Tumor stroma-infiltrating mast cells predict prognosis and adjuvant chemotherapeutic benefits in patients with muscle invasive bladder cancer

Abstract

Which subgroups patients with muscle-invasive bladder cancer (MIBC) could benefit most from adjuvant chemotherapy (ACT) is blurred. Here we tried to stratify MIBC patients with tumor infiltrating mast cells (TIMs), explore the prognostic and predictive value of TIMs, and provide possible cellular explanations. We selected 259 MIBC patients who underwent radical cystectomy from two independent clinical centers between 2002 and 2014. TIMs were evaluated and prognostic and predictive value was assessed. The CIBERSORT method, Gene Set Enrichment Analysis (GSEA) and differential gene expression analyses were performed to explore the possible cellular mechanisms. TIMs infiltration was distinct between stromal and epithelial area of MIBC specimens. Patients with higher stromal TIMs had a significant worse overall survival and recurrence free survival (HR = 2.228, 95%CI: 1.467-3.550; P = 0.001 and HR = 1.984, 95%CI: 1.105-3.374; P = 0.016). More importantly, pT2 patients with low stromal TIMs tended to have a lower risk of death and recurrence after ACT (HR = 0.233, 95%CI: 0.020-0.814; P = 0.033 and HR = 0.180, 95%CI: 0.022-0.722; P = 0.031). A negative correlativity between TIMs and CD8 + T cells was identified on TCGA-BLCA cohort. Immunohistochemistry results validated that high stromal TIMs were negatively correlated with CD8 + T cells (Spearman's rho =-0.215, P < 0.001). Differential gene expression suggested that low TIMs might represent a state of immune activation in MIBC. To conclude, high stromal TIMs infiltration was an independent unfavorable prognosticator for MIBC patients. Patients with low stromal TIMs might benefit the most from ACT, especially in pT2 stage.

Intratumoral IL22‐producing cells define immunoevasive subtype muscle‐invasive bladder cancer with poor prognosis and superior nivolumab responses

“…Thus, identifying crucial subsets to deflect immune responses may be the key to “unlock” the immune evasion. Intriguingly, we found that high IL22 + cells infiltration marked immunosuppressive contexture with increased pro‐tumor cells (Tregs, Th2, M2 and mast cells), which agreed with the defined Immunotype B MIBC with worse clinical outcomes in our previous research . Furthermore, we observed IL10 + and TGF‐β + cells were enriched in tumors with high IL22 + cells infiltration, implying these increased pro‐tumor cells determined immunoevasive subtype MIBC by secreting IL10 and TGF‐β.…”

“…Recent findings indicated that the efficacy of chemotherapy and ICIs inextricably linked to the tumor microenvironment (TME) and tumor‐infiltrating immune cells . Our previous studies have revealed immune cells infiltration patterns comprised with neutrophils, CD8 + T cells, NK cells, Treg cells, macrophages, mast cells and B cells could affect immune contexture and ACT responsiveness in MIBC . Immunoregulatory cytokines, such as IL10 and IL17 (our unpublished research), may serve critical roles in therapeutic effectiveness .…”

“…In order to explore the possible mechanism for the prognosis stratification, we attempted to characterize the immune contexture in high and low IL22 + cells infiltration groups. In our previous studies in MIBC, tumor-infiltrating mast cell (TIMs) displayed pro-tumor function, 10 and patients with poor prognosis presented stromal Immunotype B (CTL low NK low Treg high Macrophage high MastCell high ) phenotype. 11 Interestingly, we found that tumors with high IL22 + cells infiltration contained more protumor cells (Tregs: p < 0.001, Th2: p = 0.015, M2: p = 0.006, mast cells: p = 0.002; Fig.…”

“…8,9 Our previous studies have revealed immune cells infiltration patterns comprised with neutrophils, CD8 + T cells, NK cells, Treg cells, macrophages, mast cells and B cells could affect immune contexture and ACT responsiveness in MIBC. [10][11][12][13] Immunoregulatory cytokines, such as IL10 and IL17 (our unpublished research), may serve critical roles in therapeutic effectiveness. 14 As a unique member of IL10 family discovered in 2000, 15 interleukin 22 (IL22) plays a controversial part in a variety of diseases, including cancers.…”

Profiles of Immune Infiltration in Bladder Cancer and its Clinical Significance: an Integrative Genomic Analysis

“…BLCA is an immunosensitive tumor which is infiltrated by tumor-infiltrating immune cells (TIICs) including T cells, macrophages, dendritic cells, neutrophils and mast cells [7][8][9]. Studies have shown that the tumor microenvironment affects the gene expression of tumor tissues and the patient outcome, and therefore, has a diagnostic and prognostic value for BLCA [10][11][12]. TIICs, which are main components of tumor microenvironment, have been reported closely related to the effectiveness of targeted drugs and clinical outcomes.…”