and aggressive subtype of lung cancer. Programmed cell death-ligand 1 (PD-L1) expression may be induced in a variety of malignant tumors, but its prognostic implication in PPC remains unclear. METHODS: Twenty-six patients with surgically resected PPC were retrospectively reviewed. Immuno-histochemical staining was used to detect PD-L1 expression, and PD-L1 status was classified into "high" or "low" according to the percentage of tumor cells (TCs) expressing PD-L1 (tumor proportion score, TPS). RESULTS: PD-L1 expression was positive in 20 (76.9%) patients at the cut-off TPS value of 1%. A receiver-operating characteristic (ROC) analysis showed that the optimal cut-off value was 15% for prediction of cancer-specific death with the area under ROC curve of 0.701 (P = 0.107). High PD-L1 expression was associated with a favorable overall survival (88.9% vs 37.5% at 5 years; P =.046) as well as a favorable cancer-specific (100% vs 45.9% at 5 years; P =.012). A multivariate analysis indicated a trend toward a favorable prognosis associated with high PD-L1 expression (hazard ratio [HR], 0.254 [95% confidence interval, 0.054-1.200]; P = 0.084). CONCLUSIONS: PD-L1 expression was positive in most PPC cases, and high PD-L1 expression may predict a favorable prognosis in resected PPC.

Immune Checkpoint Inhibitors (ICIs) in Non-Small Cell Lung Cancer (NSCLC).

Cancer immunotherapy with immune checkpoint inhibitors (ICIs) has become a "game changer" in the treatment of advanced non-small cell lung cancer (NSCLC). Its most clinically important advantage over traditional chemotherapy using cytotoxic agents are its long-term survival benefits, and some advanced NSCLC patients treated with an antibody against programmed cell death 1 (PD-1) have survived for 5 years or longer. Immune checkpoint inhibitors (ICIs) are also potentially useful for earlier-stage NSCLC when used in combination with surgery or radiotherapy. A recent clinical trial has shown that consolidation treatment with an antibody against a ligand of PD-1 (PD-L1) following chemo-radiotherapy significantly improves progression-free survival for patients with locally advanced NSCLC. However, current single-agent treatment with an anti-PD-1/PD-L1 antibody may provide significant survival benefits only in a small subset of patients. PD-L1 expression status on tumor cells is an approved biomarker to predict response to ICIs, but is not enough for optimal patient selection. To improve the therapeutic outcomes, development of novel biomarkers other than PD-L1 expression status is essential. Combination treatment strategies based on blockade of PD-1/PD-L1 may also be promising, and a variety of combinations, such as ICIs plus chemotherapy, are being examined in ongoing clinical trials. Here we review and discuss the current status and future perspectives of immunotherapy with ICIs.

[Analysis of Advanced or Postoperative Recurrent Non-small Lung Cancer Cases Treated with Nivolumab].

Recent developments in cancer immunotherapy are remarkable. Many reports have described the clinical effects of immune checkpoint inhibitors (ICIs), supporting their utility as a promising therapy that will achieve prominent effects even in patients resistant to cytotoxic anticancer drugs or gene-targeting therapy. ICIs may also prolong overall survival. We analyzed 10 cases of advanced lung cancer targeted with nivolumab, which is one of ICIs in our hospital and reviewed the literature regarding ICIs. We retrospectively analyzed 10 cases that consisted of 6 males and 4 females, which comprised 7 adenocarcinomas, 2 squamous cell carcinomas and one pleomorphic carcinoma. Epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase mutations were negative in all the adenocarcinoma cases. The 10 analyzed cases included 9 inoperable cases and 1 postoperative recurrent case, 8 second-line cases, a third-line case, and a fourth-line case. The average frequency of administrations of nivolumab was 7.4 times. The survival rate was calculated by using the Kaplan-Meier method. The clinical responses to nivolumab were partial response in 2 cases, stable disease in 4 cases, and progressive disease in 4 cases. In the 10 cases, the response rate and disease control rate were 20% and 60%, respectively. The median progression-free survival time and median survival time were 115 days and 126 days, respectively. We observed 2 cases of dermatitis and one each of pyrexia, general fatigue and drug-induced pneumonia as adverse events (AEs). One of these AEs was severe (Stevens-Johnson syndrome grade 4) but could be treated by steroid pulse therapy, steroid ointment and instillation. Among the 10 examined cases of advanced lung cancer treated with ICIs at our hospital, ICIs proved effective in 2 cases. However, we also experienced a case with Stevens-Johnson syndrome grade 4 as a severe AE. These findings suggest that while ICIs may be effective in treating patients, candidates for ICIs must be carefully selected and cautiously observed.

[Placement of An Expandable Metallic Stent for Malignant Tracheal Stenosis: A Case Report].

The utility of stent placements has been widely reported. We performed a thought-provoking stent placement for malignant tracheal stenosis recently. A 90-year-old woman who was admitted to our hospital because of a urinary tract infection was treated with a course of antibiotics, but she demonstrated a rapidly progressive course with dyspnea. Chest computed tomography showed severe tracheal stenosis due to an upper mediastinal mass. She was put on noninvasive positive pressure ventilation (NPPV) because of severe respiratory failure. Bronchoscopy showed severe tracheal stenosis due to direct invasion by the upper mediastinal mass. An expandable metallic stent (EMS) was placed in the trachea, after which a bronchoscopy showed a widely patent airway, and she got off NPPV. Then she did not need supplemental oxygen. She could seat herself, and have an enough meal, independently. However, takotsubo cardiomyopathy occurred and she died 11 days after the placement of the EMS. Since a malignant airway complication can be fatal, tracheal stent placement is a useful treatment in the management of malignancy with airway stenosis. In this case, it was thought that an early intervention of airway stenosis would have reduced the risk of takotsubo cardiomyopathy in a patient with severe symptoms of airway stenosis and stress.

Factors predicting the surgical outcome in patients with T3/4 lung cancer.

PURPOSE: Locally advanced lung cancer, such as T3/4 tumors, is considered to have a significantly worse prognosis than lower-stage disease, and the treatment of these tumors is difficult. Nevertheless, the information regarding the optimal treatment of T3/4 lung cancers after an operation is still limited. This study evaluated the prognostic factors for the postoperative outcome in patients with T3/4 lung cancers. METHODS: The results of the surgical treatments were retrospectively analyzed for 212 patients with pathological T3 and 197 patients with T4 disease. RESULTS: The global 5-year survival rate was 30.7% in this series. The 5-year overall survival (OS) rate in patients with T3 disease was 36.1%, while that in patients with T4 disease was 24.8%. The prognosis in females, those with N0-1 disease and those who underwent a complete resection was better than that of the other patients in both the T3 and T4 subgroups. The examination of the OS according to a time series showed that the rate was higher in more recent versus less recent years. From the standpoint of pulmonary metastasis (PM), the 5-year OS rates in T4 patients with PM and without PM were 38.6 and 17.4%, respectively. Multivariate analyses demonstrated that female gender, T3 disease, N0-1 disease and postoperative treatment were significant favorable prognostic predictors for OS. CONCLUSIONS: These findings suggest that surgical resection remains an important treatment option, especially in cases having the aforementioned factors.

Pulmonary pleomorphic carcinoma arising in mixed squamous and glandular papilloma: A case report.

Solitary pulmonary papillomas (SPPs) are rare lung neoplasms. Histologically, SPP is classified into three subtypes, and mixed squamous and glandular papilloma (MP) is the rarest subtype. Although SPPs are considered benign tumors, there have been several reports on the synchronous malignant transformation in SPPs. An 82-year-old asymptomatic man was referred to our hospital for further examination of a 2.2 cm-sized left lung tumor. Pathology of bronchoscopic specimens showed the possibility of pulmonary papilloma but did not reveal any malignancy. The patient complained of bloody sputum during the eighth month after the initial visit. The size of the lesion had increased to 4.3 cm. These data suggested the existence of malignancy, and the patient underwent an operation. Histologically, the tumor was composed of fibrovascular cores and papillomatous fronds lined by pseudostratified columnar cells and mucin-filled goblet cells. Keratinizing squamous epithelium was also observed. Overall, the diagnosis of MP was obtained by fundamental histology. In addition, a solid part beneath mild atypical squamous epithelia, which was composed of malignant-appearing squamous cells and spindle-shaped atypical cells, was observed. The spindle portion was positive for cytokeratin AE1/AE3 and vimentin, and focally positive for alpha-smooth muscle actin (αSMA). The final diagnosis was pulmonary pleomorphic carcinoma (PPC) arising in the MP. Only two cases have been reported for atypical spindle tumor cells that are found in MP or bronchiolar adenoma/ciliated muconodular papillary tumor (BA/CMPT), which has histologically similar features to MP. This is the second case report of PPC arising in MP.

Potential predictors of the pathologic response after neoadjuvant chemoimmunotherapy in resectable non-small cell lung cancer: a narrative review.

Background and Objective: Neoadjuvant chemoimmunotherapy (NACI) is the standard of care for patients with resectable non-small cell lung cancer (NSCLC). Although the pathological complete response (pCR) after NACI reportedly exceeds 20%, an optimal predictor of pCR is yet to be established. This review aims to examine the possible predictors of pCR after NACI. Methods: We identified research article published between 2018 and 2022 in English by the PubMed database. Fifty research studies were considered as relevant article, and were examined to edit information for this narrative review. Key Content and Findings: Recently, several studies have explored potential biomarkers for the pathological response after NACI. For example, 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) imaging, tumor microenvironment (TME), genetic alternation such as circulating tumor DNA (ctDNA), and clinical markers such as neutrophil-to-lymphocyte ratio (NLR) and smoking signature were assessed in patients with resectable NSCLC to predict the pathological response after NACI. Based on the PET response criteria, the complete metabolic response (CMR) achieved a positive predictive value (PPV) of 71.4% for predicting pCR, and the decreasing rate of post-therapy maximum standardized uptake value (SUVmax) after NACI substantially correlated with the major pathological response (MPR). TME, as a significant marker for MPR in tumor specimens, was identified as an increase in CD8+ T cells and decrease in CD3+ T cells or Foxp3 T cells. Considering blood samples, TME comprised an increase in CD4+PD-1+ cells or natural killer cells and a decrease in CD3+CD56+CTLA4+ cells, total T cells, Th cells, myeloid-derived suppressor cells (MDSCs), or regulatory T cells. Although low pretreatment levels of ctDNA and undetectable ctDNA levels after NACI were markedly associated with survival, the relationship between ctDNA levels and pCR remains elusive. Moreover, the patients with a high baseline NLR had a low incidence of pCR. Heavy smoking (>40 pack-years) was favorable for predicting pathological response. Conclusions: A reduced rate of 18F-FDG uptake post-NACI and TME-related surface markers on lymphocytes could be optimal predictors for pCR. However, the role of these pCR predictors for NACI remains poorly validated, warranting further investigations. This review focuses on predictive biomarkers for pathological response after NACI in patients with resectable NSCLC.

PD-L1 mRNA derived from tumor-educated platelets as a potential immunotherapy biomarker in non-small cell lung cancer.

Background: To date, the role of programmed death ligand-1 (PD-L1) messenger RNA (mRNA) derived from tumor-educated platelets (TEPs) has not been well investigated in patients with advanced non-small cell lung cancer (NSCLC). A few reports have examined whether mRNA in TEPs can predict the clinical responses of patients with advanced NSCLC following immunotherapy. This study aimed to identify novel biomarkers to improve the clinical benefits and outcomes of NSCLC patients. Methods: Advanced NSCLC patients receiving a combination of immunotherapy and chemotherapy, or immunotherapy alone as a first- or second-line treatment at the Fudan University Shanghai Cancer Center were enrolled in this study. All the patients had wild-type epidermal growth factor receptor/anaplastic lymphoma kinase. The patients were enrolled in clinical trials for immune checkpoint inhibitors (ICIs), including nivolumab, pembrolizumab, atezolizumab, durvalumab, tremelimumab, and camrelizumab. Tumoral PD-L1 expression was tested by immunohistochemistry (PD-L1 22C3 pharmDx kit, Agilent, Santa Clara, CA, USA) in archived tissue samples, when available, to calculate the tumor proportion scores (TPSs). RNA and exosomal RNA of blood were isolated before immunotherapy using the Yunying RNA extraction kit (Yunying Medicine, Shanghai, China). The concentration and quality of the RNA was determined using a Qubit fluorometer (Life Technologies, Carlsbad, CA, USA). Finally, we analyzed the predictive value of TEP-derived PD-L1 mRNA expression and association with the level of the tumoral PD-L1 expression. Results: In total, 72 patients were enrolled in this study. Most of the patients were male (n=54, 75.0%), had adenocarcinoma (n=49, 68.1%). We found there was no significant correlation between the TEP-derived mRNA of PD-L1 and tumoral PD-L1 expression based on the results of the Pearson Correlation test (r=-0.19, P=0.233). Based on the median of PD-L1 mRNA, 72 patients were divided into a high PD-L1 group and a low PD-L1 group. We found that 19 patients (44.4%) responded to immunotherapy [partial response or progression-free survival (PFS) >6 months] in the high PD-L1 group, but only five patients (13.9%) responded to immunotherapy in the low PD-L1 group (P<0.01). The median PFS of the low PD-L1 group was lower than that of the high PD-L1 group (2.8 vs. 8.3 months, P<0.001). For the patients who were treated with immunotherapy alone (n=64), a similar PFS advantage was observed in the high PD-L1 group (2.8 vs. 8.0 months, P=0.002). Conclusions: This article presented the first data on TEP-derived PD-L1 mRNA in advanced NSCLC patients following immunotherapy and showed the potential advantage of using it as the surrogate biomarker for predicting the PFS and overall survival of patients following immunotherapy.

Prognostic implications of human leukocyte antigen class I expression in patients who underwent surgical resection for non-small-cell lung cancer.

BACKGROUND: The purpose of the present study was to clarify the prognostic significance of human leukocyte antigen (HLA) class I expression in patients with non-small-cell lung cancer who underwent complete surgical resection. PATIENTS AND METHODS: The expression of HLA class I molecules was evaluated in 403 resected NSCLC specimens using immunohistochemistry. The results were scored as the percentage of stained tumor cells and were categorized into three groups: 0%-24% (decreased), 25%-79% (heterogeneous), and 80% or more (normal). RESULTS: The expression of HLA class I was evaluated in 124 tumors in the normal expression group, 181 tumors in the heterogeneous expression group, and 98 tumors in the decreased expression group. The 5-year survival rate of all patients after surgery according to the HLA class I expression in the normal, heterogeneous, and decreased groups was 76.6%, 65.9%, and 76.1%, respectively. The prognosis was significantly better in the normal expression group than in the heterogeneous group. Normal HLA class I expression also correlated with favorable survival in patients with stage I disease. CONCLUSIONS: The normal expression of HLA class I was associated with a favorable prognosis compared with the heterogeneous expression group, but no significant difference was observed between the normal expression and decreased expression groups.

Clinical significance of human leukocyte antigen loss and melanoma-associated antigen 4 expression in smokers of non-small cell lung cancer patients.

BACKGROUND: Melanoma-associated antigen-A4 (MAGE-A4) is one of the candidates for a target of immunotherapy and is expressed in non-small cell lung cancer (NSCLC). However, tumors sometimes lose human leukocyte antigen (HLA) class I expression, and tumor-specific T cells cannot eliminate the tumor with loss of HLA. However, the relationship between MAGE-A4 expression and HLA loss has remained unclear. METHODS: Among 363 NSCLC patients who consecutively underwent curative surgery, 187 cases whose material could be analyzed were reviewed. The expression of HLA class I molecules was assessed by immunohistochemical staining. The expression of MAGE-A4 was analyzed by RT-PCR. RESULTS: Seventy-seven tumors expressed HLA normally; however, 110 tumors lost HLA. The proportion of patients with a smoking habit and expressing the MAGE-A4 gene in patients with HLA loss was higher than those with HLA expression (p = 0.04 and 0.028, respectively). Five-year overall survival (OS) rate in the patients expressing MAGE-A4 but with loss of HLA was 52.4 %, and OS was significantly poorer than their counterparts (74.0 %, p = 0.036). Multivariate analysis indicated that advanced stage or history of smoking and HLA loss was an independently poor prognostic predictor of OS in NSCLC (p < 0.01 and p = 0.04, respectively). CONCLUSION: HLA class I loss in NSCLC was related to smoking history and MAGE-A4 expression of tumors. HLA class I loss in smokers or patients with the MAGE-A4 gene was a prognostic factors in NSCLC.

Analysis of the surgical treatment for superior sulcus tumors.

PURPOSE: This study was undertaken to assess the mortality, complication, and major morbidity rates of surgical treatment for superior sulcus tumors (SSTs), and to estimate the significance of prognostic factors. METHODS: We retrospectively reviewed the hospital records of 50 consecutive patients undergoing surgical treatment for SSTs between 1992 and 2007. The significance of risk factors for an adverse outcome was investigated. RESULTS: Both the thirty-day and in-hospital mortality rates were 0 %. Complications developed in 18.0 % (9/50) of the patients. The overall 5-year survival was 32.7 %. Pathological T4 and N1 or more were the risk factors predicting an adverse outcome. Survival was not significantly influenced by the preoperative symptoms, the histological type, the invaded organ or the curability. CONCLUSION: Surgical treatment for SSTs is associated with acceptable overall morbidity and mortality rates. However, special care must be taken for the patients with pathological T4 and N1 or higher tumors. Preoperative chemoradiotherapy followed by surgical treatment has become a logical strategy for SSTs. Preoperative chemoradiotherapy for SSTs may yield better results than surgery alone.

Prognostic significance of lymph node dissection for lung cancer surgery: a narrative review.

Background and Objective: Theoretically, systematic lymph node dissection (SLND) in lung cancer surgery is a technique that leaves less cancer cells behind and is speculated to improve the prognosis, but its prognostic significance still remains controversial. In addition, the social environment surrounding lymph node dissection has changed with the advent of limited surgery for peripheral small-sized lung cancer and emergence of immune check inhibitor (ICI). Therefore, we reconsidered the role of lymph node dissection. Methods: By referring to past reports, we reviewed the process leading up to the establishment of SLND in lung cancer surgery. We compared five randomized prospective comparative studies on SLND and lymph node sampling (LNS) in lung cancer surgery. Key Content and Findings: Of the five randomized prospective comparative studies, two reported an improvement in overall survival (OS) with SLND, but the remaining three reported no significant difference in OS between SLND and LNS. One out of the five reports revealed a significant increase in complications with SLND. For peripheral non-small cell lung cancer (NSCLC) cases with tumor diameter ≤2 cm and consolidation-to-tumor ratio >0.5 segmentectomy was found to significantly improve the hazard ratio of OS, when compared to a lobectomy. However, the proportion of SLND and lobe-specific lymph node dissection (L-SLND) in each group seems to be unclear. In segmentectomy, the dissection of intersegmental lymph nodes tends to be lenient, and therefore it seems necessary to examine the significance of lymph node dissection in segmentectomy. ICIs are already showing excellent effects, and it may be necessary to examine how they will be affected by removal of regional lymph nodes where cancer-specific cytotoxic T lymphocytes (CTLs) are concentrated. SLND is essential for accurate staging, but ideally-in a host with no cancer cells in the lymph node or a host with cancer cells having a high sensitivity to ICI-it might be better to leave the regional lymph node. Conclusions: SLND may not be the right choice in all cases. A time may come when the extent of lymph node dissection is determined individually for each case. Future verification results are awaited.

Association between the modified lung immune predictive index and clinical outcomes of advanced non-small cell lung cancer treated with first-line immune checkpoint inhibitors combined with chemotherapy.

Background: As revealed by previous studies, the modified lung immune predictive index (mLIPI) can predict outcomes in patients with lung cancer receiving single-agent immunotherapy. However, the application value of the mLIPI for patients treated with combination immunotherapy requires further investigation. In this study, we aimed to explore the relationship between the mLIPI and the efficacy of treatment together with the prognosis of patients with advanced non-small cell lung cancer (NSCLC) receiving first-line immune checkpoint inhibitors (ICIs) combined with platinum-based chemotherapy. Methods: In this retrospective study, we enrolled patients with advanced NSCLC treated with ICIs plus chemotherapy from March 2019 to June 2022. The patients were classified into good, intermediate, and poor/very poor groups according to their mLIPI before treatment. We further calculated the disease control rate (DCR), objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) of the three groups. The predictive ability of the mLIPI was evaluated by plotting a time-dependent receiver operating characteristic (ROC) curve and calculating the area under the curve (AUC). Results: A total of 209 patients were included in this study. There were 75 patients in the good group, 114 patients in the intermediate group, and 20 patients in the poor/very poor group. The median PFS was 11.2 months [95% confidence interval (CI): 8.763-13.704] in the good group; 8.1 months (95% CI: 7.354-8.846) in the intermediate group; and 5.4 months (95% CI: 2.142-8.658) in the poor/very poor group. The median OS was not reached in the good group, 29.5 months (95% CI: 23.555-35.512) in the intermediate group, and 14.5 months (95% CI: 8.567-20.366) in the poor/very poor group (P<0.05). Multivariate analysis showed that the mLIPI was independently associated with PFS and OS (P<0.05); the AUC values of the mLIPI for predicting PFS at 3, 6, and 9 months were 0.673, 0.637, and 0.614, respectively, and for predicting OS at 6, 12, and 24 months were 0.715, 0.655, and 0.625, respectively. Conclusions: The pretreatment mLIPI could be used to predict outcomes in patients with NSCLC receiving first-line ICIs plus chemotherapy.

Antitumor activity of human γδ T cells transducted with CD8 and with T-cell receptors of tumor-specific cytotoxic T lymphocytes.

The difficulty in the induction and preparation of a large number of autologous tumor-specific cytotoxic T lymphocytes (CTL) from individual patients is one of major problems in their application to adoptive immunotherapy. The present study tried to establish the useful antitumor effectors by using γδ T cells through tumor-specific TCRαß genes transduction, and evaluated the efficacy of their adoptive transfer in a non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice model. The TCRαß gene was cloned from the HLA-B15-restricted CTL clone specific of the Kita-Kyushu Lung Cancer antigen-1 (KK-LC-1). The cloned TCRαß as well as the CD8 gene were transduced into γδ T cells induced from peripheral blood lymphocytes (PBL). Cytotoxic T lymphocyte activity was examined using a standard 4 h (51) Cr release assay. Mice with a xenotransplanted tumor were treated with an injection of effector cells. Successful transduction of TCRαß was confirmed by the staining of KK-LC-1-specific tetramers. The γδ T cells transduced with TCRαß and CD8 showed CTL activity against the KK-LC-1-positive lung cancer cell line in a HLA B15-restricted manner. Adoptive transfer of the effector cells in a mice model resulted in marked growth suppression of KK-LC-1- and HLA-B15-positive xenotransplanted tumors. Co-transducing TCRαß and CD8 into γδ T cells yielded the same antigen-specific activity as an original CTL in vitro and in vivo. The TCRαß gene transduction into γδ T cells is a promising strategy for developing new adoptive immunotherapy.

Helicobacter pylori, a carcinogen, induces the expression of melanoma antigen-encoding gene (Mage)-A3, a cancer/testis antigen.

Cancer/testis antigens (CTAs) are known to be expressed in various cancer types but are minimally or not expressed in normal tissues except for germline tissues. CTAs are attractive targets for cancer immunotherapy and diagnosis because of their restricted expression. The mechanisms of CTAs expression are unclear because the inducers of CTAs expression remain to be elucidated. We hypothesized that carcinogens may induce the cellular expression of CTAs. To prove this, we attempted to inoculate Helicobacter pylori, a known carcinogen, in Meth-A cells, normal gastric cells, and normal splenocytes and induce the expression of a CTA. Melanoma antigen-encoding gene (Mage)-A3, one of the CTAs, was not expressed in both normal cells but in Meth-A cells inoculated with H. pylori. Furthermore, we performed limiting dilution using Meth-A cells inoculated with H. pylori and established derivative clone from Meth-A designated as Meth-A/pylori/3C3 which permanently express Mage-A3 after excluding H. pylori. We herein report the first successful induction of a CTA in a cell line via exposure to a carcinogenic agent. Furthermore, the establishment of Meth-A/pylori/3C3, which is Meth-A expressing Mage-A3, is considered to contribute to the resolution of the mechanism of CTAs expression.