Stromal Tumor-infiltrating Lymphocytes Density Research Articles

The predictive value and role of stromal tumor-infiltrating lymphocytes in pancreatic ductal adenocarcinoma (PDAC)

ABSTRACTRecently, increasing evidence has indicated that the presence of tumor infiltrating immune cells has shown predictive significance for many solid tumors. Present study was performed to evaluate the predictive value of stromal tumor-infiltrating lymphocytes (TILs) for the presence of liver metastasis and overall survival in PDAC (pancreatic ductal adenocarcinoma) patients after complete resection and to explore the potential role of lymphocytes in PDAC. A total of 155 resectable patients with PDAC were enrolled in our study. Stromal TIL density was investigated in hematoxylin and eosin-stained sections of surgical specimens and scored. The effect and possible mechanism of lymphocytes on cancer cells was evaluated using co-culture techniques and ELISA test. Stromal TIL negative status (HR = 2.80, 95% CI 1.75-4.48, P < 0.01) was not only an independent predictor of worse OS (HR = 2.7, 95% CI 1.80-4.06, P = <0.01) but also a significant independent predictor of liver metastasis. Higher CEA (P = 0.01) or CA19-9 (P = 0.01) levels were associated with low stromal TIL density. Stromal TIL negative patients appeared to develop tumors with a higher CEA (P = 0.01), larger diameter (P = 0.05) and advanced stage (P = 0.02). The co-culture experiment suggests that lymphocytes can inhibit pancreatic cancer cell proliferation. Further ELISA and cell culture test indicate that lymphocytes may cause pancreatic cancer cells apoptosis through TNF-alpha secretion. Our data suggest a potential favorable role of stromal TILs in predicting liver metastasis and overall survival of patients with PDAC after complete resection. Lymphocytes may inhibit the growth of PDAC through TNF-alpha secretion, which suggest a potential therapeutic approach against PDAC.

Association of stromal lymphocyte infiltration with tumor invasion depth and high-grade T1 bladder cancer.

488 Background: Morphological assessment of tumor-infiltrating lymphocytes (TIL) has been shown to provide prognostic and potentially predictive significance in many different tumor types. Large studies investigating TIL in urothelial carcinoma are lacking. We investigated in a homogenous population of patients with high-grade T1 (HGT1) bladder cancer the association of TIL with clinico-pathological parameters and clinical outcomes. Methods: Pretreatment index tumors were collected between 2000 and 2015 from 147 patients with primary high-grade cT1N0M0 bladder cancer. The density of stromal TIL was evaluated using hematoxylin and eosin (H&amp;E)-based staining on whole tissue sections. Stromal TIL density was scored as percentage of stromal area infiltrated by mononuclear cells. Inter-reader assessment and stromal TIL correlation with a subset of CD3+ stained sections were evaluated. The main endpoint was correlation with overall survival (OS). Hazard ratios (HRs) and 95% CIs associated with stromal TIL were estimated through a multivariable Cox model. Results: Median follow-up was 8.2 years (6.1-9.5). Induction BCG therapy was followed by 126 patients (86%). Recurrence and progression were respectively observed in 67 patients (46%) and 40 patients (27%). Stromal TIL density was high (≥10%) in 82 tumors (56%). The overall agreement was good between the two readers (κ = 0.75). Correlation between stromal TIL density analyzed on H&amp;E-sections and CD3+ IHC staining was high (ρ = 0.71, p &lt; 1.10-5). Stromal TIL were positively associated with variant histology (p = 0.01) and tumor invasion depth (p = 0.03). For the OS analysis, intense (≥10%) vs. non-intense ( &lt; 10%) stromal TIL unadjusted HR (95% CI, p) was 1.30 (0.75-2.24, p = 0.34) and adjusted HR was 1.25 (0.72-2.16, p = 0.43). Conclusions: Density of stromal TIL was associated with tumor invasion depth and variant histology, but not with prognosis of patients with HGT1 bladder cancer. These data suggest that tumor progression is associated with an increased adaptive immune response but other factors may influence outcome of patients. Characterization of TIL subpopulations may be required to identify immune-related prognostic factors.

Effects of TP53 and PIK3CA mutations in early breast cancer: a matter of co-mutation and tumor-infiltrating lymphocytes.

The purpose of this study is to investigate whether the outcome of breast cancer (BC) patients treated with adjuvant chemotherapy is affected by co-mutated TP53 and PIK3CA according to stromal tumor-infiltrating lymphocytes (TILs). Paraffin tumors of all clinical subtypes from 1661 patients with operable breast cancer who were treated within 4 adjuvant trials with anthracycline-taxanes chemotherapy were informative for TP53 and PIK3CA mutation status (semiconductor sequencing genotyping) and for stromal TILs density. Disease-free survival (DFS) was examined. TP53 mutations were associated with higher (p<0.001) and PIK3CA with lower (p=0.004) TILs in an ER /PgR-specific manner (p<0.001). Mutations did not affect the favorable DFS of patients with lymphocyte-predominant (LP) BC. Within non-LPBC, PIK3CA-only mutations conferred best, while TP53-PIK3CA co-mutations (6% of all tumors) conferred worst DFS (HR 0.59; 95% CI 0.44-0.79; p=0.001 for PIK3CA-only). TP53-only mutations were unfavorable in patients with lower TILs, while patients with lower TILs performed worse if their tumors carried TP53-only mutations (interaction p=0.046). Multivariate analysis revealed favorable PIK3CA-only mutations in non-LPBC (HR 0.64; 95% CI 0.47-0.88; p=0.007), and unfavorable TP53 mutations in ER/PgRpos/HER2neg (HR 1.55; 95% CI 1.07-2.24; p=0.021). Mutations did not interact with TILs in non-LP triple-negative and HER2-positive patients. TP53 and PIK3CA mutations appear to have diverse effects on the outcome of early BC patients, according to whether these genes are co-mutated or not, and for TP53 according to TILs density and ER/PgR-status. These findings need to be considered when evaluating the effect of these two most frequently mutated genes in the context of large clinical trials.