Dataset Information

Quantitative assessment of tumor-infiltrating lymphocytes in mismatch repair proficient colon cancer.

ABSTRACT: Tumor infiltrating lymphocytes (TIL), which represent host adaptive response to the tumor, were first identified at scanning magnification to select areas with the highest counts on hematoxylin and eosin slides, quantitated per high-power field (HPF), and analyzed for association with recurrence-free survival (RFS) in 848 patients. Highest TIL in a single HPF was analyzed as a continuous and categorical variable, and optimal cutoff analysis was performed to predict RFS. Highest TIL count in a single HPF ranged from 0 to 45, and the optimal cutoff for TIL high vs TIL low was determined to be ≥ 3 vs < 3 with a concordance probability estimate of 0.74. In the entire cohort, 5-year RFS was 90.2% (95% CI = 83.7-94.2) in TIL high compared to 78.9% (95% CI = 74.1-82.9) in TIL low (log rank P < .0001). TIL remained significant in the mismatch repair-proficient (pMMR) cohort where 5-year RFS was 94.6% (95% CI = 88.3-97.5) in TIL high compared to 77.9% (95% CI = 69.2-84.4) in TIL low (P = .008). On multivariable analysis, TIL and AJCC Stage were independently associated with RFS in the pMMR cohort. Qualitatively in the pMMR cohort, RFS in Stage II TIL high patients was similar to that in Stage I patients and RFS in Stage III TIL high was similar to that in Stage II TIL low patients. Assessment of TIL in a single HPF using standard H&E slides provides important prognostic information independent of MMR status and AJCC stage.

SUBMITTER: Jimenez-Rodriguez RM

PROVIDER: S-EPMC7671050 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Quantitative assessment of tumor-infiltrating lymphocytes in mismatch repair proficient colon cancer.

Jimenez-Rodriguez Rosa M RM Patil Sujata S Keshinro Ajaratu A Shia Jinru J Vakiani Efsevia E Stadler Zsofia Z Segal Neil H NH Yaeger Rona R Konishi Tsuyoshi T Shimada Yoshifumi Y Widmar Maria M Wei Iris I Pappou Emmanouil E Smith J Joshua JJ Nash Garrett G Paty Philip P Garcia-Aguilar Julio J Weiser Martin R MR

Oncoimmunology 20201111 1

Tumor infiltrating lymphocytes (TIL), which represent host adaptive response to the tumor, were first identified at scanning magnification to select areas with the highest counts on hematoxylin and eosin slides, quantitated per high-power field (HPF), and analyzed for association with recurrence-free survival (RFS) in 848 patients. Highest TIL in a single HPF was analyzed as a continuous and categorical variable, and optimal cutoff analysis was performed to predict RFS. Highest TIL count in a si ...[more]

PMID: 33235819

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Project description:The aim of this study was to investigate immune response and its prognostic significance in colon carcinomas using the previously described Immunoscore (IS). A population-based series of 779 colorectal cancers, operated on between 2000 and 2010, were classified according to tumour, node, metastasis (TNM) status, mismatch repair (MMR), and BRAF mutation status. Rectal cancer cases (n = 203) were excluded as a high proportion of these patients received preoperative neoadjuvant chemoradiotherapy. Tissue microarray (TMA) samples collected from the tumour centre and invasive front were immunostained for CD3 and CD8. Lymphocytes were then digitally calculated to categorize IS from grade 0 to 4. Samples adequate for IS were available from 510 tumours. IS was significantly associated with AJCC/UICC stage, T stage, lymph node and distant metastases, perineural and lymphovascular invasion, MMR status, and BRAF mutation status. For IS0, IS1, IS2, IS3 and IS4, respectively, the 5-year disease-free survival (DFS) rates were 59, 68, 78, 83 and 94% (p < 0.001); 5-year disease-specific survival (DSS) rates were 47, 55, 75, 80, and 89% (p < 0.001); and 5-year overall survival (OS) rates were 40, 44, 66, 61, and 76% (p < 0.001). IS was also prognostic for DFS, DSS, and OS within subsets of microsatellite-stable (MSS) and microsatellite-instable (MSI) disease. Multivariable analysis showed that IS, AJCC/UICC stage, lymphovascular invasion, and lymph node ratio in AJCC/UICC stage III disease were independent prognostic factors for DFS, DSS, and OS. Age was an independent prognostic factor for DSS and OS. Gender and BRAF mutation were independent prognostic factors for OS. In conclusion, IS differentiated patients with poor versus improved prognosis in MSS and MSI disease and across AJCC/UICC stages. IS, AJCC/UICC stage, lymphovascular invasion, and lymph node ratio in AJCC/UICC stage III disease were independent prognostic factors for DFS, DSS, and OS.

Project description:BackgroundImmunotherapy with immune checkpoint inhibitors (ICIs) is highly effective in microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC); however, specific predictive biomarkers are lacking.Patients and methodsData and samples from 85 patients with MSI-H mCRC treated with ICIs were gathered. Tumor infiltrating lymphocytes (TILs) and tumor mutational burden (TMB) were analyzed in an exploratory cohort of "super" responders and "clearly" refractory patients; TILs were then evaluated in the whole cohort of patients. Primary objectives were the correlation between the number of TILs and TMB and their role as biomarkers of ICI efficacy. Main endpoints included response rate (RR), progression-free survival (PFS), and overall survival (OS).ResultsIn the exploratory cohort, an increasing number of TILs correlated to higher TMB (Pearson's test, p = .0429). In the whole cohort, median number of TILs was 3.6 in responders compared with 1.8 in nonresponders (Mann-Whitney test, p = .0448). RR was 70.6% in patients with high number of TILs (TILs-H) compared with 42.9% in patients with low number of TILs (odds ratio = 3.20, p = .0291). Survival outcomes differed significantly in favor of TILs-H (PFS: hazard ratio [HR] = 0.42, p = .0278; OS: HR = 0.41, p = .0463).ConclusionA significant correlation between higher TMB and increased number of TILs was shown. A significantly higher activity and better PFS and OS with ICI in MSI-H mCRC were reported in cases with high number of TILs, thus supporting further studies of TIL count as predictive biomarker of ICI efficacy.Implications for practiceMicrosatellite instability is the result of mismatch repair protein deficiency, caused by germline mutations or somatic modifications in mismatch repair genes. In metastatic colorectal cancer (mCRC), immunotherapy (with immune checkpoint inhibitors [ICIs]) demonstrated remarkable clinical benefit in microsatellite instability-high (MSI-H) patients. ICI primary resistance has been observed in approximately 25% of patients with MSI-H mCRC, underlining the need for predictive biomarkers. In this study, tumor mutational burden (TMB) and tumor infiltrating lymphocyte (TIL) analyses were performed in an exploratory cohort of patients with MSI-H mCRC treated with ICIs, demonstrating a significant correlation between higher TMB and increased number of TILs. Results also demonstrated a significant correlation between high number of TILs and clinical responses and survival benefit in a large data set of patients with MSI-H mCRC treated with ICI. TMB and TILs could represent predictive biomarkers of ICI efficacy in MSI-H mCRC and should be incorporated in future trials testing checkpoint inhibitors in colorectal cancer.

Project description:(1) Purpose: Although assessment of tumor-infiltrating lymphocytes (TILs) has been acknowledged to have important predictive prognostic value in muscle-invasive bladder cancer (MIBC), it is limited by inter- and intra-observer variability, hampering widespread clinical application. We aimed to evaluate the prognostic value of quantitative TILs score based on a machine learning (ML) algorithm to identify MIBC patients who might benefit from immunotherapy or the de-escalation of therapy. (2) Methods: We constructed an artificial neural network classifier for tumor cells, lymphocytes, stromal cells, and "ignore" cells from hematoxylin-and-eosin-stained slide images using the QuPath open source software. We defined four unique TILs variables based on ML to analyze TILs measurements. Pathological slide images from 133 MIBC patients were retrospectively collected as the discovery set to determine the optimal association of ML-read TILs variables with patient survival outcomes. For validation, we evaluated an independent external validation set consisting of 247 MIBC patients. (3) Results: We found that all four TILs variables had significant prognostic associations with survival outcomes in MIBC patients (p < 0.001 for all comparisons), with higher TILs score being associated with better prognosis. Univariate and multivariate Cox regression analyses demonstrated that electronic TILs (eTILs) variables were independently associated with overall survival after adjustment for clinicopathological factors including age, sex, and pathological stage (p < 0.001 for all analyses). Results analyzed in different subgroups showed that the eTILs variable was a strong prognostic factor that was not redundant with pre-existing clinicopathological features (p < 0.05 for all analyses). (4) Conclusion: ML-driven cell classifier-defined TILs variables were robust and independent prognostic factors in two independent cohorts of MIBC patients. eTILs have the potential to identify a subset of high-risk stage II or stage III-IV MIBC patients who might benefit from adjuvant immunotherapy.

Dataset Information

Quantitative assessment of tumor-infiltrating lymphocytes in mismatch repair proficient colon cancer.

Publications

Quantitative assessment of tumor-infiltrating lymphocytes in mismatch repair proficient colon cancer.

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