Clinical Validity and Utility of Tumor-Infiltrating Lymphocytes in Routine Clinical Practice for Breast Cancer Patients: Current and Future Directions

Wein, Lironne; Savas, Peter; Luen, Stephen J.; Virassamy, Balaji; Salgado, Roberto; Loi, Sherene

doi:10.3389/fonc.2017.00156

Cited by 101 publications

(84 citation statements)

References 58 publications

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“…The mechanisms underlying antitumor immune responses have been extensively investigated through in vitro and in vivo experiments as well as through clinical studies (3,4). It has been reported that co-stimulatory molecules contribute to T-cell activation and improve antitumor immunity, thereby playing an important role in tumor diagnosis and treatment (5)(6)(7).…”

Section: Introductionmentioning

confidence: 99%

Involvement of soluble B7‑H3 in combination with the serum inflammatory cytokines interleukin‑17, ‑8 and ‑6 in the diagnosis of hepatocellular carcinoma

Wang

et al. 2017

Oncol Lett

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Abstract. Previous studies have demonstrated that B7-H3, and the inflammatory cytokines interleukin (IL)-17, IL-8 and IL-6, are involved in the development of a variety of tumors. The objectives of the present study were: i) To investigate the association between soluble B7-H3 (sB7-H3) and cytokine levels of IL-17, IL-8 and IL-6 in the serum of patients with hepatocellular carcinoma (HCC); and ii) to determine their potential value for use in HCC diagnosis. Serum sB7-H3, IL-17, IL-8 and IL-6 levels in the HCC patients and healthy control subjects were measured using ELISA. The accuracy of each of these biomarkers in HCC diagnosis was compared using a receiver operating characteristic curve and the area under the curve (AUC). A logistic regression model was used to investigate the accuracy of diagnosing HCC when evaluated using combined determinations of sB7-H3, IL-17, IL-8 and IL-6 levels. The data demonstrated that serum levels of sB7-H3, IL-17, IL-8 and IL-6 were significantly increased in HCC patients compared with those in the healthy control group. Serum sB7-H3 levels were positively associated with serum IL-17, whereas serum IL-8 levels were negatively correlated with serum IL-17 levels. The AUC values for sB7-H3, IL-17, IL-8 and IL-6 were 83.2, 65.7, 95.3 and 97.0%, respectively, and indicated that all four biomarkers exhibited a statistically significant capacity for diagnosing HCC. Using the logistic regression model, the AUC value, sensitivity and specificity, as determined for the combination of the four biomarkers, were 99.2, 96.67 and 97.14%, respectively. This was significantly greater than that achieved when any single biomarker was used alone in the logistic regression model to assess their accuracy in HCC diagnosis. The optimum cutoff value of the predicted probability obtained by the combination of sB7-H3, IL-17, IL-8 and IL-6 in the regression model was 0.5745. To conclude, the present study revealed that there exists a positive association between serum sB7-H3 and IL-17 levels in HCC patients. Determinations involving the combination of serum sB7-H3, IL-17, IL-8 and IL-6 levels demonstrate great potential for use in HCC diagnosis.

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Section: Introductionmentioning

confidence: 99%

Involvement of soluble B7‑H3 in combination with the serum inflammatory cytokines interleukin‑17, ‑8 and ‑6 in the diagnosis of hepatocellular carcinoma

Wang

et al. 2017

Oncol Lett

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“…It has been established in several studies that tumor infiltrating lymphocytes in baseline, pretreatment biopsies of breast cancer are powerful prognostic markers of the clinical outcome in triple negative and HER2 positive breast cancers [11,12]. The correlation between posttreatment levels of TIL and clinical outcome is less clear, perhaps due to the fact that cases with pathological complete response are often eliminated from further analysis.…”

Section: Discussionmentioning

confidence: 99%

Influence of mutagenic versus non-mutagenic pre-operative chemotherapy on the immune infiltration of breast cancer

Tőkés

Rusz

Tóth

et al. 2018

Preprint

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Background: Chemotherapeutic agents are often mutagenic. Induction of mutation associated neo-epitopes is one of the mechanisms by which chemotherapy is thought to increase the number of tumor-infiltrating lymphocytes, but the clinical relevance of this triggered immune response is not known.We decided to investigate, whether treatment with various chemotherapeutic agents with significantly different mutagenic capacity induce a significantly different number of stromal tumor-infiltrating lymphocytes (StrTIL) in the clinical setting.Methods: 112 breast carcinoma cases treated with pre-operative chemotherapy were selected for the study. According to chemotherapy regimen 28/112 patients received platinum-based, 42/112 cyclophosphamide-based and 42/112 anthracycline-based chemotherapy. The percentage of stromal tumor-infiltrating lymphocytes (StrTIL) was evaluated on hematoxylineosin stained slides of pre-treatment core biopsy (pre-StrTIL) and post-treatment surgical tumor samples (post-StrTIL), according to the most recent recommendation of International TILs Working Group. In survival analyses, TIL changes (∆StrTIL) were calculated from the difference between post-StrTIL and pre-StrTIL.Results: Of the 112 cases, 58.0% (n=65) were hormone receptor (HR) positive and 42.0% (n=47) were HR negative. There was a trend of higher post-StrTIL compared to pre-StrTIL (median 6.25% vs. 3.00%; p<0.001). When analyzing the pre-StrTIL and post-StrTIL among the three treatment groups, we experienced significant StrTIL increase independently of the treatment applied. Based on the results of survival analyses both post-StrTIL and ∆StrTIL was found to be independent prognostic factor in HR negative cases. Each 1% increase in post-StrTIL reduced the hazard of distant metastases development by 2.6% (hazard ratio: 0.974; 3 CI: 0.948-1.000; p=0.05) and for each 1% ∆StrTIL increment, the risk of distant metastases was reduced by 4.3% (hazard ratio: 0.957; CI: 0.932-0.983; p=0.001). The prognostic role of StrTIL in HR positive cases could not be proven. Conclusions:StrTIL expression might be stimulated by highly (platinum), moderately (cyclophosphamide) and marginally (taxane, anthracycline) mutagenic chemotherapeutic agents. Increase in StrTIL in residual cancer compared to pre-treatment tumor tissue is associated with improved distant metastasis-free survival in cases with HR negative breast carcinoma.

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“…1), which account for about 11% of all invasive breast carcinomas [10]. TILs are more frequently observed in high-grade lesions, in TNBC and HER2-positive breast carcinomas [11][12][13]. In a recently reported cohort of breast carcinoma patients treated with neoadjuvant chemotherapy, TIL mean values for TNBCs, HER2-positive carcinomas and luminal carcinomas were reported as 28.5, 26.5 and 24%, respectively [14].…”

Section: Tumor-infiltrating Lymphocytesmentioning

confidence: 99%

The Multifaceted Nature of Tumor Microenvironment in Breast Carcinomas

et al. 2020

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Heterogeneity in breast carcinomas can be appreciated at various levels, from morphology to molecular alterations, and there are well-known genotypic-phenotypic correlations. Clinical decision-making is strictly focused on the evaluation of tumor cells and is based on the assessment of hormone receptors and of the HER2 status, by means of a combination of immunohistochemical and in situ hybridization techniques. The tumor microenvironment (TME) also shows a multifaceted nature stemming from the different actors populating the intratumoral and the peritumoral stroma of breast carcinomas. Of note, we have now evidence that tumor-infiltrating lymphocytes (TILs) are clinically meaningful as their quantification in the intratumoral stroma strongly correlates with good prognosis, in particular in triple-negative and HER2-positive breast cancer patients. Nevertheless, TILs are just one of the many actors orchestrating the com-plexity of the TME, which is populated by immune and nonimmune cells (cancer-associated fibroblasts, cancer-associated adipocytes), as well as non-cellular components such as chemical inflammation mediators. In this review article we will overview the main features of the distinct cell compartments by discussing (i) the potential impact the TME may have on the prognostic stratification of breast cancers and (ii) the possible predictive value of some markers in the context of immunotherapy in light of the recent results of phase III studies in advanced and early triple-negative breast cancer patients.

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Clinical Validity and Utility of Tumor-Infiltrating Lymphocytes in Routine Clinical Practice for Breast Cancer Patients: Current and Future Directions

Cited by 101 publications

References 58 publications

Involvement of soluble B7‑H3 in combination with the serum inflammatory cytokines interleukin‑17, ‑8 and ‑6 in the diagnosis of hepatocellular carcinoma

Involvement of soluble B7‑H3 in combination with the serum inflammatory cytokines interleukin‑17, ‑8 and ‑6 in the diagnosis of hepatocellular carcinoma

Influence of mutagenic versus non-mutagenic pre-operative chemotherapy on the immune infiltration of breast cancer

The Multifaceted Nature of Tumor Microenvironment in Breast Carcinomas

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