- PD-L1 for tailoring therapeutic strategies in bladder cancer. - The prognostic role of PD-L1 in bladder cancer has been investigated in previous studies, but the results remain inconclusive. - Results: Patients in the PD-L1-low-exhausted group had the worst prognosis and showed the worst antigen- presenting cell (APC) immunosuppression status. - The PD-L1-low-exhausted group showed the highest amount of infiltration by macrophage M2 cells, nạve B cells and resting mast cells. - The TMB and the effectiveness of anti-PD-1 treatment were significantly increased in the PD-L1-high expression groups compared with the PD-L1-low. - In the PD-L1-high groups, patients who underwent chemotherapy exhibited better overall survival rates than patients who did not undergo chemotherapy, whereas there was no significant difference in the PD-L1-low groups. - We performed gene set enrichment analysis (GSEA) to explore the critical pathways that were active in the PD-L1-low-exhausted group, including the myogenesis, epithelial-mesenchymal transition and adipogenesis pathways. - Copy number variations (CNVs) were related to the expression levels of differentially expressed genes upregulated in the PD-L1-low-exhausted group, including LCNL1, FBP1 and RASL11B. - In addition, RASL11B played a role in predicting overall survival according to The Cancer Genome Atlas data, and this finding was validated in the PD-L1-low-exhausted group in the Gene Expression Omnibus database (GEO).. - PD-L1 antibodies, there remains a critical need to ex- plore mechanisms of resistance [11].. - GSEA at the RNA level and CNV ana- lysis at the DNA level were performed to identify the key pathways and key genes in the PD-L1-low-exhausted group and provide potential strategies for patients with various immune statuses.. - The primary anti- body was PD-L1 (mouse anti-human PD-L1 monoclonal, dilution 1:100, Abcam). - We divided patients into four subgroups according to PD-L1 expression and the type of immune modulation.. - “exhaustion” response was suggested by the T cell ex- haustion signature [25], we analysed the PD-L1 mRNA expression level in two subgroups. - The exhausted group exhibited increased PD-L1 mRNA expression than the active group vs P = 0.012) (Fig.. - For a more comprehensive study, we estimated the prognostic role of PD-L1 using immuno- histochemistry. - Patient biopsy samples (n = 106) were assessed for PD-L1 expression in tumour tissues (Fig.. - The results suggested that PD-L1 overexpression could predict worse survival outcomes in bladder cancer (P = 0.045) (Fig. - The PD-L1-low-exhausted group had a worse prognosis compared with the other groups. - We next investigated the clinical characteristics across subgroups and PD-L1 expression levels. - We detected the highest proportion of the luminal papillary subgroup within the PD-L1-low-activated group (chi-square, 80.9%, P <. - 0.0001), whereas the basal squamous sub- group harboured the highest proportion of the PD-L1- high-activated and PD-L1-high-exhausted groups (chi- square, 49.3 and 67.6%, P <. - The PD-L1-high-actived group had the highest prolifera- tion rate (Fig. - PD-L1-high-exhausted, P = 0.235. - PD-L1- low-actived, P <. - PD-L1-low-exhausted, P <. - PD-L1-high-exhausted, P <. - PD-L1-low-actived, P <. - PD-L1-low-exhausted, P <. - PD-L1-low- exhausted, P = 0.583), and macrophage regulation (vs. - 1 Immune subgroups according to PD-L1 expression and the type of immune modulation. - c The exhausted group showed higher PD-L1 mRNA expression than the active group (1.54 vs 1.22, P = 0.012). - d Representative immunohistochemical staining of PD-L1. - Right: strong PD-L1 expression. - left: negative PD-L1 expression. - e Kaplan-Meier plot showing that PD-L1 overexpression predicts worse survival outcomes in bladder cancer.. - PD-L1-low-actived, P <. - PD-L1-low-exhausted, P = 0.538) and wound heal- ing signatures (vs. - PD-L1-high-exhausted, P = 0.750. - PD- L1-low-actived, P <. - The PD-L1-high-exhausted group exhibited the high- est IFN-γ signature (vs. - PD-L1-low- actived, P <. - The PD-L1-low-actived group was defined by the lowest leukocyte fraction and IFN-γ signature (vs. - PD- L1-low-exhausted, P = 0.040), TGF-β signature (vs. - PD- L1-low-exhausted, P <. - The PD-L1-low-exhausted group displayed the highest macrophage M2 infiltration, CTA scores, a low-to- moderate proliferation rate, IFN-γ signature, TGF-β Table 1 Clinicopathological features of subgroups. - PD-L1-high-actived PD-L1-high-Exhausted PD-L1-low-actived PD-L1-low-Exhausted. - The top-ranked genes with differences be- tween subgroups included CXCL9, CXCL10, CCL5, TNFRSF18, ITGB2, ICAM1 and all the HLA genes (con- sistent with their known interferon inducibility), which were most highly expressed in the PD-L1-high- exhausted group (P <. - The PD-L1-high-actived and PD-L1-high-exhausted groups exhibited the highest infiltration of M1 macrophages and CD8 T cells (P <. - The PD-L1-high-actived and PD-L1-low-actived groups showed the highest infiltration of activated DCs (P <. - 0.001), whereas the PD-L1-low-actived group exhib- ited the highest infiltration of Tregs (P <. - The PD- L1-low-exhausted group showed the highest infiltration of nạve B cells and resting mast cells, whereas the low- est number of activated mast cells and follicular helper T cells was also observed in this group (P <. - The TMB was significantly higher in the PD-L1-high expression groups compared with the PD-L1-low ex- pression groups [15.06 (PD-L1-high-actived) and 22.32 (PD-L1-high-exhausted) vs. - 0.001], which con- firmed that the effectiveness of anti-PD-1 treatment in the PD-L1-high expression groups [7.64 (PD-L1-high- actived) and 7.69 (PD-L1-high-exhausted) vs. - h Kaplan-Meier plot showing that patients who underwent chemotherapy and patients who did not undergo chemotherapy had significantly different prognoses in the PD-L1-high and PD-L1-low subgroups. - the PD-L1-high-exhausted group, including nilotinib, belinostat, paclitaxel, vinblastine, doxorubicin, trameti- nib, bortezomib, idelalisib, cabozantinib, and bleomycin.. - Dabrafenib and lenalidomide showed the highest sensi- tivities in the PD-L1-high-activated group. - Only axitinib showed sensitivity in the PD-L1-low-activated and PD- L1-low-exhausted groups. - In addition, in the PD-L1- high groups, patients who underwent chemotherapy ex- hibited better overall survival rates compared with pa- tients who did not undergo chemotherapy (P whereas there was no significant difference in the PD- L1-low groups (P Fig. - FGFR3, which supported cancer-associated fibroblast (CAF) sur- vival and activation, exhibited significantly higher ex- pression in the PD-L1-low-actived and PD-L1-low- exhausted groups compared with the other groups.. - We performed GSEA to explore the critical pathways in the PD-L1-low-exhausted group (Fig. - Exploring therapeutic targets through CNV analysis We evaluated the CNV patterns that occurred in the PD-L1-low-exhausted group but not in the other groups.. - The total number of different CNV events in the PD-L1- low-exhausted group was 381 (P <. - The results revealed that 141 CNV-driven changes in mRNA expression of the 381 CNVs were associated with the PD-L1-low-exhausted group. - To identify the expression characteristics of the PD-L1-low-exhausted group, we further investigated DEGs (Fig. - Through analysis of the GEO validation data, we found that RASL11B (PD-L1-low-exhausted group . - P = 0.017) showed higher ex- pression in the PD-L1-low-exhausted group (n = 119) compared with the other groups (n = 182), which was comparable to the results in TCGA dataset.. - To explore the interaction of the two elements, we divided patients into four subgroups based on a combination of PD-L1 expression and the type of immune modulation. - Inter- estingly, the PD-L1-low-exhausted group showed a worse prognosis than the other groups.. - a GSEA results are indicated by bubbles between the PD-L1-low-exhausted group and the other groups. - chemotherapy may help liberate neoantigens to induce T cell responses and improve the effects of immunotherapy in the group with the second highest number of SNV neoantigens, the PD-L1-high-exhausted group . - The PD-L1-low-actived group was defined by de- creased leukocyte chemotaxis, similar to an immunologic- ally quiet subtype [22], leading to fewer immune cells and better outcomes [18].. - M1 macrophages and CD8+ T cells highly infiltrated the tu- mours in the PD-L1-high-actived and PD-L1-high- exhausted groups. - In the PD-L1-high subgroups, patients who under- went chemotherapy exhibited better overall survival rates than patients who did not undergo chemotherapy, which may have inhibited high chemosensitivity in these two subgroups.. - It should be noted that most of the chemotherapeutic drugs tested in this study had the highest sensitivities in the PD-L1-high-exhausted group, but chemotherapy suppresses the antitumour response of CD8+ T cells [32, 33] and induces IL-10-producing M2 macrophages, which may lead to transformation towards a PD-L1-low- exhausted status [34].. - The highest infiltration of Tregs and the lowest infil- tration of CD8+ T cells were found in the PD-L1-low- actived group. - In addition, the PD-L1-low-actived group exhibited the lowest infiltration of M1 macrophages, which may cause low chemosensitivity. - Therefore, a CD40 antibody may improve the che- mosensitivity of patients in the PD-L1-low-actived group. - The results revealed that axitinib showed sensitiv- ity in the PD-L1-low-exhausted group. - The PD- L1-low-exhausted group showed high infiltration of M2 macrophages and low infiltration of CD8+ T cells.. - How- ever, the poor antigen-presenting cell (APC) status of the PD-L1-low-exhausted group leads to inefficient pres- entation of antigen to CD8+ T cells and includes high infiltration of nạve B cells and low T follicular helper cell and DC activation. - We performed GSEA to explore the critical pathways in the PD-L1-low-exhausted group. - a Differential CNVs between the PD-L1-low-exhausted group and the other groups. - b DEGs between the PD- L1-low-exhausted group and the other groups. - g RASL11B expression was significantly upregulated in the PD-L1-low-exhausted group compared with the other groups in the GEO validation database. - The results revealed that 141 CNV-driven changes in mRNA expression of the 381 CNVs were associated with the PD-L1-low-exhausted. - DEG testing gave a set of 48 gene-level tran- scripts consistently associated with the PD-L1-low- exhausted group. - 5 Immune environments and therapeutics used in the immune subgroups and crosstalk in the PD-L1-low-exhausted group. - a The PD-L1-high-actived group: M1 macrophages and CD8+ T cells highly infiltrated the tumours. - The PD-L1-high-exhausted group: The highest infiltration of M1 macrophages and CD8+ T cells and low infiltration of activated dendritic cells. - The PD-L1-low-actived group: The highest infiltration of Tregs and the lowest infiltration of CD8+ T cells. - The PD-L1-low-exhausted group: The highest infiltration of M2 macrophages, low infiltration of CD8+ T cells, high infiltration of nạve B cells, low T follicular helper cells and activated dendritic cells. - In addition, CNV analysis provided translational benefits in the DEG RASL11B, which may be a target for the PD-L1-low-exhausted group. - Re- garding the lower number of SNV neoantigens in the PD-L1-high-exhausted subgroup, radiotherapy and chemotherapy in combination with anti-PD-1/PD-L1 therapy may be useful in these cases. - In the immuno- logically quiet stage, PD-L1-low-actived patients showed the highest infiltration of Tregs and the lowest infiltra- tion of M1 macrophages and CD8+ T cells and thus may benefit from STAT3 inhibition in combination with radiation or an agonistic CD40 antibody. - First, we adopted the CD274 mRNA expression level as a surrogate for PD-L1 expression. - In this study, we identified common immune subgroups based on a combination of PD-L1 expression and the type of immune modulation and performed a series of analyses. - The PD-L1-low-exhausted group exhibited a worse prognosis than the other groups and showed tumourici- dal features (high infiltration of M2 macrophages and low infiltration of CD8+ T cells) and poor APC immune status and activated CAF status. - Targeting the immune status of the PD-L1-low-exhausted group would have a tremendous impact on individual treatment.. - Copy number variations (CNVs) and differentially expressed genes upregulated in the PD-L1-low-exhausted group, such as RASL11B, played a role in predicting over- all survival in TCGA data and was validated in the PD-L1- low-exhausted group in the GEO database
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