Th1 cytokine interferon gamma improves response in HER2 breast cancer by modulating the ubiquitin proteasomal pathway

Jia, Yongsheng; Kodumudi, Krithika; Ramya, G.; Basu, Amrita; Snyder, Colin; Wiener, Doris; Pilon‐Thomas, Shari; Grover, Payal; Zhang, Hongtao; Greene, Mark I.; Mo, Qianxing; Tong, Zhongsheng; Chen, Yongzi; Costa, Ricardo; Han, Hyo S.; Lee, Catherine; Soliman, Hatem; Conejo-Garcia, José R.; Koski, Gary K.; Czerniecki, Brian J.

doi:10.1016/j.ymthe.2020.12.037

Cited by 28 publications

(20 citation statements)

References 42 publications

(45 reference statements)

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“…CD4 + T cells accumulated in the tumors of mice treated with HER3 peptide-pulsed DC1, suggesting a contribution of the CD4 + response in tumor regression. We validated the significance of Author Manuscript Published OnlineFirst on November 16, 2021; DOI: 10.1158/2326-6066.CIR-21-0454 [35] and hence, HER3-DC1 treatment may reduce HER3 expression by CD4 + Th1 stimulation.…”

Section: Discussionmentioning

confidence: 53%

Identification of Immunogenic MHC Class II Human HER3 Peptides that Mediate Anti-HER3 CD4+ Th1 Responses and Potential Use as a Cancer Vaccine

Basu

Albert

Awshah

et al. 2021

Cancer Immunology Research

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The HER3/ERBB3 receptor is an oncogenic receptor tyrosine kinase that forms heterodimers with EGFR family members and is overexpressed in numerous cancers. HER3 overexpression associates with reduced survival and acquired resistance to targeted therapies, making it a potential therapeutic target in multiple cancer types. Here, we report on immunogenic, promiscuous MHC class II–binding HER3 peptides, which can generate HER3-specific CD4+ Th1 antitumor immune responses. Using an overlapping peptide screening methodology, we identified nine MHC class II–binding HER3 epitopes that elicited specific Th1 immune response in both healthy donors and breast cancer patients. Most of these peptides were not identified by current binding algorithms. Homology assessment of amino acid sequence BLAST showed >90% sequence similarity between human and murine HER3/ERBB3 peptide sequences. HER3 peptide–pulsed dendritic cell vaccination resulted in anti-HER3 CD4+ Th1 responses that prevented tumor development, significantly delayed tumor growth in prevention models, and caused regression in multiple therapeutic models of HER3-expressing murine tumors, including mammary carcinoma and melanoma. Tumors were robustly infiltrated with CD4+ T cells, suggesting their key role in tumor rejection. Our data demonstrate that class II HER3 promiscuous peptides are effective at inducing HER3-specific CD4+ Th1 responses and suggest their applicability in immunotherapies for human HER3-overexpressing tumors.

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Section: Discussionmentioning

confidence: 53%

Identification of Immunogenic MHC Class II Human HER3 Peptides that Mediate Anti-HER3 CD4+ Th1 Responses and Potential Use as a Cancer Vaccine

Basu

Albert

Awshah

et al. 2021

Cancer Immunology Research

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“…IFN-γ has the potential to mediate degradation of HER2 through a ubiquitin proteasomal pathway in HER2 pos BC cells. 25 IFN-γ in combination with anti-HER2 antibodies, trastuzumab and pertuzumab, has been shown to increase senescence and apoptosis via STAT1 signaling activation in HER2 pos BC cells. 28 This study provides confirmative evidence for the previous finding that enhanced STAT1 activation was observed following HER2-DC1 i.t.…”

Section: Discussionmentioning

confidence: 99%

“…Evidence exists that Th1 cytokines including IFN-γ can mediate HER2 degradation via the ubiquitin proteasomal pathway and also via caspase 3 in HER2 pos BC cells. 25 26 IFN-γ also enhances expression of MHC class I/II and programmed death ligand-1 (PD-L1) on tumor cells, leading to recognition by immune cells. 27 More recently, we showed that treatment of Th1 cytokines in combination with trastuzumab and pertuzumab synergistically increased tumor senescence and apoptosis via STAT1 signaling in HER2 pos BC cells.…”

Section: Introductionmentioning

confidence: 99%

Intratumoral delivery of dendritic cells plus anti-HER2 therapy triggers both robust systemic antitumor immunity and complete regression in HER2 mammary carcinoma

Ramya

Kodumudi

Snyder

et al. 2022

J Immunother Cancer

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BackgroundHuman epidermal growth factor receptor 2 (HER2) targeted antibodies in combination with chemotherapy has improved outcomes of HER2 positive (pos) breast cancer (BC) but toxicity of therapy remains a problem. High levels of tumor-infiltrating lymphocytes are associated with increased pathologic complete responses for patients treated with neoadjuvant therapy. Here we sought to investigate whether delivery of intratumoral (i.t.) multiepitope major histocompatibility complex (MHC) class II HER2 peptides-pulsed type I polarized dendritic cells (HER2-DC1) in combination with anti-HER2 antibodies without chemotherapy could enhance tumor regression by increasing anti-HER2 lymphocyte infiltration into the tumor.MethodsBALB/c mice bearing orthotopic TUBO tumors, BALB/c mice bearing subcutaneous (s.c.) CT26 hHER2 tumors, or BALB-HER2/neu transgenic mice were all treated with i.t. or s.c. HER2-DC1, anti-HER2 antibodies, paclitaxel, T-DM1 or in combination. Immune response, host immune cells and effector function were analyzed using flow cytometry, interferon-γ ELISA and cytokine/chemokine arrays. The contributions of CD4+ and CD8+ T cells and antibody dependent cellular cytotoxicity (ADCC) were assessed using depleting antibodies and FcγR KO mice. Molecular changes were evaluated by immunohistochemistry and western blot.ResultsHER2-DC1 combined with anti-HER2 antibodies delivered i.t. compared to s.c. induced complete tumor regression in 75–80% of treated mice, with increased tumor infiltrating CD4+ and CD8+ T, B, natural killer T cells (NKT) and natural killer cells, and strong anti-HER2 responses in all HER2pos BC models tested. The therapy caused regression of untreated distant tumors. Labeled HER2-DC1 migrated prominently into the distant tumor and induced infiltration of various DC subsets into tumors. HER2-DC1 i.t. combined with anti-HER2 antibodies displayed superior antitumor response compared to standard chemotherapy with anti-HER2 antibodies. Lasting immunity was attained which prevented secondary tumor formation. The presence of CD4+ and CD8+ T cells and ADCC were required for complete tumor regression. In the HER2pos BC models, HER2-DC1 i.t. combined with anti-HER2 antibodies effectively diminished activation of HER2-mediated oncogenic signaling pathways.ConclusionsHER2-DC1 i.t. with anti-HER2 antibodies mediates tumor regression through combined activation of T and B cell compartments and provides evidence that HER2-DC1 i.t. in combination with anti-HER2 antibodies can be tested as an effective alternative therapeutic strategy to current chemotherapy and anti-HER2 antibodies in HER2pos BC.

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“…Our group has also reported that restoration of the anti-HER2 Th1 response culminated in improved survival in HER2+ BC patients ( 46 , 119 ). The molecular basis of this effect was investigated, and we now know that the Th1 cytokine IFN-γ increased E3 ubiquitin ligase Cullin-5, which led to ubiquitination and degradation of surface HER2 receptors, translating into tumor senescence and diminished tumor growth ( 121 ).…”

Section: Loss Of Anti-her2 Th1 Response During Breast Tumorigenesismentioning

confidence: 99%

“…Another study showed HER2/neu oncogene constructed DC vaccine and trastuzumab combination treatment prevented spontaneous mammary carcinoma growth in HER2/neu-overexpressing transgenic mice, as the combination treatment was able to induce strong HER2/neu-specific CD8+ CTL immunity, which prevented tumor growth in mice ( 126 , 167 ). Recently, it has been observed that HER2-DC1 vaccine, in combination with anti-HER2 antibodies, was able to completely arrest tumor growth in HER2/neu BC preclinical model ( 121 ).…”

Section: Vaccination In Addition To Targeted Therapy For Her2+ Breast Cancermentioning

confidence: 99%

Intercepting Premalignant, Preinvasive Breast Lesions Through Vaccination

et al. 2021

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Breast cancer (BC) prevention remains the ultimate cost-effective method to reduce the global burden of invasive breast cancer (IBC). To date, surgery and chemoprevention remain the main risk-reducing modalities for those with hereditary cancer syndromes, as well as high-risk non-hereditary breast lesions such as ADH, ALH, or LCIS. Ductal carcinoma in situ (DCIS) is a preinvasive malignant lesion of the breast that closely mirrors IBC and, if left untreated, develops into IBC in up to 50% of lesions. Certain high-risk patients with DCIS may have a 25% risk of developing recurrent DCIS or IBC, even after surgical resection. The development of breast cancer elicits a strong immune response, which brings to prominence the numerous advantages associated with immune-based cancer prevention over drug-based chemoprevention, supported by the success of dendritic cell vaccines targeting HER2-expressing BC. Vaccination against BC to prevent or interrupt the process of BC development remains elusive but is a viable option. Vaccination to intercept preinvasive or premalignant breast conditions may be possible by interrupting the expression pattern of various oncodrivers. Growth factors may also function as potential immune targets to prevent breast cancer progression. Furthermore, neoantigens also serve as effective targets for interception by virtue of strong immunogenicity. It is noteworthy that the immune response also needs to be strong enough to result in target lesion elimination to avoid immunoediting as it may occur in IBC arising from DCIS. Overall, if the issue of vaccine targets can be solved by interrupting premalignant lesions, there is a potential to prevent the development of IBC.

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Th1 cytokine interferon gamma improves response in HER2 breast cancer by modulating the ubiquitin proteasomal pathway

Cited by 28 publications

References 42 publications

Identification of Immunogenic MHC Class II Human HER3 Peptides that Mediate Anti-HER3 CD4+ Th1 Responses and Potential Use as a Cancer Vaccine

Identification of Immunogenic MHC Class II Human HER3 Peptides that Mediate Anti-HER3 CD4+ Th1 Responses and Potential Use as a Cancer Vaccine

Intratumoral delivery of dendritic cells plus anti-HER2 therapy triggers both robust systemic antitumor immunity and complete regression in HER2 mammary carcinoma

Intercepting Premalignant, Preinvasive Breast Lesions Through Vaccination

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