Immunotherapy Using Oxygenated Water and Tumor-Derived Exosomes Potentiates Antitumor Immune Response and Attenuates Malignancy Tendency in Mice Model of Breast Cancer

Breast cancer is one of the most common type of tumor and the leading cause of death in the world’s female population. Various therapeutic approaches have been used to treat tumors but have not led to complete recovery and have even damaged normal cells in the body. Moreover, metastatic tumors such as breast cancer are much more resistant to treatment, and current treatments have not been very successful in treating them and remain a challenge. Therefore, new approaches should be applied to overcome this problem. Given the importance of hypoxia in tumor survival, we aimed to test the antitumor effects of oxygenated water to decrease hypoxia along with tumor-derived exosomes to target tumor. The purpose of administering oxygenated water and tumor exosomes was to reduce hypoxia and establish an effective immune response against tumor antigens, respectively. For this purpose, the breast cancer mice model was induced using the 4T1 cell line in Balb/c mice and treated with oxygenated water via an intratumoral (IT) and/or intraperitoneal (IP) route and/or exosome (TEX). Oxygenation via the IT+IP route was more efficient than oxygenation via the IT or IP route. The efficiency of oxygenation via the two routes along with TEX led to the best therapeutic outcome. Antitumor immune responses directed by TEX became optimized when systemic (IP) and local (IT) oxygenation was applied compared to administration of TEX alone. Results demonstrated a significant reduction in tumor size and the highest levels of IFN-γ and IL-17 and the lowest levels of IL-4 FoxP3, HIF-1α, VEGF, MMP-2, and MMP-9 in the IT+IP+TEX-treated group. Oxygenated water on the one hand could reduce tumor size, hypoxia, angiogenesis, and metastasis in the tumor microenvironment and on the other hand increases the effective immune response against the tumor systemically. This therapeutic approach is proposed as a new strategy for devising vaccines in a personalized approach.

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Immunotherapeutic efficacy of a Lactobacillus casei lysate as an adjuvant combined with a heated-4T1 mammary carcinoma cell lysate in a murine model of breast cancer

Asian Biomedicine ◽

10.5372/1905-7415.1004.494 ◽

2017 ◽

Vol 10 (4) ◽

pp. 327-334 ◽

Cited By ~ 1

Author(s):

Ruhollah Dorostkar ◽

Mohammad Sadegh Hashemzadeh ◽

Sajjad Jafari ◽

Mahdi Tat ◽

Majdedin Ghalavand ◽

...

Keyword(s):

Breast Cancer ◽

Murine Model ◽

Mammary Carcinoma ◽

Tumor Size ◽

Lactobacillus Casei ◽

Tumor Antigens ◽

Carcinoma Cell ◽

Mammary Carcinoma Cell ◽

Cell Lysate ◽

4T1 Cells

Abstract Background Immunotherapy, during which the immune system of the patient is manipulated to act against tumors has been among the most successful methods in the treatment of breast cancer, a leading cause of mortality among women worldwide. Objectives To investigate the immunotherapeutic efficacy of Lactobacillus casei lysate as an adjuvant in combination with a heated-4T1 mammary carcinoma cell lysate in a model of breast cancer. Methods After ethics committee approval of all animal procedures, a murine model of breast cancer was induced in BALB/c mice using 4T1 cells. These mice were immunized with a combination of lysates of heated 4T1 cells and L. casei. Subsequent changes in tumor size and weight, and the production of TNF-α, IL-2, IL-12, IL-17, and IL13 were measured. Lung weights were measured as an indicator of metastasis to other organs. Results The tumor size and weight in mice immunized with the combined vaccine were significantly reduced compared with controls. The combined immunotherapy altered the pattern of cytokine production to the advantage of antitumor immunity, and was significantly more potent than immunization with heated-4T1-cell lysate or L. casei lysate alone. Conclusions Coadministration of L. casei lysate enhanced the immunotherapeutic efficacy of the heated-4T1-cell lysate as a source of tumor-associated antigens. L. casei can potentially be used as an adjuvant combined with sources of tumor antigens in the treatment of cancers, and as a safe alternative to the current adjuvants that cause greater irritation to hosts. Further studies are required to clarify the mechanisms underlying these effects.

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The Abscopal Effect: Could a Phenomenon Described Decades Ago Become Key to Enhancing the Response to Immune Therapies in Breast Cancer?

Breast Care ◽

10.1159/000511431 ◽

2020 ◽

Vol 15 (5) ◽

pp. 443-449

Author(s):

Hans-Christian Kolberg ◽

Oliver Hoffmann ◽

René Baumann

Keyword(s):

Breast Cancer ◽

Immune Response ◽

Checkpoint Inhibitors ◽

Immune Therapy ◽

Antitumor Immune Response ◽

Abscopal Effect ◽

Antitumor Effects ◽

Effective Combination ◽

Immunological Mechanisms ◽

Immune Therapies

Background: The term “abscopal effect” was defined in 1953. In oncology the term is used to describe systemic antitumor effects triggered by local irradiation (nontarget effect). Although the mechanism of the abscopal effect is not completely understood yet, it has been demonstrated that in situ tumor vaccination, and the resulting antitumor immune response, is one of the key factors. Summary: The development of immune therapies has recently led to concepts combining local radiotherapy and immune therapy with the aim of enhancing the response to immune therapy by the immunological mechanisms summarized in the term abscopal effect. This concept has also been investigated in less immunogenic tumors such as breast cancer. Initial data are promising but the hypothesis that the combination of checkpoint inhibitors and local radiotherapy could be an effective combination in breast cancer has to be proven by ongoing trials. Substitution of local radiotherapy by local hyperthermia could be an option in selected cases. Key Messages: Combination of checkpoint inhibitors with local radiation or hyperthermia in breast cancer is a promising approach and could enhance the response rates generated by immune therapy alone through the antitumor immune response initiated by the abscopal effect.

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Biological mechanisms that trigger breast cancer (BC) tumor progression are molecular subtype dependent

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.10581 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 10581-10581 ◽

Cited By ~ 1

Author(s):

C. Sotiriou ◽

C. Desmedt ◽

B. Haibe-Kains ◽

A. Harris ◽

D. Larsimont ◽

...

Keyword(s):

Breast Cancer ◽

Immune Response ◽

Clinical Outcome ◽

Tumor Size ◽

Tumor Invasion ◽

Molecular Mechanisms ◽

Molecular Subtypes ◽

Proliferation Index ◽

P Value ◽

Prognostic Impact

10581 Background: We have recently developed several gene expression indices related to hallmarks of breast cancer involving various biological processes such as tumor invasion, impairment of immune response, sustained angiogenesis, evasion of apoptosis and self- sufficiency in growth signal, and investigated their impact on clinical outcome. Here, we aim to refine our biological understanding and the prognostic impact of these indices according to the previously described molecular subtypes based on the estrogen (ER) and ERBB2 receptors. Methods: Each of these indices were developed in a series of 581 BC samples and then computed on several publicly available microarray studies totaling over 2100 BC patients. Multivariate analyses were used to study the dependency patterns between these indices, the molecular subtypes and their impact on survival. Results: ER-/ERBB2- and ERBB2+ subgroups were significantly associated with high expression levels of the proliferation, tumor invasion, angiogenesis and immune response indices. Multivariate analysis showed that in the ER+/ERBB2- subgroup, only tumor size and the proliferation and tumor invasion indices were significantly associated with clinical outcome, with the proliferation index having the largest HR and most significant p-value (HR 3.25; CI 2.31–4.56; p=1.2 10-11). In contrast, in the ER-/ERBB2- subgroup, only tumor size (HR 2.08; CI 1.14–3.81; p=0.01) and immune response index (HR 0.66; CI 0.46–0.95; p=0.02) were associated with prognosis whereas in the ERBB2+ tumors only nodal status (HR 3.40; CI 0.96–12.10; p=0.05) and tumor invasion index (HR 3.03; CI 1.32–6.95; p=0.009) showed significant association with survival. Of interest, proliferation index lost its significance as almost all ER- /ERBB2- and ERBB2 + tumors showed high proliferation levels. Conclusions: Although proliferation seems to be the strongest parameter predicting clinical outcome in ER+/ERBB2- subtype, immune response and tumor invasion appear to be the main molecular mechanisms associated with prognosis in the ER-/ERBB2- and ERBB2+ subgroups respectively. Defining these clinico-genomic models in the specific molecular subgroups will be the key to success for personalized medicine. No significant financial relationships to disclose.

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Apolipoprotein E Allelic Frequency Altered in Women with Early-onset Breast Cancer

Breast Cancer Basic and Clinical Research ◽

10.1177/117822341000400005 ◽

2010 ◽

Vol 4 ◽

pp. 117822341000400 ◽

Cited By ~ 1

Author(s):

Tirtsa Porrata-Doria ◽

Jaime L. Matta ◽

Summer F. Acevedo

Keyword(s):

Breast Cancer ◽

Risk Factor ◽

Apolipoprotein E ◽

Potential Risk ◽

Tumor Size ◽

Early Onset ◽

Late Onset ◽

The United States ◽

The Body ◽

Early Onset Breast Cancer

Among women, the most prevalent type of cancer is breast cancer, affecting 1 out of every 8 women in the United States; in Puerto Rico, 70 out of every 100,000 will develop some type of breast cancer. Therefore, a better understanding of the potential risk factors for breast cancer could lead to the development of early detection tools. A gene that has been proposed as a risk factor in several populations around the world is Apolipoprotein E (apoE). ApoE functions as a mechanism of transport for lipoproteins and cholesterol throughout the body, with 3 main isoforms present in humans (apoE2, apoE3, and apoE4). Whether or not apoE4 is a risk factor for breast cancer remains controversial. Previous studies have either included test subjects of all ages (20–80) or have focused on late-onset (after age 50) breast cancer; none has concentrated specifically on early-onset (aged 50 and younger) breast cancer. The objectives of this study was to examine (in a Puerto Rican population) the differences in the relative frequency of occurrence of apoE4 in non-breast cancer versus breast cancer patients and to examine, as well, the potential differences of same in early- versus late-onset patients. We found an increased frequency of apoE4 (odds ratio 2.15) only in early-onset breast cancer survivors, which is similar to the findings of those studies that combined or adjusted for age as well as for an association between apoE4 and decreased tumor size. ApoE is also a potential risk factor for long-term cognitive effects after chemotherapy and affects response to hormone replacement. Our data supports the theory that knowing the apoE genotype of women who are at risk of developing breast cancer may be beneficial, as such knowledge would aid in the prediction of tumor size and the development of treatment regimens.

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Assessment of Breast Cancer Immunohistochemical Properties with Demographics and Pathological Features; A Retrospective Study

International Journal of Cancer Management ◽

10.5812/ijcm.114577 ◽

2021 ◽

Vol 14 (11) ◽

Author(s):

Vahid Ariabod ◽

Maryam Sohooli ◽

Ramin Shekouhi ◽

Kiana Payan

Keyword(s):

Breast Cancer ◽

Tumor Size ◽

Tumor Grade ◽

Histological Type ◽

Tumor Diameter ◽

Breast Cancers ◽

Luminal A ◽

Cross Sectional ◽

Familial History ◽

Female Population

Background: Breast cancer is considered the most common malignant disease in the female population. It is known as an emerging epidemy with a great burden on women's health, which can be associated with poor outcomes. Some factors including histological type, immunohistochemistry (IHC), tumor grade, and tumor size can have effects on breast cancer. Objectives: This study aimed at assessing the effects of mentioned factors on IHC type of breast cancer. Methods: This retrospective cross-sectional study was conducted on 142 patients, who were referred to one of the referral centers for breast cancer in Mashhad. Information including age, histological type, familial history, menopause status, tumor grade, tumor size, and IHC properties was collected from the patient’s medical records. Allred score was used for reporting hormonal status. The data were analyzed by version 26 of SPSS software. Results: The mean age of patient was 50.2 ± 12.7. The frequency of luminal A and luminal B type was calculated as 29.7 and 18.9%, respectively. In addition, triple-negative IHC type has a prevalence of 24.3% and HER2 had a prevalence of 27%. There were no significant differences between age (P = 0.34), familial history (P = 0.42), menopause (P = 0.36), histological type (invasive: P = 0.11, in situ: P = 0.45), and IHC properties. However, tumor diameter (P = 0.0001) and tumor grading (P = 0.002) had significant association with IHC properties. Conclusions: Factors including tumor size and pathological grade can have effects on the gene expression properties of breast cancers. Luminal IHC type A is more common in breast cancer and is associated with better outcomes. However, age, histological type, familial history, and menopause status had no effects on the IHC properties of breast cancer.

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Nanovaccine impact on dendritic cells: transcriptome analysis enables new insights into antigen and adjuvant effects

Nanomedicine ◽

10.2217/nnm-2019-0460 ◽

2020 ◽

Vol 15 (21) ◽

pp. 2053-2069

Author(s):

David Paßlick ◽

Jonas Reinholz ◽

Johanna Simon ◽

Keti Piradashvili ◽

Shuai Jiang ◽

...

Keyword(s):

Immune Response ◽

Dendritic Cells ◽

Transcriptome Analysis ◽

Soluble Form ◽

Antitumor Effects ◽

Form Versus ◽

Interferon Stimulated Genes ◽

Effective Immune Response ◽

Adjuvant Effects ◽

Proteome Expression

Aim: For vaccines the combination between an antigen and adjuvants are both crucially important to trigger an effective immune response in dendritic cells. Innovative adjuvants like resiquimod or muramyldipeptide have their target protein inside the cell. Materials & methods: Up/downregulation and proteome expression was investigated for the adjuvant combination resiquimod and muramyldipeptide in a soluble form versus encapsulated into a nanocarrier. Results: We found that 1225 genes were upregulated after nanocarrier treatment while 478 genes were downregulated. Most prominent were interferon-stimulated genes with more than 25-times higher expression after nanocarrier treatment, for example RSAD2 and ISG15, which were recently found to have antiviral or antitumor effects. Conclusion: Encapsulation gives a more effective upregulation of vaccine-related genes.

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A study of the humoral immune response of breast cancer patients to a panel of human tumor antigens identified by phage display

Cancer Detection and Prevention ◽

10.1016/j.cdp.2006.05.004 ◽

2006 ◽

Vol 30 (3) ◽

pp. 248-256 ◽

Cited By ~ 10

Author(s):

Emiliano Pavoni ◽

Andrea Pucci ◽

Paola Vaccaro ◽

Giorgia Monteriù ◽

Adolfo De Pasquale Ceratti ◽

...

Keyword(s):

Breast Cancer ◽

Immune Response ◽

Phage Display ◽

Cancer Patients ◽

Humoral Immune Response ◽

Tumor Antigens ◽

Human Tumor ◽

Breast Cancer Patients ◽

Humoral Immune

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Peritumoral immune infiltrates in primary tumours are not associated with the presence of axillary lymph node metastasis in breast cancer: a retrospective cohort study

PeerJ ◽

10.7717/peerj.9779 ◽

2020 ◽

Vol 8 ◽

pp. e9779

Author(s):

Carlos López ◽

Ramón Bosch-Príncep ◽

Guifré Orero ◽

Laia Fontoura Balagueró ◽

Anna Korzynska ◽

...

Keyword(s):

Breast Cancer ◽

Immune Response ◽

Histological Grade ◽

The Body ◽

Multivariate Logistic Regression Model ◽

Axillary Lymph Nodes ◽

Axillary Lymph ◽

Breast Cancer Patients ◽

Immune Markers ◽

Body Regions

Background The axillary lymph nodes (ALNs) in breast cancer patients are the body regions to where tumoral cells most often first disseminate. The tumour immune response is important for breast cancer patient outcome, and some studies have evaluated its involvement in ALN metastasis development. Most studies have focused on the intratumoral immune response, but very few have evaluated the peritumoral immune response. The aim of the present article is to evaluate the immune infiltrates of the peritumoral area and their association with the presence of ALN metastases. Methods The concentration of 11 immune markers in the peritumoral areas was studied in 149 patients diagnosed with invasive breast carcinoma of no special type (half of whom had ALN metastasis at diagnosis) using tissue microarrays, immunohistochemistry and digital image analysis procedures. The differences in the concentration of the immune response of peritumoral areas between patients diagnosed with and without metastasis in their ALNs were evaluated. A multivariate logistic regression model was developed to identify the clinical-pathological variables and the peritumoral immune markers independently associated with having or not having ALN metastases at diagnosis. Results No statistically significant differences were found in the concentrations of the 11 immune markers between patients diagnosed with or without ALN metastases. Patients with metastases in their ALNs had a higher histological grade, more lymphovascular and perineural invasion and larger-diameter tumours. The multivariate analysis, after validation by bootstrap simulation, revealed that only tumour diameter (OR = 1.04; 95% CI [1.00–1.07]; p = 0.026), lymphovascular invasion (OR = 25.42; 95% CI [9.57–67.55]; p < 0.001) and histological grades 2 (OR = 3.84; 95% CI [1.11–13.28]; p = 0.033) and 3 (OR = 5.18; 95% CI [1.40–19.17]; p = 0.014) were associated with the presence of ALN metastases at diagnosis. This study is one of the first to study the association of the peritumoral immune response with ALN metastasis. We did not find any association of peritumoral immune infiltrates with the presence of ALN metastasis. Nevertheless, this does not rule out the possibility that other peritumoral immune populations are associated with ALN metastasis. This matter needs to be examined in greater depth, broadening the types of peritumoral immune cells studied, and including new peritumoral areas, such as the germinal centres of the peritumoral tertiary lymphoid structures found in extensively infiltrated neoplastic lesions.

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Study of anticancer activity of cecropin B on 7, 12-dimethylbenz (a) anthracene-induced breast cancer

Journal of Shahrekord University of Medical Sciences ◽

10.34172/jsums.2020.17 ◽

2020 ◽

Vol 22 (3) ◽

pp. 106-112

Author(s):

Fereshte Ghandehari ◽

Mahnoosh Fatemi

Keyword(s):

Breast Cancer ◽

Tumor Size ◽

Hematological Parameters ◽

The Body ◽

Female Rats ◽

Control Group ◽

Histopathological Analysis ◽

Mean Cell Volume ◽

Cecropin B ◽

Cancer Group

Background and aims: Antimicrobial peptides constitute a family of bioactive peptides that are involved in the body defense. Recently, their anti-cancer properties, especially by inducing apoptosis, have been proven in in vitro studies. Therefore, in this study, the effects of cecropin B as an antimicrobial peptide on breast cancer growth, hematological parameters, and histopathological changes in rats were evaluated. Methods: Twenty-four female rats were randomly divided into 4 groups. The cancer group, control group, cecropin B group, and cancer group treated with cecropin B. The tumor size was measured at the beginning and the completion of the treatment period. Blood samples were collected for assessment of the hematological parameters and Bax and Bcl2 levels. Tumor tissues were removed for histopathological analysis. Results: The tumor size had a significant increase in the cancer group and cancer group treated with cecropin at the end of the treatment. A significant decrease in mean cell volume, white blood cell count and Bcl2 level and a significant increase in hemoglobin and Bax levels were observed in the cancer group treated with cecropin B compared to cancer group. Changes in other parameters were not significant. Histopathological study showed the invasion of mitotic cells to stromal and muscular tissues of the breast in the cancer group, while focal destruction of tissue and cell death were observed in the cancer group treated with cecropin B. Conclusion: The results showed that cecropin B has been able to reduce tumor growth and have little side effects on hematologic factors probably through apoptosis.

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