Folate Receptor Alpha Expression and the Tumor Immune Microenvironment in Patients with Cervical Cancer.

Folate receptor α (FRα) is a cell-surface protein and an attractive target for cancer treatment. We investigated the association between FRα expression and the tumor immune microenvironment in patients with cervical cancer. We examined whole tumor sections of 123 patients with cervical cancer: 67 and 56 sections of squamous cell carcinoma (SCC) and non-SCC, respectively. FRα expression was assessed using immunohistochemical staining with the anti-FRα monoclonal antibody clone 26B3. Programmed death-ligand 1 (PD-L1) expression was assessed using a combined positive score (CPS). The intratumoral CD3 and CD8 cell densities were calculated as the average number of positive cells in five independent areas. FRα-positivity was identified in 72.4% of the patients, and it differed by histology (SCC vs. non-SCC; 55.2% vs. 92.9%, P<0.001). PD-L1 status was positive (CPS ≥1) in 75.6% and was more commonly expressed in patients with SCC (SCC vs. non-SCC; 83.5% vs. 66.1%, P=0.02). FRα expression had a weak correlation with PD-L1 expression (r=-0.22, P<0.001) and CD8-positive cells (r=-0.19, P=0.03). FRα-positivity was more frequently observed in the PD-L1 CPS <10 group than in the PD-L1 CPS ≥10 group (81% vs. 64%, P=0.03). FRα-high was significantly associated with poor prognosis, especially in the PD-L1 CPS ≥10 groups (hazard ratio: 4.10, 95% confidence interval: 1.39-12.06, P=0.01). In conclusion, FRα expression was higher in patients with cervical cancer and PD-L1 CPS <10 than in those with CPS ≥10. Targeting FRα expression may be a potential therapeutic strategy for cervical cancer patients with low or negative PD-L1 expression.

Yazaki S ，Chiba Y ，Kojima Y ，Yoshida H ，Takamizawa S ，Kitadai R ，Saito A ，Kita S ，Yamamoto K ，Sumiyoshi-Okuma H ，Nishikawa T ，Sudo K ，Shimoi T ，Noguchi E ，Uno M ，Ishikawa M ，Kato T ，Fujiwara Y ，Yonemori K ... -  《-》

Prognostic significance of combined PD-L1 expression in malignant and infiltrating cells in hepatocellular carcinoma treated with atezolizumab and bevacizumab.

Programmed death-ligand 1 (PD-L1) expression is abundant not only in malignant cells but also in infiltrating cells within the tumor microenvironment (TME) of hepatocellular carcinoma (HCC). This study explored the association between PD-L1 expression in TME and outcomes in HCC patients treated with atezolizumab plus bevacizumab (AB), emphasizing the implications of PD-L1 expression in both malignant and tumor-infiltrating cells. This study included 72 patients with HCC who underwent percutaneous core needle liver biopsy before AB treatment between September 2020 and December 2023. PD-L1 expression on tumor tissues was assessed using the combined positive score (CPS) with cutoff values of 1 and 10, utilizing antibody clone 22C3 (Dako). The distribution of PD-L1 CPS included 24 patients with CPS <1, 33 patients with CPS 1-10, and 15 patients with CPS ≥10. Significant differences in overall survival (OS) were observed across the three groups, with CPS ≥10 showing the highest survival rates (p = 0.010). Patients with CPS ≥10 had better OS than those with CPS <10 (median OS 14.8 vs. 8.3 months, P = 0.046), and CPS ≥1 had better OS than CPS <1 (P = 0.021). For progression-free survival (mPFS), the CPS ≥10 group had the highest median PFS of 11.0 months among the three groups (P = 0.044). Objective response rates (ORR) were higher in the PD-L1 CPS ≥10 group than in the 1-10 and <1 group (53.3%, 27.3%, and 16.7%, respectively; P = .047). Multivariate analysis identified that PD-L1 expression ≥10 and ≥1 were associated with favorable outcomes regarding OS (hazard ratio [HR] 0.283, P = .027 and HR 0.303, P = .006, respectively). Combined analysis of PD-L1 expression in malignant and tumor-infiltrating cells can be a promising biomarker for the prognosis of HCC patients treated with AB.

Lee J ，Yoo JS ，Kim JH ，Lee DY ，Yang K ，Kim B ，Choi JI ，Jang JW ，Choi JY ，Yoon SK ，Han JW ，Sung PS ... -  《Frontiers in Immunology》

Infiltration of CD8(+) cytotoxic T-cells and expression of PD-1 and PD-L1 in ovarian clear cell carcinoma.

Ovarian clear cell carcinoma (OCCC) is resistant to chemotherapy, with limited treatment options for advanced and recurrent disease. The prevalence of OCCC differs by region. Assessing the expression of programmed cell death ligand 1 (PD-L1), PD-1, and CD8+T cell infiltration in OCCC is crucial, as their correlation with patient survival may provide valuable prognostic insights. We collected data from 36 samples from 18 OCCC patients, including 18 pairs of tumors and adjacent nonneoplastic samples. The optimized multiplex immunofluorescence technique was used to stain paraffin sections for immune factors related to the immune microenvironment of OCCC and clinical prognosis. The expression of PDL1 and PD1 in the tumor cells and tumor stromal cells was not significantly correlated with prognosis. Professional quantitative pathological analysis software was used to count the CD8+ cytotoxic T-cells in tumor regions and adjacent nonneoplastic regions in postoperative specimens. There were more CD8+ cytotoxic T-cells in the adjacent nonneoplastic areas than in the tumor tissue samples (p < 0.001). Further analysis revealed that a difference in cell density between CD8+ non-tumor-infiltrating lymphocytes (NTILs) and CD8+ tumor-infiltrating lymphocytes (TILs) exceeding 70 cells/mm2 was associated with poorer progression-free survival (PFS) (p = 0.042). In adjacent nonneoplastic regions, worse PFS was significantly observed in patients with high CD8+ T-cell expression in both total and stromal cells than those with low expression (p = 0.012 vs p = 0.007). The presence of CD8+ T-cells had significant potential for predicting the prognosis of patients with OCCC, which lays a foundation for the development of biomarkers for immune checkpoint blockade treatment response in OCCC patients.

Fu M ，Zhou H ，Yang J ，Cao D ，Yuan Z ... -  《Scientific Reports》

Clinical significance of CD155 expression in surgically resected lung squamous cell carcinoma.

Cluster of differentiation 155 (CD155) is expressed in many tumor types. CD155 is involved in the immune avoidance of tumor cells and contributes to tumor development and progression. Therefore, CD155 is a novel target for cancer immunotherapy. The clinical significance of CD155 expression in lung squamous cell carcinoma (LUSC) has not been fully elucidated. We performed a retrospective analysis of 264 patients with surgically resected LUSC. Immunohistochemistry was used to evaluate CD155 expression. The association of CD155 expression with clinicopathological features and clinical outcomes was assessed. We also analyzed the relationship between CD155 expression and programmed cell death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocytes. Among the 264 patients, 137 patients (51.9%) were classified in the high CD155 expression group. High CD155 expression was significantly associated with pleural invasion, vascular invasion, PD-L1 positivity, and high CD3, CD4, and CD8 expressions. In multivariate analysis, the presence of pleural invasion and PD-L1 positivity were independent predictors of high CD155 expression. Kaplan-Meier curve analysis showed that high CD155 expression was significantly associated with shorter disease-free survival and overall survival. In multivariate analysis, high CD155 expression was an independent poor prognostic factor for overall survival, but not for disease-free survival. Subgroup analyses revealed that the prognostic effect of CD155 expression was observed in the PD-L1 positive group but not the PD-L1 negative group. Our analysis revealed that high CD155 expression significantly predicted poor prognosis in patients with surgically resected LUSC, especially in patients with PD-L1-positive tumors.

Nagano T ，Takada K ，Hashinokuchi A ，Matsudo K ，Kinoshita F ，Akamine T ，Kohno M ，Shimokawa M ，Takenaka T ，Oda Y ，Yoshizumi T ... -  《-》

Relationship Between Short-Term Outcomes and PD-L1 Expression Based on Combined Positive Score and Tumor Proportion Score in Recurrent or Metastatic Head and Neck Cancers Treated With Anti-PD-1 Antibody Monotherapy.

PD-L1 expression in tumors and immune cells is a biomarker for the efficacy of anti-PD-1 antibody (APA) therapy across diverse cancers. Based on the results from the KEYNOTE-048 trial, pembrolizumab monotherapy is indicated for platinum-sensitive recurrent/metastatic head and neck squamous cell carcinoma (R/M-HNSCC) with a positive combined positive score (CPS). Conversely, nivolumab is utilized for platinum-pretreated R/M-HNSCC regardless of the positive tumor proportion score (TPS) following the results of the CheckMate-141; however, its subgroup analysis indicated that TPS-positive population tended to have a relatively high overall response rate and progression-free survival (PFS). Although, the superior PD-L1 evaluation method for predicting APA therapy efficacy in R/M-HNSCC and the appropriate cut-off value remain undetermined. This study aims to elucidate the relationship between short-term outcomes and PD-L1 expression based on CPS and TPS in R/M-HNSCC patients undergoing APA monotherapy. R/M-HNSCC patients receiving APA monotherapy from 2018 to 2021 with available samples were enrolled. An experienced pathologist evaluated CPS and TPS utilizing the PD-L1 IHC 22C3 pharmDx assay. Short-term outcomes were assessed by clinical benefit rate (CBR), objective response rate (ORR), and PFS. Fifty-three R/M-HNSCC patients received APA monotherapy. Forty-seven had CPS ≥ 1, and 44 had TPS ≥ 1%. By receiver-operating characteristic curve analysis, the CPS cut-off value for predicting better CBR was determined to be 50. The ORR/CBR tended to be higher when CPS was positive. Although differences in PFS were not observed for a cut-off value of 1 or 20, they were observed for 50 (3.2 vs. 8.4 months; hazard ratio 0.44, p = 0.02). ORR and CBR were respectively 12.5% and 12.5% in the TPS < 1% group and 33.3% and 48.9% in the ≥ 1% group. The TPS < 1% group showed significantly poorer PFS (1.9 vs. 4.5 months, hazard ratio 0.40, p = 0.01). The short-term efficacy of APA monotherapy in R/M-HNSCC patients tended to be better when CPS was positive. TPS helps predict the population that does not benefit from APA monotherapy.

Ohara A ，Mori T ，Itoyama M ，Yokoyama K ，Yamamoto S ，Kato K ，Honma Y ... -  《Cancer Reports》