High Stroma T-Cell Infiltration is Associated with Better Survival in Stage pT1 Bladder Cancer

Abstract

Stage pT1 bladder cancer (BC) shows highly diverse outcomes. Predictive markers are required to stratify patients for personalized treatment. The present study aimed to validate immune response quantification as a prognostic marker. Patients with pT1 BC (n = 167) treated by transurethral resection of the bladder (TURB) were enrolled. Formaldehyde-fixed paraffin-embedded material was stained for CD3 and CD8. Corresponding T cells were counted in three regions with the highest immune response. Numbers of tertiary lymphoid structures (TLS) and lymphocyte aggregates (LA) were quantified. High CD3+ stroma T-cell infiltration was associated with improved survival (p = 0.045), especially in the G3 subgroup (p = 0.01). Cluster with higher immune response showed less recurrence (p = 0.034) and favorable overall survival (OS) (p = 0.019). In contrast, higher CD3+ and CD8+ tumor T-cell infiltration seemed to have a negative impact on prognosis. TLS and LA were more frequently observed in G3 tumors, indicating an increased anti-tumoral immune response. We proved the role of immune cell infiltration and showed that higher infiltration numbers of CD3+ (not CD8+) lymphocytes in the stroma are associated with favorable outcome. Immune cell quantification could be used as a marker to help stratify patients’ risk and therefore, to optimize patients’ management and follow-up examination as well as possible therapies.

Tertiary lymphoid structures and B lymphocytes in cancer prognosis and response to immunotherapies

“…In addition, other gene signatures containing 8 and 19 genes related to the presence of T follicular helper cells, type 1 helper CD4 + T cells and B cells were reported in breast 54 and gastric 55 cancers. Collectively, this has led to the detection of TLS in lung, 41 , 45 , 56 , 57 oral squamous cell carcinoma, 58 breast, 54 , 59–61 colon, 51 , 62 stomach, 55 , 63 , 64 liver, 65 sarcoma, 3 , 66 , 67 bladder, 68 clear cell renal cell carcinoma, 4 ovarian cancer 46 , 69 and melanoma 4 , 5 , 15 , 44 , 50 , 70 ( Table 1 ). TLS formation and densities vary between tumor types, and between patients.…”

“… 66 Sarcoma GIST Primary tumors Naive Tumor Multiplex immunohistochemistry Presence of TLS associated with smaller tumor size, reduced relapse and increased survival Presence of TLS are associated with reduced probability of future development of imatinib resistances 67 Kidney Various histological subtypes Primary tumors andmetastases Naive and pretreated patients Tumor Genes signature No impact of B cell-lineage B cell signature presence of TLS associated with response to immunotherapy 4 Bladder pT1 bladder cancer Primary tumors Naive Tumor and peri-tumoral tisue CD3 + and CD8 + T cells Associated with advanced disease and poor prognosis N.A. 68 Ovarian High-grade serous ovarian cancer Primary tumors Naive Tumor stroma CD3 + and CD8 + T cells, CD20 + B cells, CD21 + FDC and CD38 + CD138 + CD79a + plasma cells High tumor-infiltration with plasma cells are associated with increased survival N.A. 46 Ovarian High-grade serous ovarian cancer Primary tumors Naive Tumor stroma B cells (CD20 + ) and mature DC (DC-Lamp + ) Favorable N.A.…”

The Immunoscore in Localized Urothelial Carcinoma Treated with Neoadjuvant Chemotherapy: Clinical Significance for Pathologic Responses and Overall Survival

“…The importance of immune infiltration, particularly CD8+ T lymphocytes, has been consistently found to be a prognostic tool for advanced UC [ 31 ]. In non-muscle-invasive UC, CD3 and CD8 lymphocytic infiltrates, stratified by localization in the tumor, have been recently associated with prognosis [ 32 ]. The prognostic impact of immune parameters in localized MIBC has been reported in other studies, with a positive association between lymphocyte infiltration and survival [ 33 , 34 ].…”

“…The tumor microenvironment, the Immunoscore, and immune contexture vary according to UC subtypes and variants, and their prognostic and predictive value in these specific settings warrants further assessment [ 38 ]. Interestingly, the CD3 and CD8 infiltration has also been associated with the tumor histologic grade [ 32 ]. The aforementioned reports point toward heterogeneity in the distribution of CD3 and CD8 lymphocyte densities across subtypes and settings.…”

Cell Therapies in Bladder Cancer Management

“…This suggests a key role of T cells in BC anti-tumor defense, leading to the exploration of possible ICI and BCG combinations or the use of ICI after BCG failure (clinical trials on Table 1 ) [ 35 , 36 ]. In fact, high CD3+ stroma T cell infiltration was associated with improved survival in stage pT1 BC [ 37 ], whereas intratumoral CXCR5+CD8+ T cells indicated an excellent prognosis in MIBC basal and stromal-rich subtypes [ 38 ]. Since an abundance of infiltrated CD8+ T cells is associated with improved survival in MIBC patients [ 39 ], the presence of tumor-associated macrophages (TAMs) and immunosuppressive regulatory T cells (Tregs) correlated with a poor prognosis in those MIBC patients, pointing out the influence of tumor microenvironment (TME) in therapeutic responses [ 40 ].…”