Immunostimulatory Properties of Chemotherapy in Breast Cancer: From Immunogenic Modulation Mechanisms to Clinical Practice

Breast cancer (BC) is the most common malignancy among females. Chemotherapy drugs remain the cornerstone of treatment of BC and undergo significant shifts over the past 100 years. The advent of immunotherapy presents promising opportunities and constitutes a significant complementary to existing therapeutic strategies for BC. Chemotherapy as a cytotoxic treatment that targets proliferation malignant cells has recently been shown as an effective immune-stimulus in multiple ways. Chemotherapeutic drugs can cause the release of damage-associated molecular patterns (DAMPs) from dying tumor cells, which result in long-lasting antitumor immunity by the key process of immunogenic cell death (ICD). Furthermore, Off-target effects of chemotherapy on immune cell subsets mainly involve activation of immune effector cells including natural killer (NK) cells, dendritic cells (DCs), and cytotoxic T cells, and depletion of immunosuppressive cells including Treg cells, M2 macrophages and myeloid-derived suppressor cells (MDSCs). Current mini-review summarized recent large clinical trials regarding the combination of chemotherapy and immunotherapy in BC and addressed the molecular mechanisms of immunostimulatory properties of chemotherapy in BC. The purpose of our work was to explore the immune-stimulating effects of chemotherapy at the molecular level based on the evidence from clinical trials, which might be a rationale for combinations of chemotherapy and immunotherapy in BC.

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Crosstalk between Tumor-Infiltrating Immune Cells and Cancer-Associated Fibroblasts in Tumor Growth and Immunosuppression of Breast Cancer

Journal of Immunology Research ◽

10.1155/2021/8840066 ◽

2021 ◽

Vol 2021 ◽

pp. 1-15

Author(s):

Jarupa Soongsathitanon ◽

Pranisa Jamjuntra ◽

Nuttavut Sumransub ◽

Supaporn Yangngam ◽

Marjorie De la Fuente ◽

...

Keyword(s):

Breast Cancer ◽

T Cells ◽

Immune Cells ◽

Immune Cell ◽

Cytotoxic T Cells ◽

Suppressor Cells ◽

Tumor Infiltrating Lymphocytes ◽

Cancer Associated Fibroblasts ◽

Stromal Component ◽

The Impact

Signals from the tumor microenvironment (TME) have a profound influence on the maintenance and progression of cancers. Chronic inflammation and the infiltration of immune cells in breast cancer (BC) have been strongly associated with early carcinogenic events and a switch to a more immunosuppressive response. Cancer-associated fibroblasts (CAFs) are the most abundant stromal component and can modulate tumor progression according to their secretomes. The immune cells including tumor-infiltrating lymphocytes (TILs) (cytotoxic T cells (CTLs), regulatory T cells (Tregs), and helper T cell (Th)), monocyte-infiltrating cells (MICs), myeloid-derived suppressor cells (MDSCs), mast cells (MCs), and natural killer cells (NKs) play an important part in the immunological balance, fluctuating TME between protumoral and antitumoral responses. In this review article, we have summarized the impact of these immunological players together with CAF secreted substances in driving BC progression. We explain the crosstalk of CAFs and tumor-infiltrating immune cells suppressing antitumor response in BC, proposing these cellular entities as predictive markers of poor prognosis. CAF-tumor-infiltrating immune cell interaction is suggested as an alternative therapeutic strategy to regulate the immunosuppressive microenvironment in BC.

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Thyroid status regulates tumor microenvironment delineating breast cancer fate

Endocrine Related Cancer ◽

10.1530/erc-20-0277 ◽

2021 ◽

Author(s):

Helena Andrea Sterle ◽

Ximena Hildebrandt ◽

Matías Valenzuela Álvarez ◽

María Alejandra Paulazo ◽

Luciana Mariel Gutierrez ◽

...

Keyword(s):

Breast Cancer ◽

T Cells ◽

Tumor Microenvironment ◽

Lung Metastasis ◽

Cytotoxic T Cells ◽

Suppressor Cells ◽

Thyroid Status ◽

Cd8 Cells ◽

Regulatory T Lymphocytes ◽

Starting Point

The patient’s hormonal context plays a crucial role in the outcome of cancer. However, the association between thyroid disease and breast cancer risk remains unclear. We evaluated the effect of thyroid status on breast cancer growth and dissemination in an immunocompetent mouse model. For this, hyperthyroid and hypothyroid Balb/c mice were orthotopically inoculated with triple negative breast cancer 4T1 cells. Tumors from hyperthyroid mice showed increased growth rate and an immunosuppressive tumor microenvironment, characterized by increased IL-10 levels and decreased percentage of activated cytotoxic T cells. On the other hand, a delayed tumor growth in hypothyroid animals was associated with increased tumor infiltration of activated CD8+ cells and a high IFNγ/IL-10 ratio. Paradoxically, hypothyroid mice developed a higher number of lung metastasis than hyperthyroid animals. This was related to an increased secretion of tumor CCL2 and an immunosuppressive systemic environment, with increased proportion of regulatory T cells and IL-10 levels in spleens. A lower number of lung metastasis in hyperthyroid mice was related to the reduced presence of mesenchymal stem cells in tumors and metastatic sites. These animals also exhibited decreased percentages of regulatory T lymphocytes and myeloid-derived suppressor cells in spleens, but increased activated CD8+ cells and IFNγ/IL-10 ratio. Therefore, thyroid hormones modulate the cellular and cytokine content of the breast tumor microenvironment. The better understanding of the mechanisms involved in these effects could be a starting point for the discovery of new therapeutic targets for breast cancer.

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Blockade of Lactate Dehydrogenase-A (LDH-A) Improves Efficacy of Anti-Programmed Cell Death-1 (PD-1) Therapy in Melanoma

Cancers ◽

10.3390/cancers11040450 ◽

2019 ◽

Vol 11 (4) ◽

pp. 450 ◽

Cited By ~ 22

Author(s):

Saeed Daneshmandi ◽

Barbara Wegiel ◽

Pankaj Seth

Keyword(s):

T Cells ◽

Cell Death ◽

Lactate Dehydrogenase ◽

Programmed Cell Death ◽

Immune Cell ◽

Cytotoxic T Cells ◽

Treg Cells ◽

Interferon Γ ◽

Mitochondrial Activity ◽

Small Subset

Immunotherapy is a curable treatment for certain cancers, but it is still only effective in a small subset of patients. We have recently reported that programmed cell death protein-1 (PD-1) ligand (PD-L1) expression is regulated by lactate present at high levels in the tumor microenvironment (TME). We hypothesized that the efficacy of anti-PD-1 treatment can be improved by blocking the lactate-generating enzyme, lactate dehydrogenase-A (LDH-A). Anti-PD-1 treatment of mice harboring LDH-A deficient B16-F10 melanoma tumors led to an increase in anti-tumor immune responses compared to mice implanted with tumors expressing LDH-A. Specifically, we observed heightened infiltration of natural killer (NK) cells and CD8+ cytotoxic T cells in the LDH-A deficient tumors. These infiltrated cytotoxic cells had an elevated production of interferon-γ (IFN-γ) and granzyme B. Mechanistically, CD8+ T cells isolated from the TME of LDH-A deficient B16-F10 melanoma tumors and treated with anti-PD-1 showed enhanced mitochondrial activity and increased reactive oxygen species (ROS) levels. Moreover, infiltration of T regulatory (Treg) cells was diminished in LDH-A deficient tumors treated with anti-PD-1. These altered immune cell profiles were clinically relevant as they were accompanied by significantly reduced tumor growth. Our study suggests that blocking LDH-A in the tumor might improve the efficacy of anti-PD-1 therapy.

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MMP1, MMP9, and COX2 Expressions in Promonocytes Are Induced by Breast Cancer Cells and Correlate with Collagen Degradation, Transformation-Like Morphological Changes in MCF-10A Acini, and Tumor Aggressiveness

BioMed Research International ◽

10.1155/2013/279505 ◽

2013 ◽

Vol 2013 ◽

pp. 1-15 ◽

Cited By ~ 15

Author(s):

G. K. Chimal-Ramírez ◽

N. A. Espinoza-Sánchez ◽

D. Utrera-Barillas ◽

L. Benítez-Bribiesca ◽

J. R. Velázquez ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Immune Cells ◽

Immune Cell ◽

Morphological Changes ◽

Tumor Stroma ◽

Collagen Degradation ◽

Tumor Aggressiveness ◽

Soluble Factors ◽

Immune Effector

Tumor-associated immune cells often lack immune effector activities, and instead they present protumoral functions. To understand how tumors promote this immunological switch, invasive and noninvasive breast cancer cell (BRC) lines were cocultured with a promonocytic cell line in a Matrigel-based 3D system. We hypothesized that if communication exists between tumor and immune cells, coculturing would result in augmented expression of genes associated with tumor malignancy. Upregulation of proteasesMMP1andMMP9and inflammatoryCOX2genes was found likely in response to soluble factors. Interestingly, changes were more apparent in promonocytes and correlated with the aggressiveness of the BRC line. Increased gene expression was confirmed by collagen degradation assays and immunocytochemistry of prostaglandin 2, a product of COX2 activity. Untransformed MCF-10A cells were then used as a sensor of soluble factors with transformation-like capabilities, finding that acini formed in the presence of supernatants of the highly aggressive BRC/promonocyte cocultures often exhibited total loss of the normal architecture. These data support that tumor cells can modify immune cell gene expression and tumor aggressiveness may importantly reside in this capacity. Modeling interactions in the tumor stroma will allow the identification of genes useful as cancer prognostic markers and therapy targets.

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Beyond Trastuzumab and Lapatinib: New Options for HER2-Positive Breast Cancer

American Society of Clinical Oncology Educational Book ◽

10.14694/edbook_am.2013.33.e2 ◽

2013 ◽

pp. e2-e11

Author(s):

Dimitrios Zardavas ◽

David Cameron ◽

Ian Krop ◽

Martine Piccart

Keyword(s):

Breast Cancer ◽

Clinical Trials ◽

Molecular Mechanisms ◽

Molecular Subtype ◽

Targeted Agents ◽

Her2 Positive ◽

Clinical Issue ◽

Her2 Positive Breast Cancer ◽

Metastatic Setting ◽

Positive Breast Cancer

HER2-positive breast cancer (BC) constitutes a molecular subtype of the disease with an aggressive biologic behavior. Trastuzumab revolutionized the treatment of this disease, changing its natural history. Lapatinib is active in the metastatic setting, approved for patients who were pretreated with trastuzumab. However, resistance to anti-HER2 agents is a major clinical issue, occurring in both early-stage and advanced disease, and new treatment options are clearly needed. An abundance of HER2-targeted agents are being clinically developed: monoclonal antibodies, small molecule inhibitors, and antibody drug conjugates (ADC). Combining HER2-targeted agents in regimens of dual HER2 blockade has already reached clinical practice in the metastatic setting, confirming the preclinical efficacy of enhanced HER2 inhibition. Promising results have been generated in the neoadjuvant setting, and large randomized trials are seeking evidence for dual HER2 blockade in the adjuvant setting. ADC represent another hope for improved treatment outcomes of HER2-positive BC, as exemplified by the positive results of clinical trials employing trastuzumab-DM1 (trastuzumab emtansine, T-DM1). Moreover, an understanding of the molecular mechanisms mediating resistance to HER2 blockade has opened new therapeutic avenues, with several targeted agents entering clinical trials. This paper presents the clinical data of the HER2-targeted agents under development, as well as an overview of the biologic rationale for the development of agents aimed at circumventing anti-HER2 resistance.

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Utilizing cell-based therapeutics to overcome immune evasion in hematologic malignancies

Blood ◽

10.1182/blood-2015-12-629089 ◽

2016 ◽

Vol 127 (26) ◽

pp. 3350-3359 ◽

Cited By ~ 24

Author(s):

Chuang Sun ◽

Gianpietro Dotti ◽

Barbara Savoldo

Keyword(s):

Tumor Cells ◽

Immune Cell ◽

Checkpoint Inhibitors ◽

Cytotoxic T Cells ◽

Hematologic Malignancies ◽

Donor Lymphocyte Infusion ◽

Cell Transplant ◽

Hematopoietic Stem ◽

Immune Effector ◽

Effector Cells

Abstract Hematologic malignancies provide a suitable testing environment for cell-based immunotherapies, which were pioneered by the development of allogeneic hematopoietic stem cell transplant. All types of cell-based therapies, from donor lymphocyte infusion to dendritic cell vaccines, and adoptive transfer of tumor-specific cytotoxic T cells and natural killer cells, have been clinically translated for hematologic malignancies. The recent success of chimeric antigen receptor–modified T lymphocytes in B-cell malignancies has stimulated the development of this approach toward other hematologic tumors. Similarly, the remarkable activity of checkpoint inhibitors as single agents has created enthusiasm for potential combinations with other cell-based immune therapies. However, tumor cells continuously develop various strategies to evade their immune-mediated elimination. Meanwhile, the recruitment of immunosuppressive cells and the release of inhibitory factors contribute to the development of a tumor microenvironment that hampers the initiation of effective immune responses or blocks the functions of immune effector cells. Understanding how tumor cells escape from immune attack and favor immunosuppression is essential for the improvement of immune cell–based therapies and the development of rational combination approaches.

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The Potential of Combining Tubulin-Targeting Anticancer Therapeutics and Immune Therapy

International Journal of Molecular Sciences ◽

10.3390/ijms20030586 ◽

2019 ◽

Vol 20 (3) ◽

pp. 586 ◽

Cited By ~ 7

Author(s):

Alexis Fong ◽

Amanda Durkin ◽

Hoyun Lee

Keyword(s):

Anticancer Agents ◽

Immune Cell ◽

Cytotoxic T Cells ◽

Immune Therapy ◽

Cell Types ◽

Treg Cells ◽

Dendritic Cell Maturation ◽

Microtubule Inhibitors ◽

M1 Macrophage ◽

Effective Option

Cancer immune therapy has recently shown tremendous promise to combat many different cancers. The microtubule is a well-defined and very effective cancer therapeutic target. Interestingly, several lines of evidence now suggest that microtubules are intimately connected to the body’s immune responses. This raises the possibility that the combination of microtubule inhibitors and immune therapy can be a highly effective option for cancer treatments. However, our understanding on this potentially important aspect is still very limited, due in part to the multifaceted nature of microtubule functions. Microtubules are not only involved in maintaining cell morphology, but also a variety of cellular processes, including the movement of secretory vesicles and organelles, intracellular macromolecular assembly, signaling pathways, and cell division. Microtubule inhibitors may be subdivided into two classes: Anti-depolymerization agents such as the taxane family, and anti-polymerization agents such as colchicine and vinka alkaloids. These two different classes may have different effects on immune cell subtypes. Anti-depolymerization agents can not only induce NK cells, but also appear to inhibit T regulatory (Treg) cells. However, different inhibitors may have different functions even among the same class. For example, the doxetaxel anti-depolymerization agent up-regulates cytotoxic T cells, while paclitaxel down-regulates them. Certain anti-polymerization agents such as colchicine appear to down-regulate most immune cell types, while inducing dendritic cell maturation and increasing M1 macrophage population. In contrast, the vinblastine anti-polymerization agent activates many of these cell types, albeit down-regulating Treg cells. In this review, we focus on the various effects of tubulin inhibitors on the activities of the body’s immune system, in the hope of paving the way to develop an effective cancer therapy by combining tubulin-targeting anticancer agents and immune therapy.

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Novel Therapeutic Strategies for Solid Tumor Based on Body’s Intrinsic Antitumor Immune System

Cellular Physiology and Biochemistry ◽

10.1159/000489979 ◽

2018 ◽

Vol 47 (2) ◽

pp. 441-457 ◽

Cited By ~ 7

Author(s):

Haifeng Duan

Keyword(s):

Immune System ◽

Nk Cells ◽

Cell Function ◽

Immune Cell ◽

Tumor Therapy ◽

Suppressor Cells ◽

Nutritional Supplement ◽

Treg Cells ◽

Tumor Burden ◽

Antitumor Action

The accumulation of mutated somatic cells due to the incompetency of body’s immune system may lead to tumor onset. Therefore, enhancing the ability of the system to eliminate such cells should be the core of tumor therapy. The intrinsic antitumor immunity is triggered by tumor-specific antigens (TSA) or TSA-sensitized dendritic cells (DC). Once initiated, specific anti-tumor antibodies are produced and tumor-specific killer immune cells, including cytotoxic T lymphocytes (CTL), NK cells, and macrophages, are raised or induced. Several strategies may enhance antitumor action of immune system, such as supplying tumor-targeted antibody, activating T cells, enhancing the activity and tumor recognition of NK cells, promoting tumor-targeted phagocytosis of macrophages, and eliminating the immunosuppressive myeloid-derived suppressor cells (MDSCs) and Treg cells. Apart from the immune system, the removal of tumor burden still needs to be assisted by drugs, surgery or radiation. And the body’s internal environment and tumor microenvironment should be improved to recover immune cell function and prevent tumor growth. Multiple microenvironment modulatory therapies may be applied, including addressing hypoxia and oxidative stress, correcting metabolic disorders, and controlling chronic inflammation. Finally, to cure tumor and prevent tumor recurrence, repairing or supporting therapy that consist of tissue repair and nutritional supplement should be applied properly.

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Uncovering the Mechanisms of Adenosine Receptor-Mediated Pain Control: Focus on the A3 Receptor Subtype

International Journal of Molecular Sciences ◽

10.3390/ijms22157952 ◽

2021 ◽

Vol 22 (15) ◽

pp. 7952

Author(s):

Elisabetta Coppi ◽

Federica Cherchi ◽

Elena Lucarini ◽

Carla Ghelardini ◽

Felicita Pedata ◽

...

Keyword(s):

Clinical Trials ◽

Adenosine Receptor ◽

Pain Control ◽

Molecular Mechanisms ◽

Immune Cell ◽

Opioid Analgesics ◽

Receptor Subtype ◽

A3ar Agonist ◽

A3 Adenosine Receptor ◽

Gi Protein

Agonists of the Gi protein-coupled A3 adenosine receptor (A3AR) have shown important pain-relieving properties in preclinical settings of several pain models. Active as a monotherapy against chronic pain, A3AR agonists can also be used in combination with classic opioid analgesics. Their safe pharmacological profile, as shown by clinical trials for other pathologies, i.e., rheumatoid arthritis, psoriasis and fatty liver diseases, confers a realistic translational potential, thus encouraging research studies on the molecular mechanisms underpinning their antinociceptive actions. A number of pathways, involving central and peripheral mechanisms, have been proposed. Recent evidence showed that the prototypical A3AR agonist Cl-IB-MECA and the new, highly selective, A3AR agonist MRS5980 inhibit neuronal (N-type) voltage-dependent Ca2+ currents in dorsal root ganglia, a known pain-related mechanism. Other proposed pathways involve reduced cytokine production, immune cell-mediated responses, as well as reduced microglia and astrocyte activation in the spinal cord. The aim of this review is to summarize up-to-date information on A3AR in the context of pain, including cellular and molecular mechanisms underlying this effect. Based on their safety profile shown in clinical trials for other pathologies, A3AR agonists are proposed as novel, promising non-narcotic agents for pain control.

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Human G-MDSCs are neutrophils at distinct maturation stages promoting tumor growth in breast cancer

Life Science Alliance ◽

10.26508/lsa.202000893 ◽

2020 ◽

Vol 3 (11) ◽

pp. e202000893

Author(s):

Meliha Mehmeti-Ajradini ◽

Caroline Bergenfelz ◽

Anna-Maria Larsson ◽

Robert Carlsson ◽

Kristian Riesbeck ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Tumor Growth ◽

Tumor Progression ◽

Immune Cell ◽

Human Tumor ◽

Metastatic Breast ◽

Suppressor Cells ◽

Breast Cancer Patients ◽

Maturation Stages

Myeloid-derived suppressor cells (MDSCs) are known to contribute to immune evasion in cancer. However, the function of the human granulocytic (G)-MDSC subset during tumor progression is largely unknown, and there are no established markers for their identification in human tumor specimens. Using gene expression profiling, mass cytometry, and tumor microarrays, we here demonstrate that human G-MDSCs occur as neutrophils at distinct maturation stages, with a disease-specific profile. G-MDSCs derived from patients with metastatic breast cancer and malignant melanoma display a unique immature neutrophil profile, that is more similar to healthy donor neutrophils than to G-MDSCs from sepsis patients. Finally, we show that primary G-MDSCs from metastatic breast cancer patients co-transplanted with breast cancer cells, promote tumor growth, and affect vessel formation, leading to myeloid immune cell exclusion. Our findings reveal a role for human G-MDSC in tumor progression and have clinical implications also for targeted immunotherapy.

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