Differential kynurenine pathway metabolism in highly metastatic aggressive breast cancer subtypes: beyond IDO1-induced immunosuppression

Abstract Background Immunotherapy has recently been proposed as a promising treatment to stop breast cancer (BrCa) progression and metastasis. However, there has been limited success in the treatment of BrCa with immune checkpoint inhibitors. This implies that BrCa tumors have other mechanisms to escape immune surveillance. While the kynurenine pathway (KP) is known to be a key player mediating tumor immune evasion and while there are several studies on the roles of the KP in cancer, little is known about KP involvement in BrCa. Methods To understand how KP is regulated in BrCa, we examined the KP profile in BrCa cell lines and clinical samples (n = 1997) that represent major subtypes of BrCa (luminal, HER2-enriched, and triple-negative (TN)). We carried out qPCR, western blot/immunohistochemistry, and ultra-high pressure liquid chromatography on these samples to quantify the KP enzyme gene, protein, and activity, respectively. Results We revealed that the KP is highly dysregulated in the HER2-enriched and TN BrCa subtype. Gene, protein expression, and KP metabolomic profiling have shown that the downstream KP enzymes KMO and KYNU are highly upregulated in the HER2-enriched and TN BrCa subtypes, leading to increased production of the potent immunosuppressive metabolites anthranilic acid (AA) and 3-hydroxylanthranilic acid (3HAA). Conclusions Our findings suggest that KMO and KYNU inhibitors may represent new promising therapeutic targets for BrCa. We also showed that KP metabolite profiling can be used as an accurate biomarker for BrCa subtyping, as we successfully discriminated TN BrCa from other BrCa subtypes.

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Differential kynurenine pathway metabolism in highly-metastatic aggressive breast cancer subtypes: beyond IDO1-induced immunosuppression

10.21203/rs.3.rs-57673/v1 ◽

2020 ◽

Author(s):

Benjamin Heng ◽

Ayse A. Bilgin ◽

David B Lovejoy ◽

Vanessa X Tan ◽

Heloisa Helena Milioli ◽

...

Keyword(s):

Breast Cancer ◽

Checkpoint Inhibitors ◽

Immune Surveillance ◽

Kynurenine Pathway ◽

Clinical Samples ◽

Tumor Immune Evasion ◽

Cancer Subtypes ◽

Metabolomic Profiling ◽

Promising Treatment ◽

Aggressive Breast Cancer

Abstract Background: Immunotherapy has recently been proposed as a promising treatment to stop breast cancer (BrCa) progression and metastasis. However, there has been limited success in the treatment of BrCa with immune checkpoint inhibitors. This implies that BrCa tumors have other mechanism(s) to escape immune surveillance. While the kynurenine pathway (KP) is known to be a key player mediating tumor immune evasion and while there are several studies on the roles of the KP in cancer, little is known about KP involvement in BrCa.Methods: To understand how KP is regulated in BrCa, we examined the KP profile in BrCa cell lines and clinical samples (n = 1,997) that represent major subtypes of BrCa (luminal, HER2, and triple-negative (TN)). We carried out qPCR, western blot/immunohistochemistry and ultra-high pressure liquid chromatography on these samples to quantify KP enzyme gene, protein and activity respectively.Results: We revealed that the KP is highly dysregulated in the HER2-enriched and TN BrCa subtype. Gene, protein expression and KP metabolomic profiling have shown that the downstream KP enzymes KMO and KYNU are highly upregulated in the HER2-enriched and TN BrCa subtypes, leading to increased production of the potent immunosuppressive metabolites anthranilic acid (AA) and 3-hydroxylanthranilic acid (3HAA).Conclusions: Our findings suggest that KMO and KYNU inhibitors may represent new promising therapeutic targets for BrCa. We also showed that KP metabolite profiling can be used as an accurate biomarker for BrCa subtyping, as we successfully discriminated TN BrCa from other BrCa subtypes.

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Differential kynurenine pathway metabolism in highly-metastatic aggressive breast cancer subtypes: beyond IDO1-induced immunosuppression

10.21203/rs.3.rs-57673/v2 ◽

2020 ◽

Author(s):

Benjamin Heng ◽

Ayse A. Bilgin ◽

David B Lovejoy ◽

Vanessa X Tan ◽

Heloisa Helena Milioli ◽

...

Keyword(s):

Breast Cancer ◽

Checkpoint Inhibitors ◽

Immune Surveillance ◽

Kynurenine Pathway ◽

Clinical Samples ◽

Tumor Immune Evasion ◽

Cancer Subtypes ◽

Metabolomic Profiling ◽

Promising Treatment ◽

Aggressive Breast Cancer

Abstract Background: Immunotherapy has recently been proposed as a promising treatment to stop breast cancer (BrCa) progression and metastasis. However, there has been limited success in the treatment of BrCa with immune checkpoint inhibitors. This implies that BrCa tumors have other mechanism(s) to escape immune surveillance. While the kynurenine pathway (KP) is known to be a key player mediating tumor immune evasion and while there are several studies on the roles of the KP in cancer, little is known about KP involvement in BrCa.Methods: To understand how KP is regulated in BrCa, we examined the KP profile in BrCa cell lines and clinical samples (n = 1,997) that represent major subtypes of BrCa (luminal, HER2-enriched, and triple-negative (TN)). We carried out qPCR, western blot/immunohistochemistry and ultra-high pressure liquid chromatography on these samples to quantify KP enzyme gene, protein and activity respectively.Results: We revealed that the KP is highly dysregulated in the HER2-enriched and TN BrCa subtype. Gene, protein expression and KP metabolomic profiling have shown that the downstream KP enzymes KMO and KYNU are highly upregulated in the HER2-enriched and TN BrCa subtypes, leading to increased production of the potent immunosuppressive metabolites anthranilic acid (AA) and 3-hydroxylanthranilic acid (3HAA).Conclusions: Our findings suggest that KMO and KYNU inhibitors may represent new promising therapeutic targets for BrCa. We also showed that KP metabolite profiling can be used as an accurate biomarker for BrCa subtyping, as we successfully discriminated TN BrCa from other BrCa subtypes.

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Crosstalk between HER2 and PD-1/PD-L1 in Breast Cancer: From Clinical Applications to Mathematical Models

Cancers ◽

10.3390/cancers12030636 ◽

2020 ◽

Vol 12 (3) ◽

pp. 636 ◽

Cited By ~ 10

Author(s):

Regina Padmanabhan ◽

Hadeel Shafeeq Kheraldine ◽

Nader Meskin ◽

Semir Vranic ◽

Ala-Eddin Al Moustafa

Keyword(s):

Breast Cancer ◽

Mathematical Models ◽

Immune Checkpoint ◽

Checkpoint Inhibitors ◽

Breast Cancers ◽

Treatment Protocols ◽

Cancer Subtypes ◽

Cancer Management ◽

Her2 Breast Cancer ◽

Programmed Death

Breast cancer is one of the major causes of mortality in women worldwide. The most aggressive breast cancer subtypes are human epidermal growth factor receptor-positive (HER2+) and triple-negative breast cancers. Therapies targeting HER2 receptors have significantly improved HER2+ breast cancer patient outcomes. However, several recent studies have pointed out the deficiency of existing treatment protocols in combatting disease relapse and improving response rates to treatment. Overriding the inherent actions of the immune system to detect and annihilate cancer via the immune checkpoint pathways is one of the important hallmarks of cancer. Thus, restoration of these pathways by various means of immunomodulation has shown beneficial effects in the management of various types of cancers, including breast. We herein review the recent progress in the management of HER2+ breast cancer via HER2-targeted therapies, and its association with the programmed death receptor-1 (PD-1)/programmed death ligand-1 (PD-L1) axis. In order to link research in the areas of medicine and mathematics and point out specific opportunities for providing efficient theoretical analysis related to HER2+ breast cancer management, we also review mathematical models pertaining to the dynamics of HER2+ breast cancer and immune checkpoint inhibitors.

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Epigenetic Regulation of Immunotherapy Response in Triple-Negative Breast Cancer

Cancers ◽

10.3390/cancers13164139 ◽

2021 ◽

Vol 13 (16) ◽

pp. 4139

Author(s):

Pere Llinàs-Arias ◽

Sandra Íñiguez-Muñoz ◽

Kelly McCann ◽

Leonie Voorwerk ◽

Javier I. J. Orozco ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Immune Escape ◽

Checkpoint Inhibitors ◽

Early Stage ◽

Regulatory Elements ◽

Her2 Overexpression ◽

Breast Cancers ◽

Cancer Subtypes

Triple-negative breast cancer (TNBC) is defined by the absence of estrogen receptor and progesterone receptor and human epidermal growth factor receptor 2 (HER2) overexpression. This malignancy, representing 15–20% of breast cancers, is a clinical challenge due to the lack of targeted treatments, higher intrinsic aggressiveness, and worse outcomes than other breast cancer subtypes. Immune checkpoint inhibitors have shown promising efficacy for early-stage and advanced TNBC, but this seems limited to a subgroup of patients. Understanding the underlying mechanisms that determine immunotherapy efficiency is essential to identifying which TNBC patients will respond to immunotherapy-based treatments and help to develop new therapeutic strategies. Emerging evidence supports that epigenetic alterations, including aberrant chromatin architecture conformation and the modulation of gene regulatory elements, are critical mechanisms for immune escape. These alterations are particularly interesting since they can be reverted through the inhibition of epigenetic regulators. For that reason, several recent studies suggest that the combination of epigenetic drugs and immunotherapeutic agents can boost anticancer immune responses. In this review, we focused on the contribution of epigenetics to the crosstalk between immune and cancer cells, its relevance on immunotherapy response in TNBC, and the potential benefits of combined treatments.

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Association of adiposity, dysmetabolisms, and inflammation with aggressive breast cancer subtypes: a cross-sectional study

Breast Cancer Research and Treatment ◽

10.1007/s10549-016-3802-3 ◽

2016 ◽

Vol 157 (1) ◽

pp. 179-189 ◽

Cited By ~ 16

Author(s):

Roberto Agresti ◽

Elisabetta Meneghini ◽

Paolo Baili ◽

Pamela Minicozzi ◽

Alberto Turco ◽

...

Keyword(s):

Breast Cancer ◽

Cross Sectional Study ◽

Breast Cancer Subtypes ◽

Sectional Study ◽

Cross Sectional ◽

Cancer Subtypes ◽

Aggressive Breast Cancer

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Checkpoint Inhibitors and Their Application in Breast Cancer

Breast Care ◽

10.1159/000445335 ◽

2016 ◽

Vol 11 (2) ◽

pp. 108-115 ◽

Cited By ~ 27

Author(s):

Davide Bedognetti ◽

Cristina Maccalli ◽

Salha B.J. Al Bader ◽

Francesco M. Marincola ◽

Barbara Seliger

Keyword(s):

Breast Cancer ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitors ◽

Treatment Options ◽

Immune Surveillance ◽

Significant Proportion ◽

Immune Checkpoints ◽

Immune Recognition ◽

Breast Cancers ◽

Inhibitory Molecules

Immune checkpoints are crucial for the maintenance of self-tolerance and for the modulation of immune responses in order to minimize tissue damage. Tumor cells take advantage of these mechanisms to evade immune recognition. A significant proportion of tumors, including breast cancers, can express co-inhibitory molecules that are important formediating the escape from T cell-mediated immune surveillance. The interaction of inhibitory receptors with their ligands can be blocked by specific molecules. Monoclonal antibodies (mAbs) directed against the cytotoxic T lymphocyte-associated antigen-4 (CTLA4) and, more recently, against the programmed cell death protein 1 (PD1), have been approved for the therapy of melanoma (anti-CTLA4 and anti-PD1 mAbs) and non-small cell lung cancer (anti-PD1 mAbs). Moreover, inhibition of PD1 signaling has shown extremely promising signs of activity in breast cancer. An increasing number of molecules directed against other immune checkpoints are currently under clinical development. In this review, we summarize the evidence supporting the implementation of checkpoint inhibition in breast cancer by reviewing in detail data on PD-L1 expression and its regulation. In addition, opportunities to boost anti-tumor immunity in breast cancer with checkpoint inhibitor-based immunotherapies alone and in combination with other treatment options will be discussed.

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