scholarly journals MTL-CEBPA Combined with Immunotherapy or RFA Enhances Immunological Anti-Tumor Response in Preclinical Models

2021 ◽  
Vol 22 (17) ◽  
pp. 9168
Author(s):  
Kai-Wen Huang ◽  
Choon Ping Tan ◽  
Vikash Reebye ◽  
Cheng Ean Chee ◽  
Dimitris Zacharoulis ◽  
...  
Keyword(s):  
Tumor Response ◽  
Checkpoint Inhibitor ◽  
Myeloid Cell ◽  
Tumor Infiltrating Lymphocytes ◽  
Cancer Model ◽  
Preclinical Models ◽  
Immune Microenvironment ◽  
Clinical Role ◽  
Tumor Immune Microenvironment ◽  
Infiltrating Lymphocytes

The transcription factor CEBPA is a master regulator of liver homeostasis, myeloid cell differentiation and is downregulated in several oncogenic diseases. MTL-CEBPA is a small activating RNA drug which upregulates gene expression of CEBPA for treatment of hepatocellular carcinoma (HCC). We investigate whether MTL-CEBPA has immune modulatory effects by combining MTL-CEBPA with an anti-PD-1 checkpoint inhibitor (CPI) and/or radiofrequency ablation (RFA) in two preclinical models. First, mice with two flanks of HCC tumors (BNL) were treated with combinations of RFA (right flank), anti-PD-1 or MTL-CEBPA. The reduction of the left flank tumors was most pronounced in the group treated with RFA+anti-PD1+MTL-CEBPA and 7/8 animals responded. This was the only group with a significant increase in CD8+ and CD49b+/CD45+ tumor infiltrating lymphocytes (TIL). Second, a combination of anti-PD-1+MTL-CEBPA was tested in a CT26 colon cancer model and this treatment significantly reduced tumor size, modulated the tumor immune microenvironment and increased TILs. These data suggest a clinical role for combination treatment with CPIs, RFA and MTL-CEBPA through synergistic priming of the immune tumor response, enabling RFA and CPIs to have a pronounced anti-tumor effect including activity in non-treated tumors in the case of RFA.

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 The Ovarian Cancer Tumor Immune Microenvironment (TIME) as Target for Therapy: A Focus on Innate Immunity Cells as Therapeutic Effectors

2020 ◽  
Vol 21 (9) ◽  
pp. 3125 ◽  
Author(s):  
Denisa Baci ◽  
Annalisa Bosi ◽  
Matteo Gallazzi ◽  
Manuela Rizzi ◽  
Douglas M. Noonan ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
T Lymphocytes ◽  
Nk Cells ◽  
Tumor Infiltrating Lymphocytes ◽  
Immune Microenvironment ◽  
New Era ◽  
Tumor Immune Microenvironment ◽  
Cancer Tumor ◽  
Immune Contexture ◽  
Infiltrating Lymphocytes

Ovarian cancer (OvCA) accounts for one of the leading causes of death from gynecologic malignancy. Despite progress in therapy improvements in OvCA, most patients develop a recurrence after first-line treatments, dependent on the tumor and non-tumor complexity/heterogeneity of the neoplasm and its surrounding tumor microenvironment (TME). The TME has gained greater attention in the design of specific therapies within the new era of immunotherapy. It is now clear that the immune contexture in OvCA, here referred as tumor immune microenvironment (TIME), acts as a crucial orchestrator of OvCA progression, thus representing a necessary target for combined therapies. Currently, several advancements of antitumor immune responses in OvCA are based on the characterization of tumor-infiltrating lymphocytes, which have been shown to correlate with a significantly improved clinical outcome. Here, we reviewed the literature on selected TIME components of OvCA, such as macrophages, neutrophils, γδ T lymphocytes, and natural killer (NK) cells; these cells can have a role in either supporting or limiting OvCA, depending on the TIME stimuli. We also reviewed and discussed the major (immune)-therapeutic approaches currently employed to target and/or potentiate macrophages, neutrophils, γδ T lymphocytes, and NK cells in the OvCA context.

scholarly journals CD8+Foxp3+ tumor infiltrating lymphocytes accumulate in the context of an effective anti-tumor response

2010 ◽  
Vol 129 (3) ◽  
pp. 636-647 ◽  
Author(s):  
Dung T. Le ◽  
Brian H. Ladle ◽  
Timothy Lee ◽  
Vivian Weiss ◽  
Xiaosai Yao ◽  
...  
Keyword(s):  
Tumor Response ◽  
Tumor Infiltrating Lymphocytes ◽  
Infiltrating Lymphocytes

Immune microenvironment features and efficacy of PD-1/PD-L1 blockade in non-small cell lung cancer (NSCLC) patients with EGFR or HER2 exon 20 insertions.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21540-e21540 ◽  
Author(s):  
Kaiyan Chen ◽  
Guoqiang Pan ◽  
Yanjun Xu ◽  
Yun Fan
Keyword(s):  
Tumor Infiltrating Lymphocytes ◽  
Small Cell Lung ◽  
Immune Microenvironment ◽  
Limited Efficacy ◽  
Mutational Burden ◽  
Tumor Mutational Burden ◽  
Exon 20 ◽  
Nsclc Patients ◽  
L1 Protein ◽  
Infiltrating Lymphocytes

e21540 Background: This study aimed to investigate the immune microenvironment features and efficacy of PD-1/PD-L1 blockade of NSCLC with insertions in exon 20 (Ex20ins) of EGFR or HER2. Methods: Molecular spectrum, tumor mutational burden (TMB), PD-L1 protein expression, and the abundance of CD4+ and CD8+ tumor-infiltrating lymphocytes (TILs) were reviewed for NSCLC patients with Ex20ins of EGFR or HER2. Results: Thirty-five patients carrying EGFR Ex20ins and 21 patients harboring HER2 Ex20ins were retrospectively enrolled between April 2016 and September 2018. The average TMB was 3.3 mutations/megabase. PD-L1 expression in patients with EGFR Ex20ins was significantly higher than those with HER2 mutations (48.6% vs. 19.0%, P=0.027). High TMB and PD-L1 expression was independently associated with considerably poor prognosis (P=0.025, P=0.045; respectively). Finally, patients harboring EGFR Ex20ins seemed to be sensitive to PD-1/PD-L1 blockage whereas it showed limited efficacy in patients with HER2 Ex20ins. Conclusions: NSCLC patients with EGFR/ HER2 Ex20ins had distinct immune features. Patients with EGFR Ex20ins had significantly higher PD-L1 expression than those with HER2 mutations, which may be the underlying reason for the different responses to PD-1/PD-L1 blockage.

scholarly journals Immunophenotypes Based on the Tumor Immune Microenvironment Allow for Unsupervised Penile Cancer Patient Stratification

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1796 ◽  
Author(s):  
Chengbiao Chu ◽  
Kai Yao ◽  
Jiangli Lu ◽  
Yijun Zhang ◽  
Keming Chen ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Cytotoxic T Lymphocyte ◽  
Granzyme B ◽  
Expression Patterns ◽  
Tumor Infiltrating Lymphocytes ◽  
Immune Checkpoints ◽  
Immune Microenvironment ◽  
Tumor Immune Microenvironment

The tumor immune microenvironment (TIME) plays an important role in penile squamous cell carcinoma (peSCC) pathogenesis. Here, the immunophenotype of the TIME in peSCC was determined by integrating the expression patterns of immune checkpoints (programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1), cytotoxic T lymphocyte antigen 4 (CTLA-4), and Siglec-15) and the components of tumor-infiltrating lymphocytes, including CD8+ or Granzyme B+ T cells, FOXP3+ regulatory T cells, and CD68+ or CD206+ macrophages, in 178 patients. A high density of Granzyme B, FOXP3, CD68, CD206, PD-1, and CTLA-4 was associated with better disease-specific survival (DSS). The patients with diffuse PD-L1 tumor cell expression had worse prognoses than those with marginal or negative PD-L1 expression. Four immunophenotypes were identified by unsupervised clustering analysis, based on certain immune markers, which were associated with DSS and lymph node metastasis (LNM) in peSCC. There was no significant relationship between the immunophenotypes and high-risk human papillomavirus (hrHPV) infection. However, the hrHPV–positive peSCC exhibited a higher density of stromal Granzyme B and intratumoral PD-1 than the hrHPV–negative tumors (p = 0.049 and 0.002, respectively). In conclusion, the immunophenotypes of peSCC were of great value in predicting LNM and prognosis, and may provide support for clinical stratification management and immunotherapy intervention.

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