scholarly journals Combination Therapy of Bifidobacterium longum RAPO With Anti-PD-1 Treatment Enhances Anti-tumor Immune Response in Association With Gut Microbiota Modulation

2021 ◽  
Vol 5 (Supplement_2) ◽  
pp. 1131-1131
Author(s):  
Hyeyoon Kim ◽  
Rira Oh ◽  
Sangjun Park ◽  
Geun Eog Ji ◽  
Myeong Soo Park ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune Response ◽  
Cell Death ◽  
Combination Therapy ◽  
Gut Microbiota ◽  
Bifidobacterium Longum ◽  
Relative Proportion ◽  
Tumor Control ◽  
Rrna Gene ◽  
Potential Candidate

Abstract Objectives Triple negative breast cancer (TNBC) has a poor prognosis with a high risk of metastasis and relapse, and accounts for approximately 35% of breast cancer death. Immune checkpoint inhibitors (ICI) have been in the spotlight recently as a novel treatment of TNBC due to the higher expressions of programmed cell death ligand 1 (PD-L1) and tumor-infiltrating lymphocytes in TNBC. Considering that gut microbiome is associated with immune response and ICI efficacy, we investigated whether Bifidobacterium longum RAPO supplementation would affect the efficacy of anti-PD-1 therapy against TNBC in vivo. Methods Female BALB/c mice bearing 4T1 breast cancer cells were randomly divided into four groups; tumor control (TC), Anti-PD-1, B. longum RAPO (RAPO), or Anti-PD-1 + RAPO (Combi). Anti-PD-1 antibody was injected i.p. 5 times at 3-day intervals and B. longum RAPO was orally administered daily from 2 days before the first injection of anti-PD-1. Spleen and tumor tissues were analyzed by flow cytometry, IHC, and qRT-PCR. Fecal samples were analyzed by 16S rRNA gene sequencing. Results Tumor volume was reduced in the Combi group than TC and Anti-PD-1 groups on day 12. PD-L1 IHC score and PD-L1 mRNA expression were significantly increased in tumors of the Combi group. The levels of the spleen CD8/CD4 ratio and tumor NK cells were also increased in the Combi group. Compared with the Anti-PD-1 group, the pro-tumor M2 macrophages and related cytokines (IL10, Arg1) were significantly decreased, while anti-tumor M1 cytokines (IFNγ, TNFα) were elevated in tumors of the Combi group. Consistently, immunogenic cell death-associated markers were significantly higher in the Combi group. We found that the relative proportion of the genus Bifidobacterium, Lachnoclostridium, Lachnospiraceae NK4A136 group, and Clostridium sensu stricto 1, which are known to be associated with the better response to ICI therapy, were significantly increased, while the genus Mucispirillum and Dubosiella were decreased in the Combi group than the Anti-PD-1 group. Conclusions Our data indicates that combination therapy of B. longum RAPO with anti-PD-1 enhances anti-tumor immune response in association with modulation of gut microbiota, suggesting that B. longum RAPO might be a potential candidate for pharmabiotics in ICI treatment. Funding Sources BIFIDO CO, the National Research Foundation of Korea grant.

452 Combination treatment using KISIMATM protein-based cancer vaccine and systemic STING agonist results in profound modulation of tumor microenvironment and improved tumor control

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A479-A479
Author(s):  
Matteo Rossi ◽  
Elodie Belnoue ◽  
Susanna Carboni ◽  
Wilma Besson-Di Berardino ◽  
Erika Riva ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Combination Therapy ◽  
Cancer Vaccine ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Tumor Control ◽  
Therapeutic Vaccination ◽  
Potent Tumor

BackgroundKISIMATM platform allows the development of protein-based cancer vaccines able to induce a potent, tumor-specific CD8 and CD4 T cells response. While the cell penetrating peptide and the Anaxa portions confer, respectively, the cell delivery and self-adjuvanticity properties, the multiantigenic domain allows the targeting of different cancer antigens, resulting in anti-tumoral efficacy in different murine models.1 The first clinical candidate developed from KISIMATM is currently tested, together with anti-PD-1 blockade, in a phase I study in metastatic colorectal cancer patients. Stimulator of interferon genes agonists (STINGa) were shown to induce a potent type I interferon response in preclinical studies. The intratumoral administration of STINGa, to promote tumor inflammation, was shown to result in a protective spontaneous immune response in several murine tumor models. However, the encouraging preclinical results are not supported by recent clinical data, challenging the efficacy of unspecific monotherapy.As it is more and more clear that an effective cancer immunotherapy will require the combination of different treatment strategies, we investigate here the efficacy of combining KISIMATM cancer vaccine with STINGa treatment.MethodsMice were vaccinated with subcutaneous (s.c.) injection of KISIMATM vaccine combined with s.c. administration of STINGa. Safety and immunogenicity were assessed by measuring temperature, serum cytokines and the peripheral antigen-specific response. Anti-tumoral efficacy as well as in depth monitoring of TILs and tumor microenvironment modulation were assessed following therapeutic vaccination in a HPV16 E6 and E7 expressing TC-1 cold tumor model.ResultsCombination treatment was well tolerated and promoted the development of circulating antigen-specific CD8 T cells. In TC-1 tumor bearing mice, KISIMATM therapeutic vaccination resulted in the infiltration of both antigen-specific CD8 and CD4 T cells within the tumor, as well as a switch of tumor associated macrophages polarization toward the more inflammatory type 1. Combination therapy further increased the tumor microenvironment modulation induced by KISIMATM vaccine, promoting the polarization of inflammatory Thelper 1 CD4 T cells and increasing the effector function of antigen-specific CD8 T cells. The profound modulation of the tumor microenvironment induced by combination therapy enhanced the beneficial effect of KISIMATM vaccination, resulting in a prolonged tumor control.ConclusionsCombination of KISIMATM cancer vaccine with systemic STINGa treatment induces the development of a potent, tumor-specific immune response resulting in a profound modulation of the TME. As check-point inhibitor (CPI) therapy is ineffective on poorly infiltrated tumors, combination with therapies able to highly enhance tumor infiltration by T cells could expand CPI indications.Ethics ApprovalThe study was approved by the Canton of Geneva Ethic Board, under the license number GE165/19ReferenceBelnoue E, et al. Targeting self and neo-epitopes with a modular self-adjuvanting cancer vaccine. JCI Insight 2019. 4:11.

Energy metabolism targeted drugs synergize with photodynamic therapy to potentiate breast cancer cell death

2014 ◽  
Vol 13 (12) ◽  
pp. 1793-1803 ◽  
Author(s):  
Xiaolan Feng ◽  
Yi Zhang ◽  
Pan Wang ◽  
Quanhong Liu ◽  
Xiaobing Wang
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Photodynamic Therapy ◽  
Energy Metabolism ◽  
Combination Therapy ◽  
Breast Cancer Cells ◽  
Ros Generation ◽  
Targeted Drugs ◽  
Cancer Cell Death ◽  
Dependent Cell

Glycolytic inhibitors can synergistically enhance the photosensitivity of breast cancer cells by triggering cellular mitochondria- and caspase-dependent cell apoptosis, which was induced by additional ROS generation in combination therapy.

Combination therapy of Ad-mda7 and trastuzumab increases cell death in Her-2/neu–overexpressing breast cancer cells

Surgery ◽  
2004 ◽  
Vol 136 (2) ◽  
pp. 437-442 ◽  
Author(s):  
Tamra McKenzie ◽  
Yanna Liu ◽  
Michelle Fanale ◽  
Stephen G. Swisher ◽  
Sunil Chada ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Combination Therapy ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Her 2

scholarly journals Induction of Paraptotic Cell Death in Breast Cancer Cells by a Novel Pyrazolo[3,4-h]quinoline Derivative through ROS Production and Endoplasmic Reticulum Stress

Antioxidants ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 117
Author(s):  
Phuong Linh Nguyen ◽  
Chang Hoon Lee ◽  
Heesoon Lee ◽  
Jungsook Cho
Keyword(s):  
Breast Cancer ◽  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Molecular Mechanisms ◽  
Quinoline Derivative ◽  
Ros Generation ◽  
Protein Accumulation ◽  
Potential Candidate ◽  
Development Of Resistance

Chemotherapy has been a standard intervention for a variety of cancers to impede tumor growth, mainly by inducing apoptosis. However, development of resistance to this regimen has led to a growing interest and demand for drugs targeting alternative cell death modes, such as paraptosis. Here, we designed and synthesized a novel derivative of a pyrazolo[3,4-h]quinoline scaffold (YRL1091), evaluated its cytotoxic effect, and elucidated the underlying molecular mechanisms of cell death in MDA-MB-231 and MCF-7 breast cancer (BC) cells. We found that YRL1091 induced cytotoxicity in these cells with numerous cytoplasmic vacuoles, one of the distinct characteristics of paraptosis. YRL1091-treated BC cells displayed several other distinguishing features of paraptosis, excluding autophagy or apoptosis. Briefly, YRL1091-induced cell death was associated with upregulation of microtubule-associated protein 1 light chain 3B, downregulation of multifunctional adapter protein Alix, and activation of extracellular signal-regulated kinase 1/2 and c-Jun N-terminal kinase. Furthermore, the production of reactive oxygen species (ROS) and newly synthesized proteins were also observed, subsequently causing ubiquitinated protein accumulation and endoplasmic reticulum (ER) stress. Collectively, these results indicate that YRL1091 induces paraptosis in BC cells through ROS generation and ER stress. Therefore, YRL1091 can serve as a potential candidate for the development of a novel anticancer drug triggering paraptosis, which may provide benefit for the treatment of cancers resistant to conventional chemotherapy.

scholarly journals Overview of New Treatments with Immunotherapy for Breast Cancer and a Proposal of a Combination Therapy

Molecules ◽  
2020 ◽  
Vol 25 (23) ◽  
pp. 5686
Author(s):  
Miguel Angel Galván Morales ◽  
Raúl Barrera Rodríguez ◽  
Julio Raúl Santiago Cruz ◽  
Luis M. Teran
Keyword(s):  
Breast Cancer ◽  
Immune Response ◽  
Combination Therapy ◽  
Natural Killer ◽  
Cytotoxic T Lymphocyte ◽  
Combined Therapy ◽  
Killer Cell ◽  
Co Activation ◽  
Novel Therapeutic Strategies ◽  
New Treatments

According to data from the U.S. National Cancer Institute, cancer is one of the leading causes of death worldwide with approximately 14 million new cases and 8.2 million cancer-related deaths in 2018. More than 60% of the new annual cases in the world occur in Africa, Asia, Central America, and South America, with 70% of cancer deaths in these regions. Breast cancer is the most common cancer in women, with 266,120 new cases in American women and an estimated 40,920 deaths for 2018. Approximately one in six women diagnosed with breast cancer will die in the coming years. Recently, novel therapeutic strategies have been implemented in the fight against breast cancer, including molecules able to block signaling pathways, an inhibitor of poly [ADP-ribose] polymerase (PARP), growth receptor blocker antibodies, or those that reactivate the immune system by inhibiting the activities of inhibitory receptors like cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death protein 1 (PD-1). However, novel targets include reactivating the Th1 immune response, changing tumor microenvironment, and co-activation of other components of the immune response such as natural killer cells and CD8+ T cells among others. In this article, we review advances in the treatment of breast cancer focused essentially on immunomodulatory drugs in targeted cancer therapy. Based on this knowledge, we formulate a proposal for the implementation of combined therapy using an extracorporeal immune response reactivation model and cytokines plus modulating antibodies for co-activation of the Th1- and natural killer cell (NK)-dependent immune response, either in situ or through autologous cell therapy. The implementation of “combination immunotherapy” is new hope in breast cancer treatment. Therefore, we consider the coordinated activation of each cell of the immune response that would probably produce better outcomes. Although more research is required, the results recently achieved by combination therapy suggest that for most, if not all, cancer patients, this tailored therapy may become a realistic approach in the near future.

scholarly journals Antidepressant Sertraline Hydrochloride Inhibits the Growth of HER2+ AU565 Breast Cancer Cell Line through Induction of Apoptosis, and Arrest of Cell Cycle

2021 ◽  
Author(s):  
Atia-tul- Wahab ◽  
Sharmeen Fayyaz ◽  
Rimsha Irshad ◽  
Rafat A. Siddiqui ◽  
Atta-ur- Rahman ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Cell Line ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Caspase 3 ◽  
Potential Candidate ◽  
Sertraline Hydrochloride ◽  
Induction Of Apoptosis

AbstractBreast cancer is one the most aggressive cancer worldwide, especially Pakistan due to limited therapeutic options. This study was conducted to repurpose the use of selective serotonin reuptake inhibitors (SSRIs), in the treatment of breast cancers, and merit to pursue drug re-positioning in oncology. Anti-proliferative activity of SSRIs, such as fluoxetine, paroxetine, and sertraline hydrochloride on the growth of AU-565, MCF-7, MDA-MB-231, and BT-474 breast cancer cell lines, along with human fibroblast BJ cells was determined in vitro. Changes in nuclear morphology (DAPI staining), and induction of apoptosis (flow cytometry, and caspase-3 activation) were also studied. Sertraline hydrochloride most effectively inhibited the growth of breast cancer cells in vitro. Therefore, pharmacological mechanism involved in sertraline mediated cell death was investigated in HER2+ AU565 cell line. Enhanced nuclear fragmentation, increased Annexin (+) cells, and caspase-3/7 activation indicated that sertraline-mediated cell death could be a result of BCl2-independent apoptosis as evidenced by expression of Bax, and BCl2 genes. Taken together, our results identified sertraline hydrochloride, as a potential candidate for the treatment of HER2-positive breast cancer. Even though these are in vitro results, this study opens great opportunity in the field of drug repurposing for the development of chemotherapeutic agents.

scholarly journals Temporal Development of the Infant Gut Microbiota in Immunoglobulin E-Sensitized and Nonsensitized Children Determined by the GA-Map Infant Array

2011 ◽  
Vol 18 (8) ◽  
pp. 1326-1335 ◽  
Author(s):  
Heidi C. Vebø ◽  
Monika Sekelja ◽  
Ragnhild Nestestog ◽  
Ola Storrø ◽  
Roar Johnsen ◽  
...  
Keyword(s):  
16S Rrna ◽  
Gut Microbiota ◽  
16S Rrna Gene ◽  
Immunoglobulin E ◽  
Bifidobacterium Longum ◽  
Human Infant ◽  
Rrna Gene ◽  
Temporal Development ◽  
Content Type ◽  
Taxonomic Level

ABSTRACTAt birth, the human infant gut is sterile, but it becomes fully colonized within a few days. This initial colonization process has a major impact on immune development. Our knowledge about the correlations between aberrant colonization patterns and immunological diseases, however, is limited. The aim of the present work was to develop the GA-map (Genetic Analysis microbiota array platform) infant array and to use this array to compare the temporal development of the gut microbiota in IgE-sensitized and nonsensitized children during the first 2 years of life. The GA-map infant array is composed of highly specific 16S rRNA gene-targeted single nucleotide primer extension (SNuPE) probes, which were designed based on extensive infant 16S rRNA gene sequence libraries. For the clinical screening, we analyzed 216 fecal samples collected from a cohort of 47 infants (16 sensitized and 31 nonsensitized) from 1 day to 2 years of age. The results showed that at a high taxonomic level,Actinobacteriawas significantly overrepresented at 4 months whileFirmicuteswas significantly overrepresented at 1 year for the sensitized children. At a lower taxonomic level, for the sensitized group, we found thatBifidobacterium longumwas significantly overrepresented at the age of 1 year andEnterococcusat the age of 4 months. For most phyla, however, there were consistent differences in composition between age groups, irrespective of the sensitization state. The main age patterns were a rapid decrease in staphylococci from 10 days to 4 months and a peak of bifidobacteria and bacteroides at 4 months. In conclusion, our analyses showed consistent microbiota colonization and IgE sensitization patterns that can be important for understanding both normal and diseased immunological development in infants.

scholarly journals The P2X7 Receptor in Tumor Immunity

2021 ◽  
Vol 9 ◽  
Author(s):  
Fabio Grassi ◽  
Benedetta De Ponte Conti
Keyword(s):  
Immune Response ◽  
Cell Death ◽  
T Cell ◽  
P2x7 Receptor ◽  
Tissue Repair ◽  
Innate Immune ◽  
Tumor Control ◽  
Extracellular Adenosine ◽  
Molecular Pattern ◽  
Cell Immunity

Extracellular adenosine triphosphate (eATP) is a potent mediator of the immune response via stimulation of purinergic P2 receptors. ATP concentration in the extracellular space increases dramatically during tissue damage and eATP acts as a danger-associated molecular pattern (DAMP) to alert innate immune system cells for tissue repair. Similarly, eATP is present at hundreds of micromolar concentration in the tumor microenvironment (TME). However, its impact on antitumor immune response is still not well established, probably because of the complexity of the responses it induces in different cells constituting the TME. On one hand, ATP released by tumor cells concomitantly to cell death can contribute to immunogenic cell death (ICD) that is proinflammatory for the innate immune compartment and beneficial for tumor control, while on the other hand, eATP can foster immune-suppressive mechanisms within the TME, thus contributing to tumor progression and metastasis. It is well established that T-cell immunity is pivotal in limiting tumor growth and possibly eradicating neoplastic cells. T cells are limited though in their antitumor activity through different mechanisms, such as exhaustion, anergy, and senescence; the pathways resulting in these cellular outcomes are not clear. Here, we review the function of P2X7 receptor in conditioning T cell-dependent immunity against cancer.

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