CD4 and CD8 T lymphocyte interplay in controlling tumor growth

Ostroumov, Dmitrij; Fekete-Drimusz, N.; Saborowski, Michael; Kühnel, Florian; Woller, Norman

doi:10.1007/s00018-017-2686-7

Cited by 406 publications

(325 citation statements)

References 240 publications

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“…37,38 Studies have shown that the recognition of neoepitopes by endogenous T cells may elicit protective immune responses without being affected by central T cell tolerance, making neoantigens an ideal target for cancer immunotherapy. 4,39,40 Neoantigen vaccines can be developed using different strategies. Premanufactured vaccines may be developed to target neoepitopes related to recurrent somatic mutations.…”

Section: Discussionmentioning

confidence: 99%

HLA class-I and class-II restricted neoantigen loads predict overall survival in breast cancer

et al. 2020

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Tumors acquire numerous mutations during development and progression. When translated into proteins, these mutations give rise to neoantigens that can be recognized by T cells and generate antibodies, representing an exciting direction of cancer immunotherapy. While neoantigens have been reported in many cancer types, the profiling of neoantigens often focused on the class-I subtype that are presented to CD8 + T cells, and the relationship between neoantigen load and clinical outcomes was often inconsistent among cancer types. In this study, we described an informatics workflow, REAL-neo, for identification, quality control (QC), and prioritization of both class-I and class-II human leukocyte antigen (HLA) bound neoantigens that arise from somatic single nucleotide mutations (SNM), small insertions and deletions (INDEL), and gene fusions. We applied REAL-neo to 835 primary breast tumors in the Cancer Genome Atlas (TCGA) and performed comprehensive profiling and characterization of the detected neoantigens. We found recurrent HLA class-I and class-II restricted neoantigens across breast cancer cases, and uncovered associations between neoantigen load and clinical traits. Both class-I and class-II neoantigen loads from SNM and INDEL were found to predict overall survival independent of tumor mutational burden (TMB), breast cancer subtypes, tumor-infiltrating lymphocyte (TIL) levels, tumor stage, and age at diagnosis. Our study highlighted the importance of accurate and comprehensive neoantigen profiling and QC, and is the first to report the predictive value of neoantigen load for overall survival in breast cancer. ARTICLE HISTORY

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Section: Discussionmentioning

confidence: 99%

HLA class-I and class-II restricted neoantigen loads predict overall survival in breast cancer

et al. 2020

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“…CD4+ and CD8+ T lymphocytes are the main players for secondary immune response against tumor. (Hung et al, ; Ostroumov, Fekete‐Drimusz, Saborowski, Kühnel, & Woller, ) Therefore, tumors' sections were stained with anti‐CD4 and anti‐CD8 antibodies to identify these two kinds of cells recruitment to the tumor site by IHC (Figure B). CD4 and CD8 are the well‐known markers of T helper and cytotoxic T lymphocyte cells, respectively.…”

Section: Resultsmentioning

confidence: 99%

“…CD4+ and CD8+ T lymphocytes are the main players for secondary immune response against tumor. (Curiel et al, ; Hung et al, ; Ostroumov et al, ) Therefore, tumors' sections were stained with anti‐CD4 and anti‐CD8 antibodies to identify these two kinds of cells recruitment to the tumor site by IHC (Figure B). Significant increase of both CD4+ and CD8+ T lymphocytes cells recruitment to the tumor site was detected at the Spirulina extract treated mice in comparison with PBS and control group.…”

Section: Discussionmentioning

confidence: 99%

Spirulina extract enriched for Braun‐type lipoprotein (Immulina®) for inhibition of 4T1 breast tumors' growth and metastasis

Kefayat

Ghahremani

Safavi

et al. 2019

Phytotherapy Research

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Spirulina platensis extracts have exhibited considerable anti-cancer effects. To investigate the efficacy of the Spirulina extract enriched for Braun-type lipoprotein (Immulina®) for breast cancer treatment, 4T1 breast tumor-bearing mice were treated with 40 mg/kg Immulina® daily and the tumors' growth and metastasis were assessed. Also, CD4, CD8, and CD56 staining were performed to investigate the Immulina® effect on the immune cells' recruitment to the tumors by immunohistochemistry. Immulina® could significantly (P < 0.001) inhibit 4T1 breast tumors' growth. Immulina®-treated group exhibited a 63% decrease in the tumors' volume in comparison with control (P < 0.001). Also, Immulina® could significantly (P < 0.001) decrease metastatic burden at the vital organs as 68% and 61% decrease in the liver and lungs metastatic colonies were observed, respectively. Also, Immulina® could increase mean survival time of the tumor-bearing mice for 29 days.The Spirulina-treated mice tumors contained significantly more infiltrated NK, CD4+, and CD8+ T lymphocytes in comparison with control. Taking together, Immulina® can be a safe anti-cancer supplement with the ability to cause direct apoptosis to the cancer cells and activate the immune system against tumor. This supplement with natural origin seems to have bright future to help breast cancer patients.

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“…Conversely, M1-like macrophage induction correlates with better control of tumor growth and also stimulation of anti-tumor protective adaptive T cells [39,40], in particular with CD4 + TH1 cells, which are key activators in the priming phase, and CD8 + T cytolytic cells in the rejection effector response against tumor [41][42][43][44].…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Murine Rnaset2 in a Colon Syngeneic Mouse Carcinoma Model Leads to Rebalance of Intra-Tumor M1/M2 Macrophage Ratio, Activation of T Cells, Delayed Tumor Growth, and Rejection

Vito

Orecchia

Balza

et al. 2020

Cancers

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Human RNASET2 acts as a powerful oncosuppressor protein in in vivo xenograft-based murine models of human cancer. Secretion of RNASET2 in the tumor microenvironment seems involved in tumor suppression, following recruitment of M1-polarized macrophages. Here, we report a murine Rnaset2-based syngeneic in vivo assay. BALB/c mice were injected with parental, empty vector-transfected or murine Rnaset2-overexpressing mouse C51 or TS/A syngeneic cells and tumor growth pattern and immune cells distribution in tumor mass were investigated. Compared to control cells, mouse Rnaset2-expressing C51 cells showed strong delayed tumor growth. CD86 + M1 macrophages were massively recruited in Rnaset2-expressing C51-derived tumors, with concomitant inhibition of MDSCs and CD206 + M2 macrophages recruitment. At later times, a relevant expansion of intra-tumor CD8 + T cells was also observed. After re-challenge with C51 parental cells, most mice previously injected with Rnaset2-expressing C51 cells still rejected C51 tumor cells, suggesting a Rnaset2-mediated T cell adaptive immune memory response. These results point at T2 RNases as evolutionary conserved oncosuppressors endowed with the ability to inhibit cancer growth in vivo through rebalance of intra-tumor M1/M2 macrophage ratio and concomitant recruitment of adaptive anti-tumor CD8 + T cells.Cancers 2020, 12, 717 2 of 18 in tumor suppression. Indeed, two independent in vivo xenograft-based murine models of human ovarian cancer have been previously used to demonstrate a marked RNASET2-mediated in vivo tumor suppression [1,2]. It has been previously shown that RNASET2 affects several important cancer-related parameters (such as modulation of cell proliferation, cytoskeletal re-organization, cell adhesion, motility, and angiogenesis) in a cell-autonomous manner, [3][4][5][6]. Moreover, further studies in both in vitro and in vivo experimental models have demonstrated a marked modulation of macrophage plasticity played by the RNASET2 protein, thus suggesting the occurrence of a RNASET2-mediated noncell-autonomous oncosuppressive role [7]. In fact, human RNASET2 overexpression in two independent human ovarian cancer cell lines, followed by challenging of immunodeficient mouse models with these cells, showed a marked tumor suppressive effect coupled with a RNASET2-mediated recruitment of M1-polarized host macrophages within the tumor mass [1,2]. These data, coupled to the well-established notion of T2 RNases as stress response genes [8,9], strongly suggest that human RNASET2 secretion by cancer cells might represent a "danger" signal for cells belonging to the monocyte/macrophage lineage, whose role would be to trigger an effective host immune response. Of note, the macrophage-activating role of T2 RNases has been recently confirmed in species far away from mammals in term of evolutionary distance, such as the invertebrate Hirudo verbana [10], thus pointing at T2 RNases as highly conserved immune system-related stress response proteins acting across many Phyla.The concept that the ...

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CD4 and CD8 T lymphocyte interplay in controlling tumor growth

Cited by 406 publications

References 240 publications

HLA class-I and class-II restricted neoantigen loads predict overall survival in breast cancer

HLA class-I and class-II restricted neoantigen loads predict overall survival in breast cancer

Spirulina extract enriched for Braun‐type lipoprotein (Immulina®) for inhibition of 4T1 breast tumors' growth and metastasis

Overexpression of Murine Rnaset2 in a Colon Syngeneic Mouse Carcinoma Model Leads to Rebalance of Intra-Tumor M1/M2 Macrophage Ratio, Activation of T Cells, Delayed Tumor Growth, and Rejection

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