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Background: The tumor microenvironment (TME) plays an important role in tumor progression and immunotherapy responses in non-small cell lung cancer (NSCLC). The programmed cell death 1 (PD-1)/ programmed cell death-ligand 1 (PD-L1) checkpoint is a central mediator of immunosuppression in the TME. However, there is still a need to identify additional biomarkers that could reflect the difference in TME and PD-L1 expression in NSCLC patients. To this end, we focused on the expression of G-protein-coupled receptor family C group 5 type A ( GPRC5A ) in NSCLC. GPRC5A , is a retinoic acid-inducible gene that plays multiple roles in NSCLC. However, little is known about the role of GPRC5A in regulating the TME and PD-L1. Our objective was to describe the critical role of GPRC5A expression in NSCLC in the setting of immune cell infiltration., Methods: We identified the relationship between GPRC5A expression and the clinicopathologic characteristics of NSCLC patients in the Fudan University Shanghai Cancer Center (FUSCC) cohort. Furthermore, we validated GPRC5A as a predictive biomarker by using public databases to reveal the relationship between GPRC5A expression and immune cell infiltration. To correlate the expression of GPRC5A with the spatial distribution of PD-L1 in NSCLC samples, we performed multiplex immunohistochemistry (mIHC)., Results: Low GPRC5A expression is associated with earlier pathological stage (pStage). Analysis of immune cell infiltration indicates there is a relationship between low GPRC5A expression and increased infiltration of CD8 + T cells, activated CD4 + T cells, and M1 macrophages within the TME. Furthermore, low GPRC5A expression is associated with an increased immunophenotype score (IPS) in NSCLC. Additionally, analysis of mIHC reveals there is a correlation between low GPRC5A expression and spatial distribution of tumoral PD-L1 expression., Conclusions: Our study revealed the relationship between low expression of GPRC5A and earlier pStage in NSCLC. Furthermore, we observed that low expression of GPRC5A is associated with increased infiltration of immune cells, higher IPS, and spatial distribution of PD-L1-positive tumor cells. Therefore, we speculate that low expression of GPRC5A is associated with immunotherapy, but further validation is still required., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-739/coif). The authors have no conflicts of interest to declare., (2024 Translational Lung Cancer Research. All rights reserved.)

Background: Anti-programmed cell death 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) immunotherapy has boosted the prognosis in advanced lung cancer. Meanwhile, accumulating cases showed the correlation between tuberculosis (TB) reactivation and anti-PD-1/PD-L1 immunotherapy. However, the safety and efficacy of anti-PD-1/PD-L1 immunotherapy for lung cancer complicated with TB infection could only be learned from real-world data., Methods: We retrospectively analyzed 562 patients with advanced lung cancer who received anti-PD-1/PD-L1 immunotherapy at Shanghai Pulmonary Hospital from 2015 to 2019, including 13 patients with TB infection. Besides, relevant literature reviews were performed online to analyze the safety and efficacy of immunotherapy and to explore the appropriate treatment strategies in this specific population., Results: In our cohort, the initiation of anti-PD-1/PD-L1 immunotherapy was from June 2015 to December 2019. Among them, 13 patients had TB infection prior to immunotherapy including 11 latent TB and 2 active TB, and all of them were treated with anti-PD-1 immunotherapy. Patients with active TB infection were treated with concurrent anti-TB and anti-PD-1 treatments, and the remaining received either mono-immunotherapy or combined immunotherapy. Neither reactivation of latent TB nor progression of active TB was monitored in our cohort during immunotherapy. Severe immune-related adverse events (irAEs) were diagnosed in two patients. Treatment strategies such as discontinuation of immunotherapy and administration of corticosteroids were provided timely, and one with latent TB infection got gradually improved, but the other one with active TB died quickly. The median progression-free survival (PFS) was 5.5 months for tumor immunotherapy in our cohort. However, the PFS of immunotherapy was merely 2.1 and 2.2 months in lung cancer patients with active TB infection., Conclusions: Immunotherapy is relatively safe for lung cancer patients complicated with previously treated latent TB, and the efficacy of immunotherapy in this specified population is not inferior to that in lung cancer patients without TB infection. TB screening before anti-PD-1/PD-L1 immunotherapy is strongly recommended, and irAEs should be monitored more cautiously in lung cancer patients with active TB infection., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/tlcr-21-524). CZ and YH serve as unpaid editorial board members of Translational Lung Cancer Research. The other authors have no conflicts of interest to declare., (2021 Translational Lung Cancer Research. All rights reserved.)

Background: It has been proven that the treatment window of small cell lung cancer (SCLC) is short, so it is vital to find other possible therapeutic targets. CD39 inhibits natural killer (NK) cells and promotes the occurrence and metastasis of tumors. There has been little research about the role of CD39 in SCLC, so we explored the correlation between CD39 and other surface antigens, and its association with survival in SCLC., Methods: This study included 75 patients with SCLC from Shanghai Pulmonary Hospital. After paraffin embedding and sectioning, immunohistochemistry (IHC) was applied. Then we identify cutoff value for CD39 and other surface antigens based on the analysis of ROC curve in RFS by SPSS. All statistical analyses were based on SPSS and Graphpad Prism8. Chi-square test, Kendall's tau-b correlation analysis, Logistic regression analysis, Kaplan-Meier method, univariate and multivariate Cox regression analysis were conducted. In all analyses, P = 0.05 distinguished whether they had statistical significance., Results: Of the 75 SCLC patients enrolled in this study, 61.33% positively expressed CD39. A correlation between CD39 and programmed cell death-ligand 1 (PD-L1) (P=0.007), CD3 (P<0.001), CD4 (P<0.001), CD8 (P<0.001), and forkhead box P3 (FOXP3) (P<0.001) on tumor-infiltrating lymphocytes (TILs) was identified by correlation analysis and logistic regression analysis. Based on Kaplan-Meier survival analysis, we found that CD39 affected relapse-free survival (RFS) [negative vs. positive, 95% confidence interval (CI): 0.2765-0.9862, P=0.0390]. SCLC patients with high-expressed CD39 and low-expressed PD-L1 had poor prognosis (P<0.001). Positive expression of CD39 and negative expression of CD3, CD4, CD8, and FOXP3 also indicated shorter RFS (P=0.0409). Univariate and multivariate Cox regression analysis was performed to confirm the factors that influenced RFS., Conclusions: CD39, programmed cell death-1 (PD-1), and PD-L1 expressed on TILs but not on tumor cells. CD39 has a significant association with PD-L1, CD3, CD4, CD8, and FOXP3 on TILs. The positive expression of CD39 predicts poor prognosis. SCLC patients with low expression of CD39 combined with high expression of PD-L1 or CD3, CD4, CD8, and FOXP3 have a more favorable prognosis., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tlcr-20-798). The authors have no conflicts of interest to declare., (2020 Translational Lung Cancer Research. All rights reserved.)

Background: Observational studies on the prognostic role of programmed cell death-ligand 1 (PD-L1) in non-small cell lung cancer (NSCLC) are controversial., Methods: To clarify the impact of PD-L1 in NSCLC survival, we performed this meta-analysis that included eligible studies. The combined hazard ratios (HR) and their corresponding 95% confidence intervals (CIs) were calculated in terms of overall survival., Results: A total of five studies with 877 patients were evaluable for this meta-analysis. Our results suggested that PD-L1 overexpression had a poor impact on survival of patients with NSCLC, the HR (95% CI) was 1.43 (1.24-1.63) overall, 1.51 (1.24-1.7954) in Asian patients, 1.35 (1.08-1.63) in non-Asian patients. Moreover, there was no heterogeneity between the studies., Conclusions: PD-L1 overexpression indicates a poor prognosis for patients with NSCLC.