Immunomodulatory effects of tumor Lactate Dehydrogenase C (LDHC) in breast cancer
<h3>Background</h3><p dir="ltr">Immunotherapy has significantly improved outcomes for cancer patients; however, its clinical benefits vary among patients and its efficacy across breast cancer subtypes remains unclear. To enhance immunotherapy efficacy, it is important to...
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2025
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| _version_ | 1864513534737514496 |
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| author | Adviti Naik (673163) |
| author2 | Remy Thomas (702843) Aljazi Al-Khalifa (20905504) Hanan Qasem (3337329) Julie Decock (44558) |
| author2_role | author author author author |
| author_facet | Adviti Naik (673163) Remy Thomas (702843) Aljazi Al-Khalifa (20905504) Hanan Qasem (3337329) Julie Decock (44558) |
| author_role | author |
| dc.creator.none.fl_str_mv | Adviti Naik (673163) Remy Thomas (702843) Aljazi Al-Khalifa (20905504) Hanan Qasem (3337329) Julie Decock (44558) |
| dc.date.none.fl_str_mv | 2025-03-19T09:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1186/s12964-025-02139-6 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/Immunomodulatory_effects_of_tumor_Lactate_Dehydrogenase_C_LDHC_in_breast_cancer/30393214 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biomedical and clinical sciences Clinical sciences Oncology and carcinogenesis LDHC Breast cancer Immune checkpoint Cytokines Chemokines |
| dc.title.none.fl_str_mv | Immunomodulatory effects of tumor Lactate Dehydrogenase C (LDHC) in breast cancer |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <h3>Background</h3><p dir="ltr">Immunotherapy has significantly improved outcomes for cancer patients; however, its clinical benefits vary among patients and its efficacy across breast cancer subtypes remains unclear. To enhance immunotherapy efficacy, it is important to gain more insight into tumor-intrinsic immunomodulatory factors that could serve as therapeutic targets. We previously identified Lactate Dehydrogenase C (LDHC) as a promising anti-cancer target due to its role in regulating cancer cell genomic integrity. In this study, we investigated the effects of tumor LDHC expression on immune responses.</p><h3>Methods</h3><p dir="ltr">TIMER AND TIDE deconvolution methods were used to investigate the relationship between tumor <i>LDHC</i> expression, immune cell infiltration and T cell dysfunction. Multiplex cytokine assays and flow cytometry were used to assess the effect of <i>LDHC</i> knockdown on the secretion of inflammatory molecules and expression of immune checkpoint molecules in breast cancer cells and cancer cell-immune cell co-cultures. T cell activity was determined by IFN-γ ELISPot assays and 7-AAD flow cytometry.</p><h3>Results</h3><p dir="ltr">TIMER and TIDE analyses revealed that tumor <i>LDHC</i> expression is associated with T cell dysfunction in breast cancer and poorer post-immunotherapy survival in melanoma. Silencing LDHC in breast cancer cell lines (MDA-MB-468, BT-549, HCC-1954) enhanced early T cell activation and cytolytic activity. To gain a better understanding of the underlying mechanisms, comparative analysis of the effects of <i>LDHC</i> knockdown in cancer cell monocultures and co-cultures was conducted. Following <i>LDHC</i> knockdown, we observed an increase in the secretion of tumor-derived pro-inflammatory cytokines (IFN-γ, GM-CSF, MCP-1, CXCL1), a decrease in the soluble levels of tumor-derived immunosuppressive factors (IL-6, Gal-9) and reduced tumor cell surface PD-L1 expression. In direct co-cultures, <i>LDHC</i> knockdown reduced the levels of pro-tumorigenic cytokines (IL-1β, IL-4 and IL-6) and increased the secretion of the chemokine CXCL1. In addition, the number of CD8 + T cells expressing PD-1 and CTLA-4 and the cell surface expression of CTLA-4, TIGIT, TIM3, and VISTA were reduced.</p><h3>Conclusions</h3><p dir="ltr">Our findings suggest that targeting LDHC could enhance anti-tumor immune responses by modulating cytokine and chemokine secretion in addition to impairing immune checkpoint signaling. Further studies are required to elucidate the molecular mechanisms by which LDHC modulates immune responses in breast cancer.</p><h2>Other Information</h2><p dir="ltr">Published in: Cell Communication and Signaling<br>License: <a href="https://creativecommons.org/licenses/by/4.0" target="_blank">https://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1186/s12964-025-02139-6" target="_blank">https://dx.doi.org/10.1186/s12964-025-02139-6</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_e06989e190a3fe451a329fe95ee15540 |
| identifier_str_mv | 10.1186/s12964-025-02139-6 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/30393214 |
| publishDate | 2025 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | Immunomodulatory effects of tumor Lactate Dehydrogenase C (LDHC) in breast cancerAdviti Naik (673163)Remy Thomas (702843)Aljazi Al-Khalifa (20905504)Hanan Qasem (3337329)Julie Decock (44558)Biomedical and clinical sciencesClinical sciencesOncology and carcinogenesisLDHCBreast cancerImmune checkpointCytokinesChemokines<h3>Background</h3><p dir="ltr">Immunotherapy has significantly improved outcomes for cancer patients; however, its clinical benefits vary among patients and its efficacy across breast cancer subtypes remains unclear. To enhance immunotherapy efficacy, it is important to gain more insight into tumor-intrinsic immunomodulatory factors that could serve as therapeutic targets. We previously identified Lactate Dehydrogenase C (LDHC) as a promising anti-cancer target due to its role in regulating cancer cell genomic integrity. In this study, we investigated the effects of tumor LDHC expression on immune responses.</p><h3>Methods</h3><p dir="ltr">TIMER AND TIDE deconvolution methods were used to investigate the relationship between tumor <i>LDHC</i> expression, immune cell infiltration and T cell dysfunction. Multiplex cytokine assays and flow cytometry were used to assess the effect of <i>LDHC</i> knockdown on the secretion of inflammatory molecules and expression of immune checkpoint molecules in breast cancer cells and cancer cell-immune cell co-cultures. T cell activity was determined by IFN-γ ELISPot assays and 7-AAD flow cytometry.</p><h3>Results</h3><p dir="ltr">TIMER and TIDE analyses revealed that tumor <i>LDHC</i> expression is associated with T cell dysfunction in breast cancer and poorer post-immunotherapy survival in melanoma. Silencing LDHC in breast cancer cell lines (MDA-MB-468, BT-549, HCC-1954) enhanced early T cell activation and cytolytic activity. To gain a better understanding of the underlying mechanisms, comparative analysis of the effects of <i>LDHC</i> knockdown in cancer cell monocultures and co-cultures was conducted. Following <i>LDHC</i> knockdown, we observed an increase in the secretion of tumor-derived pro-inflammatory cytokines (IFN-γ, GM-CSF, MCP-1, CXCL1), a decrease in the soluble levels of tumor-derived immunosuppressive factors (IL-6, Gal-9) and reduced tumor cell surface PD-L1 expression. In direct co-cultures, <i>LDHC</i> knockdown reduced the levels of pro-tumorigenic cytokines (IL-1β, IL-4 and IL-6) and increased the secretion of the chemokine CXCL1. In addition, the number of CD8 + T cells expressing PD-1 and CTLA-4 and the cell surface expression of CTLA-4, TIGIT, TIM3, and VISTA were reduced.</p><h3>Conclusions</h3><p dir="ltr">Our findings suggest that targeting LDHC could enhance anti-tumor immune responses by modulating cytokine and chemokine secretion in addition to impairing immune checkpoint signaling. Further studies are required to elucidate the molecular mechanisms by which LDHC modulates immune responses in breast cancer.</p><h2>Other Information</h2><p dir="ltr">Published in: Cell Communication and Signaling<br>License: <a href="https://creativecommons.org/licenses/by/4.0" target="_blank">https://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1186/s12964-025-02139-6" target="_blank">https://dx.doi.org/10.1186/s12964-025-02139-6</a></p>2025-03-19T09:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1186/s12964-025-02139-6https://figshare.com/articles/journal_contribution/Immunomodulatory_effects_of_tumor_Lactate_Dehydrogenase_C_LDHC_in_breast_cancer/30393214CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/303932142025-03-19T09:00:00Z |
| spellingShingle | Immunomodulatory effects of tumor Lactate Dehydrogenase C (LDHC) in breast cancer Adviti Naik (673163) Biomedical and clinical sciences Clinical sciences Oncology and carcinogenesis LDHC Breast cancer Immune checkpoint Cytokines Chemokines |
| status_str | publishedVersion |
| title | Immunomodulatory effects of tumor Lactate Dehydrogenase C (LDHC) in breast cancer |
| title_full | Immunomodulatory effects of tumor Lactate Dehydrogenase C (LDHC) in breast cancer |
| title_fullStr | Immunomodulatory effects of tumor Lactate Dehydrogenase C (LDHC) in breast cancer |
| title_full_unstemmed | Immunomodulatory effects of tumor Lactate Dehydrogenase C (LDHC) in breast cancer |
| title_short | Immunomodulatory effects of tumor Lactate Dehydrogenase C (LDHC) in breast cancer |
| title_sort | Immunomodulatory effects of tumor Lactate Dehydrogenase C (LDHC) in breast cancer |
| topic | Biomedical and clinical sciences Clinical sciences Oncology and carcinogenesis LDHC Breast cancer Immune checkpoint Cytokines Chemokines |