Characterization of the tumor immune microenvironment (TIM) with multiplex immunohistochemistry (mIHC) in patients with breast cancer following treatment with MK-2206.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e12109-e12109
Author(s):  
Douglas Kanter Marks ◽  
Robyn Denise Gartrell ◽  
Margueritta El Asmar ◽  
Thomas Hart ◽  
Yan Lu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cytotoxic T Cells ◽  
Tumor Infiltrating Lymphocytes ◽  
Akt Inhibitor ◽  
Immune Microenvironment ◽  
Immune Biomarkers ◽  
Tumor Immune Microenvironment ◽  
Before And After ◽  
Infiltrating Lymphocytes ◽  
The Impact

e12109 Background: The PAM (PI3K/Akt/mTOR) signaling pathway has been implicated in the oncogenesis of multiple solid malignancies, including breast cancer (BC). Our aim is to characterize the TIM in a series of patients with operable stage I-III BC treated with MK-2206, an allosteric Akt inhibitor within a presurgical trial. In NCT01319539 , patients received 2 doses of MK-2206 with first dose at day -9 and second at day -2 from surgery. Methods: mIHC was performed using immune biomarkers (DAPI, CD3, CD8, CD4, FOXP3, CD68, Pancytokeratin) on full section (4uM) tissue slides from core biopsy specimens and postsurgical specimens of 10 patients - 5 treated with MK-2206, 5 paired controls. Images were taken using Vectra, a novel pathology workstation and analyzed using inForm software to perform cell classification and phenotyping. T- tests were used to compare biomarker changes before and after MK-2206. Results: Our preliminary analysis demonstrates that patients treated with MK-2206 exhibited an increase in median cytotoxic T-cells (CD3CD8+) density, as compared to the control population , which was statistically significant (87% vs.0.2%, p < 0.05). We did not identify a change in macrophage (CD68) or T helper/T reg (CD4/CD4FOXP3+) density following MK-2206 treatment in this small cohort. We are currently expanding our myeloid panel as well as performing additional tissue analysis to validate our findings. As data is exploratory no correction was made for multiple comparisons. Conclusions: Tumor infiltrating lymphocytes (TILs) are both prognostic of overall survival as well as predictive of response to neoadjuvant chemotherapy in BC. At present, there are currently both FDA approved therapies, as well as agents in clinical development that exert antineoplastic activity through the PAM pathway. Investigations that endeavour to understand the impact of these therapies on the tumor immune microenvironment may lead to both an increased understanding of the bioactivity of these agents and potentially identify aspects of the immune response which can be exploited in future therapeutics.

scholarly journals Statistical framework for studying the spatial architecture of the tumor immune microenvironment

2021 ◽  
Author(s):  
Christopher Wilson ◽  
Ram Thapa ◽  
Jordan Creed ◽  
Jonathan Nguyen ◽  
Carlos Moran Segura ◽  
...  
Keyword(s):  
Overall Survival ◽  
T Cells ◽  
Immune Cells ◽  
Spatial Clustering ◽  
Cytotoxic T Cells ◽  
Tumor Infiltrating Lymphocytes ◽  
Immune Microenvironment ◽  
Tumor Immune Microenvironment ◽  
Infiltrating Lymphocytes ◽  
Spatial Architecture

AbstractNew technologies, such as multiplex immunofluorescence microscopy (mIF), are being developed and used for the assessment and visualization of the tumor immune microenvironment (TIME). These assays produce not only an estimate of the abundance of immune cells in the TIME, but also their spatial locations; however, there are currently few approaches to analyze the spatial context of the TIME. Thus, we have developed a framework for the spatial analysis of the TIME using Ripley’s K, coupled with a permutation-based framework to estimate and measure the departure from complete spatial randomness (CSR) as a measure of the interactions between immune cells. This approach was then applied to ovarian cancer using mIF collected on intra-tumoral regions of interest (ROIs) and tissue microarrays (TMAs) from 158 high-grade serous ovarian carcinoma patients in the African American Cancer Epidemiology Study (AACES) (94 subjects on TMAs resulting in 259 tissue cores; 91 subjects with 254 ROIs). Cox proportional hazard models were constructed to determine the association of abundance and spatial clustering of tumor-infiltrating lymphocytes, cytotoxic T-cells, and regulatory T-cells, and overall survival. We found that EOC patients with high abundance and low spatial clustering of tumor-infiltrating lymphocytes and cytotoxic T-cells in their tumors had the best overall survival. In contrast, patients with low levels of regulatory T-cells but with a high level of spatial clustering (compare to those with a low level of spatial clustering) had better survival. These findings underscore the prognostic importance of evaluating not only immune cell abundance but also the spatial contexture of the immune cells in the TIME. In conclusion, the application of this spatial analysis framework to the study of the TIME could lead to the identification of immune content and spatial architecture that could aid in the determination of patients that are likely to respond to immunotherapies.

scholarly journals Atezolizumab and nab-Paclitaxel in Advanced Triple-Negative Breast Cancer: Biomarker Evaluation of the IMpassion130 Study

2021 ◽  
Author(s):  
Leisha A Emens ◽  
Luciana Molinero ◽  
Sherene Loi ◽  
Hope S Rugo ◽  
Andreas Schneeweiss ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Clinical Benefit ◽  
Triple Negative ◽  
Locally Advanced ◽  
Immune Microenvironment ◽  
Immune Biomarkers ◽  
Improved Outcomes ◽  
Tumor Immune Microenvironment ◽  
The Impact

Abstract Background Understanding the impact of the tumor immune microenvironment and BRCA-related DNA repair deficiencies on the clinical activity of immune checkpoint inhibitors may help optimize both patient and treatment selection in metastatic triple-negative breast cancer (mTNBC). In this substudy from the phase 3 IMpassion130 trial, immune biomarkers and BRCA alterations were evaluated for association with clinical benefit with atezolizumab (A) + nab-paclitaxel (nP) vs placebo + nP in unresectable locally advanced or mTNBC. Methods Patients were randomized 1:1 to nab-paclitaxel 100 mg/m2 (days 1, 8, and 15 of a 28-day cycle) + atezolizumab 840 mg every 2 weeks or placebo until progression or toxicity. Progression-free survival (PFS) and overall survival (OS) were evaluated based on programmed death-ligand 1 (PD-L1) expression on immune cells (IC) and tumor cells (TC), intratumoral CD8, stromal tumor-infiltrating lymphocytes (sTILs), and BRCA1/2 mutations. Results PD-L1 IC+ in either primary or metastatic tumor tissue was linked to PFS and OS benefit with A+nP. PD-L1 IC+ low (26.9%; 243 of 902 patients) and high (13.9%; 125 of 902 patients) populations had improved outcomes that were comparable. Intratumoral CD8 and sTILs positivity were associated with PD-L1 IC+ status; A+nP vs P+nP improved outcomes were observed only in CD8+ and sTIL+ patients who were also PD-L1 IC+. BRCA1/2 mutations (occurring in 14.5% [89 of 612 patients]) were not associated with PD-L1 IC status, and PD-L1 IC+ patients benefited from A+nP regardless of BRCA1/2 mutation status. Conclusions Although A+nP was more efficacious in patients with richer tumor immune microenvironment, clinical benefit was only observed in patients whose tumors were PD-L1 IC+.S

scholarly journals Tumor microenvironment in triple-negative breast cancer: the correlation of tumor-associated macrophages and tumor-infiltrating lymphocytes

2021 ◽  
Author(s):  
H. Kuroda ◽  
T. Jamiyan ◽  
R. Yamaguchi ◽  
A. Kakumoto ◽  
A. Abe ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Cytotoxic T Cells ◽  
Tumor Infiltrating Lymphocytes ◽  
Tumor Associated Macrophages ◽  
Free Survival ◽  
Infiltrating Lymphocytes

Abstract Purpose Immune cells such as cytotoxic T cells, helper T cells, B cells or tumor-associated macrophages (TAMs) contribute to the anti-tumor response or pro-tumorigenic effect in triple negative breast cancer (TNBC). The interrelation of TAMs, T and B tumor-infiltrating lymphocytes (TILs) in TNBC has not been fully elucidated. Methods We evaluated the association of tumor-associated macrophages, T and B TILs in TNBC. Results TNBCs with a high CD68+, CD163+ TAMs and low CD4+, CD8+, CD20+ TILs had a significantly shorter relapse-free survival (RFS) and overall survival (OS) than those with low CD68+, CD163+ TAMs and high CD4+, CD8+, CD20+ TILs. TNBCs with high CD68+ TAMs/low CD8+ TILs showed a significantly shorter RFS and OS and a significantly poorer prognosis than those with high CD68+ TAMs/high CD8+ TILs, low CD68+ TAMs/high CD8+ TILs, and low CD68+/low CD8+. TNBCs with high CD163+ TAMs/low CD8+, low CD20 + TILs showed a significantly shorter RFS and OS and a significantly poorer prognosis than those with high CD163+ TAMs/high CD8+ TILs and high CD163+ TAMs /high CD20+ TILs. Conclusions Our study suggests that TAMs further create an optimal tumor microenvironment (TME) for growth and invasion of cancer cells when evasion of immunoreactions due to T and B TILs occurs. In TNBCs, all these events combine to affect prognosis. The process of TME is highly complex in TNBCs and for an improved understanding, larger validation studies are necessary to confirm these findings.

scholarly journals Proteomics-derived basal biomarker DNA-PKcs is associated with intrinsic subtype and long-term clinical outcomes in breast cancer

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Karama Asleh ◽  
Nazia Riaz ◽  
Angela S. Cheng ◽  
Dongxia Gao ◽  
Samuel C. Y. Leung ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Infiltrating Lymphocytes ◽  
Tissue Microarrays ◽  
Immune Checkpoint Blockade ◽  
Intrinsic Subtype ◽  
Cancer Tissue ◽  
Immune Biomarkers ◽  
Basal Like Breast Cancer ◽  
Poor Outcomes ◽  
Infiltrating Lymphocytes

AbstractPrecise biomarkers are needed to guide better diagnostics and therapeutics for basal-like breast cancer, for which DNA-dependent protein kinase catalytic subunit (DNA-PKcs) has been recently reported by the Clinical Proteomic Tumor Analysis Consortium as the most specific biomarker. We evaluated DNA-PKcs expression in clinically-annotated breast cancer tissue microarrays and correlated results with immune biomarkers (training set: n = 300; validation set: n = 2401). Following a pre-specified study design per REMARK criteria, we found that high expression of DNA-PKcs was significantly associated with stromal and CD8 + tumor infiltrating lymphocytes. Within the basal-like subtype, tumors with low DNA-PKcs and high tumor-infiltrating lymphocytes displayed the most favourable survival. DNA-PKcs expression by immunohistochemistry identified estrogen receptor-positive cases with a basal-like gene expression subtype. Non-silent mutations in PRKDC were significantly associated with poor outcomes. Integrating DNA-PKcs expression with validated immune biomarkers could guide patient selection for DNA-PKcs targeting strategies, DNA-damaging agents, and their combination with an immune-checkpoint blockade.

Tumor infiltrating lymphocytes before and after dual HER2 blockade in HER2-amplified early breast cancer: A TRYPHAENA substudy.

2016 ◽  
Vol 34 (15_suppl) ◽  
pp. 11507-11507 ◽  
Author(s):  
Michail Ignatiadis ◽  
Gert G. Van den Eynden ◽  
Roberto Salgado ◽  
Marco Fornili ◽  
Christine Desmedt ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Early Breast Cancer ◽  
Tumor Infiltrating Lymphocytes ◽  
Before And After ◽  
Infiltrating Lymphocytes

Correlation of Tumor-Infiltrative Lymphocyte Subtypes Alteration with Neoangiogenesis before and after Neoadjuvant Chemotherapy Treatment in Breast Cancer Patients

2014 ◽  
Vol 29 (3) ◽  
pp. 193-203 ◽  
Author(s):  
Monica SM Chan ◽  
Shi-Fan Chen ◽  
Saulo JA Felizola ◽  
Lin Wang ◽  
Noriko Nemoto ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Tumor Antigens ◽  
Cytotoxic T Cells ◽  
Surrogate Marker ◽  
Tumor Infiltrating Lymphocytes ◽  
Pathological Response ◽  
Breast Cancer Patients ◽  
Dynamic Activity ◽  
Before And After

The two most important factors in tumor-stromal interactions are tumor-infiltrating lymphocytes (TIL) and neoangiogenesis (NAng). While changes of these parameters in responders of neoadjuvant chemotherapy (NCTx) have been reported, their correlation with pathological response in breast cancer (BC) patients treated with NCTx have not been described. We therefore evaluated alterations of the TIL subtypes ratio and alterations of NAng using the vasohibin-1-positive ratio (VPR) in BC patients during the course of NCTx. To this aim we used: (i) double immunohistochemistry of CD8 cytotoxic T cells and T regulatory cells (Treg) with Foxp3, determining the CD8+/Foxp3 ratio; (ii) immunostaining of CD31 and vasohibin-1, yielding the VPR, which reflects the NAng status. Changes between the CD8+/Foxp3 ratio and VPR before and after therapy were then correlated with the pathological response of the patients. A concomitant significant decrement of Foxp3 and NAng, represented by VPR, were detected only in NCTx pathological responders (p<0.001 and p=0.044, respectively). The CD8+/Foxp3 ratio increased in both responders and non-responders, but to greater extent in responders (p=0.02). The changes of VPR in the NCTx-treated group differed from those recorded for the patients treated with aromatase inhibitors and shown in our earlier study; this indicates that the reactions of the tumor-stromal interaction to therapy were different among different treatments in BC patients. Changes in Foxp3 and VPR in responders may reflect the dynamic activity of tumor stroma and host immune response to tumor antigens in the tumor microenvironment in response to the NCTx. VPR can be a potential surrogate marker in BC specimens for predicting the response to NCTx, incorporating both features of carcinoma and stromal cells.

scholarly journals Comparison of Tumor - Infiltrating Lymphocytes Between Primary and Metastatic Tumors in Her2+ and HER2-Breast Cancer Patients

2018 ◽  
Vol 69 (11) ◽  
pp. 3133-3137 ◽  
Author(s):  
Claudia Mehedintu ◽  
Elvira Bratila ◽  
Costin Berceanu ◽  
Monica Mihaela Cirstoiu ◽  
Ramona Ileana Barac ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Growth Factor Receptor ◽  
Tumor Infiltrating Lymphocytes ◽  
Breast Cancer Patients ◽  
Metastatic Tumors ◽  
Tumor Biopsy ◽  
Her2 Breast Cancer ◽  
Infiltrating Lymphocytes ◽  
The Impact

The impact of tumor infiltrating lymphocytes (TILs) on survival was confirmed in various cancer types. Our study aims to investigate the prognostic role of TILs on survival in patients with primary and metastatic tumors in breast cancer patients. We retrospectively identified 29 patients with human epidermal growth factor receptor - 2 (HER2+) and HER2 - early breast cancer diagnosed between 2012 and 2018 at Institute of Oncology Prof. Dr. Al. Trestioreanu Bucharest and who subsequently experienced regional or distant recurrence confirmed by tumor biopsy/resection.

Predictive value of tumor infiltrating lymphocytes (TIL) for response to breast cancer neoadjuvant chemotherapy (NCT).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 585-585
Author(s):  
Elena Garcia-Martinez ◽  
Gines Luengo-Gil ◽  
Asuncion Chaves ◽  
Lorena Velazquez ◽  
Enrique Gonzalez-Billalabeitia ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Predictive Value ◽  
Pathologic Complete Response ◽  
Disease Free Survival ◽  
Tumor Infiltrating Lymphocytes ◽  
Residual Tumor ◽  
Complete Response ◽  
Before And After ◽  
Pre Treatment ◽  
Infiltrating Lymphocytes

585 Background: The association of tumor microenvironment immune response with outcome after breast cancer (BC) NCT has been suggested by several studies. However, the relevance of each TIL subpopulation is still controversial. The objective of this study was to evaluate the predictive and prognostic value of TIL before and after NCT in patients with BC. Methods: We analyzed TIL and CD68 cells in pre- and post-chemotherapy biopsies of BC patients treated with NCT (80.4% sequential AC-docetaxel). A tissue microarray with paired pre- and post-NCT biopsies was built, and stained with immunohistochemistry (IHC) for CD3, CD4, CD8, CD20, FOXP3 and CD68. Morphometric analysis (TIL count/mm2) was performed after slide scanning and digitalization. Results: We included 121 consecutive patients with invasive BC, most of them with stages IIB (28%) or IIIA-C (56.4%). IHC phenotype: 50.4% Her2- hormone-sensitive (HS), 13.2% Her2+ HS, 10.7% Her2+ non-HS, and 21.5% triple negative. Pathologic complete response (pCR): 17.4%. Median overall survival (OS) and disease free survival (DFS) has not been reached (median follow-up: 60 months). Higher than median pre-NCT TIL infiltration was predictive of pCR to NCT: CD3 > 172/mm2 (p=0.001; Hazard Ratio [HR]: 9,61, 95% confidence interval [95%CI] 2.49–37.02); CD4 > 67/mm2 (p=0.001; HR: 8.82, 95%CI 2.43–31.96); CD20 > 42/mm2 (p=0.001; HR: 8.71, 95%CI 2.31–32.74). Logistic regression multivariate models including grade and IHC phenotype confirmed the independent predictive value of higher pre-NCT CD3, CD4, and CD20 for pCR. In the group of patients with HS Her2- BC without pCR (n=44), higher infiltration (cut-point: median value) by some TIL subpopulations and by CD68 cells in post-NCT residual tumor associated to lower DFS: CD8 > 37/mm2 (log-rank; p=0.04), CD20 > 14/mm2 (p=0.07) and CD68> 39/mm2 (p=0.06). Conclusions: Higher pre-treatment CD3, CD4 and CD20 TIL predicted pRC in patients with invasive BC receiving anthracyclines and taxanes NCT, while higher infiltration of residual tumor by CD8 associated to worse DFS in patients with HS Her2- BC without pCR after NCT. TIL might be useful as predictive factors in the setting of NCT for BC [Supported by GEICAM-Beca Ana Balil].

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