Tertiary lymphoid structure and neutrophil–lymphocyte ratio coordinately predict outcome of pembrolizumab

Abstract

Emerging evidence suggests that the presence of tertiary lymphoid structures (TLS) and neutrophil–lymphocyte ratio (NLR) in peripheral blood is associated with the treatment response to checkpoint inhibitors (CPIs), whereas there is limited knowledge regarding whether these factors reciprocally impact the treatment outcomes of CPIs in metastatic urothelial carcinoma (mUC). Herein, we investigated treatment outcomes of platinum‐refractory mUC patients (50 cases with whole‐exome and transcriptome sequencing) treated with pembrolizumab. The pathological review identified 24% of cases of TLS in the specimens. There was no significant difference in the NLR between the TLS− and TLS+ groups (p = 0.153). In the lower NLR group, both overall survival and progression‐free survival were significantly longer in patients with TLS than in those without TLS, whereas the favorable outcomes associated with TLS were not observed in patients in the higher NLR group. We explored transcriptomic differences in UC with TLS. The TLS was comparably observed between luminal (20%) and basal (25%) tumor subtypes (p = 0.736). Exploring putative immune‐checkpoint genes revealed that ICOSLG (B7‐H2) was significantly increased in tumors with lower NLR. KRT expression levels exhibited higher basal cell markers (KRT5 and KRT17) in the higher NLR group and lower differentiated cell markers (KRT8 and KRT18) in patients with TLS. In conclusion, the improved outcomes of pembrolizumab treatment in mUC are restricted to patients with lower NLR. Our findings begin to elucidate a distinct molecular pattern for the presence of TLS according to the NLR in peripheral blood.

Association between tertiary lymphoid structures and clinical outcomes in cancer patients treated with immune checkpoint inhibitors: an updated meta-analysis

“…Due to small sample sizes, the 4 studies ( 14 , 17 – 19 ), were only included in the systematic review. Therefore, this meta-analysis selected 9 studies ( 11 – 13 , 15 , 16 , 21 , 28 – 30 ) investigating the correlation between TLSs and clinical outcomes in cancer patients treated with immune checkpoint inhibitors. Figure 1 shows the flow diagram for literature retrieval and selection.…”

“…Among the 9 included studies, six cohorts had a retrospective study design, and three cohorts were prospectively designed or from prospective trials ( 12 , 21 , 29 ). Among the 9 included studies evaluating the prognostic value of TLSs in cancer patients treated with ICIs: 6 studies evaluated overall survival (OS) ( 11 , 12 , 21 , 28 – 30 ), 3 studies evaluated progression‐free survival (PFS) ( 13 , 16 , 21 ), and 4 studies evaluated objective response rate (ORR) ( 12 , 13 , 15 , 16 ). All the studies included in the analysis obtained moderately high scores on quality assessments conducted using the Newcastle-Ottawa Scale.…”

“…Among the 9 studies selected for this meta-analysis, 6 studies reported the association between OS and TLSs ( 11 , 13 , 21 , 28 – 30 ). Considering the low heterogeneity (I 2 = 0%), a fixed effects model was used for analysis.…”

“…The ORR was reported in 4 studies which included 398 cancer patients treated with ICIs ( 12 , 13 , 15 , 16 ). The pooled OR was 3.78 (95% CI: 2.26–6.33, p < 0.001, I 2 = 32%, Figure 5 ) suggesting that TLSs were associated with lower tumor response.…”

Heterogeneity of Cervical Cancer-Associated Tertiary Lymphoid Structures (TLSs) and Their Specific Interrelation With Clinicopathological Parameters

“…Related to the cellular component of TLS, a readily evaluable biomarker is represented by the percentage of peripheral blood lymphocytes and the existence of TLSs. Literature data describes the impact of this parameter or the neutrophil/lymphocyte ratio in peripheral blood on the postoperative prognosis of oncological patients, such as patients with squamous cell lung tumors [ 28 ] or urothelial carcinomas, where an increased number of TLSs associated with a reduced neutrophil/lymphocyte ratio has been reported to increase the response to pembrolizumab therapy [ 29 ]. In our study, the presence of an increased number of TLSs was significantly correlated with an increased number of peripheral lymphocytes.…”