FOXP3 expression in tumor cells and tumor-infiltrating lymphocytes is associated with breast cancer prognosis

145 Background: Clinical trials have shown that adoptive cell transfer therapy is a promising method for cancer treatment. In the current study, we aim to generate and characterize anti-tumor tumor-infiltrating lymphocytes from patients with breast cancer for adoptive cell transfer therapy. Methods: In vitro culture method was used to generate anti-tumor, tumor-infiltrating lymphocytes from patients with breast cancer. FACS analysis, ELISA, and Elispot assay were used to characterize tumor-infiltrating lymphocytes. Autologous anti-tumor tumor-infiltrating lymphocytes from patients with breast cancer were used in adoptive cell transfer therapy. Results: FACS analysis indicated that tumor-infiltrating lymphocytes were present in the tumor tissues, but not detectable in the normal breast tissues from patients with breast cancer. Tumor-infiltrating lymphocytes could be generated in vitro from fresh tumor specimens of patients with breast cancer. Both CD4 T cells and CD8 T cells were detected in tumor-infiltrating lymphocytes. Autologous tumor cells could also generate in vitro from fresh tumor tissue samples of patients with breast cancer. Among 22 samples screened, 6 samples (25%) of tumor-infiltrating lymphocytes are tumor-reactive. Anti-tumor, tumor-infiltrating lymphocytes could recognize autologous tumor cells and allogenic tumor cells. After a large scale T cell expansion, anti-tumor reactivity was maintained in tumor-infiltrating lymphocytes. All of tumor-infiltrating lymphocytes were NK cells in some samples from patients with breast cancer, and these NK cells could recognize autologous tumor cells and a panel of allogenic tumor cells. T cell cloning assay demonstrated that some of the tumor-reactive, tumor-infiltrating lymphocytes were CD4 T cells. Conclusions: The results suggest that anti-tumor, tumor-infiltrating lymphocytes may be generated from patients with breast cancer, which may be used in clinical applications of adoptive cell transfer therapy for patients with breast cancer. The clinical trial of adoptive cell transfer therapy using autologous anti-tumor tumor-infiltrating lymphocytes for patients with breast is under way.

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Overexpression of an Immune Checkpoint (CD155) in Breast Cancer Associated with Prognostic Significance and Exhausted Tumor-Infiltrating Lymphocytes: A Cohort Study

Journal of Immunology Research ◽

10.1155/2020/3948928 ◽

2020 ◽

Vol 2020 ◽

pp. 1-9 ◽

Cited By ~ 2

Author(s):

Yu-Chen Li ◽

Quan Zhou ◽

Qing-Kun Song ◽

Rui-Bin Wang ◽

Shuzhen Lyu ◽

...

Keyword(s):

Breast Cancer ◽

Overall Survival ◽

Cohort Study ◽

Tumor Cells ◽

Immune Checkpoint ◽

Prognostic Significance ◽

Tumor Infiltrating Lymphocytes ◽

Immune Microenvironment ◽

Infiltrating Lymphocytes ◽

Low Expression

Purpose. The immune checkpoint inhibitor is approved for breast cancer treatment, but the low expression of PD-L1 limits the immunotherapy. CD155 is another immune checkpoint protein in cancers and interacts with ligands to regulate immune microenvironment. This study is aimed at investigating the expression of CD155 and the association with prognosis and pathological features of breast cancer. Methods. 126 patients were recruited this cohort study consecutively, and CD155 expression on tumor cells was detected by immunohistochemistry. The Kaplan-Meier survival curve and Cox hazard regression model were used to estimate the association. Results. 38.1% patients had an overexpression of CD155, and the proportion of tumor cells with CD155 overexpression was 17%, 39%, 37%, and 62% among Luminal A, Luminal B, HER2-positive, and triple negative breast cancer cases, respectively (p<0.05). Patients with CD155 overexpression had the Ki-67 index significantly higher than that of patients with low expression (42% vs. 26%). Though the number of tumor-infiltrating lymphocytes was higher among patients with CD155 overexpression (144/HPF vs. 95/HPF), the number of PD-1+ lymphocytes was significantly higher (52/HPF vs. 25/HPF, p<0.05). Patients of CD155 overexpression had the disease-free and overall survival decreased by 13 months and 9 months, respectively (p<0.05). CD155 overexpression was associated with an increased relapse (HR=13.93, 95% CI 2.82, 68.91) and death risk for breast cancer patients (HR=5.47,1.42,20.99). Conclusions. Overexpression of CD155 was correlated with more proliferative cancer cells and a dysfunctional immune microenvironment. CD155 overexpression introduced a worse relapse-free and overall survival and might be a potential immunotherapy target for breast cancer.

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Subpopulation composition of tumor-infiltrating lymphocytes in luminal breast cancer and its effect on effectiveness of neoadjuvant chemotherapy

Medical alphabet ◽

10.33667/2078-5631-2020-29-32-37 ◽

2020 ◽

pp. 32-37

Author(s):

E. I. Kovalenko ◽

E. V. Artamonova ◽

T. N. Zabotina ◽

Z. G. Kadagidze ◽

S. G. Bagrova ◽

...

Keyword(s):

Breast Cancer ◽

Neoadjuvant Chemotherapy ◽

Initial Level ◽

Tumor Infiltrating Lymphocytes ◽

Cancer Prognosis ◽

Luminal Breast Cancer ◽

Tumor Subtype ◽

Luminal A ◽

Ki 67 ◽

Infiltrating Lymphocytes

Tumor-infiltrating lymphocytes (TILs) play a key role in the formation of anti-tumor immunity and, as studies have shown, can be one of the markers of treatment effectiveness and cancer prognosis. The aim was to study the subpopulation composition of the lymphoid infiltrate in early luminal breast cancer in patients receiving neoadjuvant chemotherapy (NACT) and its effect on achieving a pathological complete response (pCR). Materials and methods. We included 24 patients who received anthracycline-taxane-contain-ing preoperative chemotherapy. The subpopulation composition of TIL was assessed in core-biopsy samples before starting NACT in all patients; after treatment, the assessment was made on postoperative material. The analysis was carried out by flow cytometry. Clinical and immunological assessment was carried out for the following seven subpopulations of lymphocytes: CD3+, CD3+CD4+, CD3+CD8+, CD4+CD127+CD25+, CD3 CD19+ CD3CD16+CD56+, CD3+CD16+CD56+. Results. The incidence pCR was 16.7 %. It was revealed that the initial level before treatment of CD3+, CD3+CD4+, CD3+CD8+, CD4+C-D127+CD25+, CD3-CD19+, CD3 CD16+CD56+, CD3+CD16+CD56+ lymphocytes did not differ depending on the stage of the disease (II or III), tumor subtype (luminal A/B) and Ki-67 level (up to 20, 20-39, 40 and more). No correlations were found between Ki-67 and TIL content. When conducting regression analysis, it was revealed that only the level of CD3+, CD3+CD8+ and CD19+ was a significant factor in achieving a pCR (p = 0.005). When an empirical subgroup was identified, which was characterized by a high content (above or equal to the median) of CD3+, CD3+CD8+ and low (below the median) CD19+ (four observations), the frequency of pCR reached 75 %. Conclusion. Thus, the initial level of T-lymphocytes (CD3+, CD3+CD8+) and B-lymphocytes (CD19+) in the tumor, regardless of the stage of the disease, tumor subtype, ki-67 index, was a predictor of high sensitivity to neoadjuvant chemotherapy of luminal breast cancer and was associated with higher frequency of pCR.

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Prognostic role of tumor-inflating lymphocytes in gastric cancer: A systematic review and meta-analysis.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e15578 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e15578-e15578

Author(s):

Der Sheng Sun ◽

Jung Soo Lee ◽

Soon Auck Hong ◽

Hye Sung Won ◽

Yoon Ho Ko

Keyword(s):

Gastric Cancer ◽

Overall Survival ◽

Survival Data ◽

Meta Analysis ◽

Disease Free Survival ◽

Tumor Infiltrating Lymphocytes ◽

Foxp3 Expression ◽

Survival Outcome ◽

Cancer Prognosis ◽

Infiltrating Lymphocytes

e15578 Background: Tumor-infiltrating lymphocytes(TILs) may act as major determinants of the host immune response to tumor cells. However, the potential prognostic value of TILs in gastric cancer remains controversial. This meta-analysis analyzed the associations between TILs and survival outcomes in gastric cancer. Methods: Eligible 24 published studies were identified by searching the PubMed and Google scholar databases. The primary clinical outcome was defined as overall survival (OS) or disease-free survival (DFS), which were analyzed by subgroups such as TILs subtype. The total of the study sample sizes in eligible 24 published studies was 3,229, which ranged from 52 to 273 (median, 120) patients. All studies were non-randomized and retrospective study. The only multivariate hazard ratio(HR) among patient survival data were pooled, and pooled multivariate HR with 95% confidence intervals (95% CI) were used to calculate the strength of this association between TILs expression and survival outcome. Results: The pooled multivariate hazard ratios suggested that high expression of TILs was associated with better overall survival outcome (pooled HR = 0.69, 95% CI 0.57–0.82), compared to low TILs expression in twenty-three eligible studies, particularly in CD8(+) lymphocytes (pooled HR = 0.63, 95% CI 0.48 –0.83). In contrast, a pooled analysis of the FOXP3 (+) T cells or Treg subgroup showed that high FOXP3 (+) expression was negatively correlated with OS (pooled HR = 1.88, 95% CI 1.34 –2.63). In an analysis of seven studies on DFS, the infiltration by TILs, CD4(+) or CD8(+) lymphocytes (pooled HR = 0.59, 95% CI 0.42 –0.81), not by the infiltration of FOXP3 (+) T lymphocytes (pooled HR = 1.82, 95% CI 1.30 – 2.53), was significantly associated with better survival outcome. Conclusions: The results from this meta-analysis suggest that TILs and TILs subsets expression can be a potential prognostic biomarker in patients with gastric cancer. Key Words: Tumor-infiltrating lymphocytes, gastric cancer, prognosis, meta-analysis

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Breast Cancer Prognosis and Occult Lymph Node Metastases, Isolated Tumor Cells, and Micrometastases

JNCI Journal of the National Cancer Institute ◽

10.1093/jnci/djq008 ◽

2010 ◽

Vol 102 (6) ◽

pp. 410-425 ◽

Cited By ~ 153

Author(s):

M. de Boer ◽

J. A. A. M. van Dijck ◽

P. Bult ◽

G. F. Borm ◽

V. C. G. Tjan-Heijnen

Keyword(s):

Breast Cancer ◽

Lymph Node ◽

Tumor Cells ◽

Lymph Node Metastases ◽

Breast Cancer Prognosis ◽

Cancer Prognosis ◽

Isolated Tumor Cells ◽

Node Metastases

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Cytokeratin 19-positive circulating tumor cells in early breast cancer prognosis

Future Oncology ◽

10.2217/fon.09.147 ◽

2010 ◽

Vol 6 (2) ◽

pp. 209-219 ◽

Cited By ~ 12

Author(s):

Emmanouil Saloustros ◽

Dimitris Mavroudis

Keyword(s):

Breast Cancer ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Early Breast Cancer ◽

Breast Cancer Prognosis ◽

Cancer Prognosis ◽

Cytokeratin 19

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Comparing syngeneic and autochthonous models of breast cancer to identify tumor immune components that correlate with response to immunotherapy in breast cancer

10.21203/rs.3.rs-57679/v2 ◽

2021 ◽

Author(s):

Jessica Castrillon Lal ◽

Anita K. Mehta ◽

Madeline G. Townsend ◽

Madisson Oliwa ◽

Eric Miller ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Cells ◽

Myeloid Cells ◽

Tumor Infiltrating Lymphocytes ◽

Immune Checkpoint Blockade ◽

Laboratory Findings ◽

Cancer Models ◽

Mammary Fat Pad ◽

Infiltrating Lymphocytes

Abstract Background: The heterogeneity of the breast tumor microenvironment (TME) may contribute to the lack of durable responses to immune checkpoint blockade (ICB), however, mouse models to test this are currently lacking. Proper selection and use of preclinical models are necessary for rigorous, preclinical studies to rapidly move laboratory findings into the clinic to treat patients.Methods: We compared 3 versions of a common syngeneic and autochthonous mouse model to elucidate how tumor latency and TME heterogeneity contributes to ICB resistance. We performed comprehensive characterization of the TME using quantitative flow-cytometry and RNA expression analysis (NanoString) utilizing three distinct syngeneic breast cancer models, all derived from the MMTV-PyMT autochthonous model. A commonly used protocol was used to obtain tumor cells from MMTV-PyMT mice and 1E6, 1E5 or 1E4 cells were immediately injected into the mammary fat pad of FVB/NJ wild type mice. We then performed deep immunophenotyping and tested ICB efficacy in the 3 syngeneic models compared to the autochthonous model. Results: The 4 models had vastly different TMEs that correlated to ICB responses. We found that the number of cells used to generate syngeneic tumors significantly influences tumor latency, infiltrating leukocyte population and response to ICB. Compared to the autochthonous model, all 3 syngeneic models had significantly more tumor infiltrating lymphocytes (TILs; CD3+, CD4+, and CD8+) and higher proportions of PD-L1 positive myeloid cells, whereas the MMTV-PyMT model had the highest frequency of myeloid cells out of total leukocytes. Increased TILs correlated with response to anti-PD-L1 and anti-CTLA-4 therapy; but PD-L1expression on tumor cells or PD-1 expression of T-cells did not.Conclusions: These studies reveal that the commonly used syngeneic models have low concordance with the autochthonous model. We have identified ICB-sensitive and resistant syngeneic breast cancer models, generated from the same tumor cell inoculum, and find that only the 1E4 syngeneic model is representative of the slow growing, autochthonous model. Given the lack of benefit from ICB in breast cancer, the identification of robust murine models presented here provides the opportunity to further interrogate the TME for breast cancer treatment and provide novel insights into therapeutic combinations to overcome ICB resistance.

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