Melisa B Nicoud1, Mónica A Táquez Delgado1, María de la Paz Sarasola1, Agustina Vidal2, Daniela Speisky3, Graciela A Cremaschi4, Helena A Sterle4, Vanina A Medina5. 1. Laboratory of Tumour Biology and Inflammation, Institute for Biomedical Research (BIOMED), School of Medical Sciences, Pontifical Catholic University of Argentina (UCA), National Scientific and Technical Research Council (CONICET), Buenos Aires, Argentina. 2. Institute for Biomedical Research (BIOMED), School of Medical Sciences, Pontifical Catholic University of Argentina (UCA), National Scientific and Technical Research Council (CONICET), Buenos Aires, Argentina. 3. Pathology Department, British Hospital, Buenos Aires, Argentina. 4. Neuroimmunomodulation and Molecular Oncology Division, Institute for Biomedical Research (BIOMED), School of Medical Sciences, Pontifical Catholic University of Argentina (UCA), National Scientific and Technical Research Council (CONICET), Buenos Aires, Argentina. 5. Laboratory of Tumour Biology and Inflammation, Institute for Biomedical Research (BIOMED), School of Medical Sciences, Pontifical Catholic University of Argentina (UCA), National Scientific and Technical Research Council (CONICET), Buenos Aires, Argentina. vanina_medina@uca.edu.ar.
Abstract
BACKGROUND: The histamine H4 receptor (H4R) is preferentially expressed in immune cells and is a potential therapeutic target for inflammatory and autoimmune diseases. This study aimed at further exploring the role of H4R in the immunobiology of breast cancer. METHODS: We used wild type (WT) and H4R deficient mice (KO) to evaluate whether H4R genotypes show a different distribution of T cell subsets in spleens, tumours and tumour draining lymph nodes (TDLN) in a syngeneic ErbB2-positive breast cancer model developed orthotopically with LM3 cells and its impact on tumour growth. RESULTS: The presence of tumours had a differential impact on the distribution of T cells in TDLN from KO mice compared to WT ones. At day 21 post-inoculation (p.i.) of cells, despite no significant changes in the tumour weight, TDLN from KO mice showed a significantly increased proportion of CD8+ T cells compared to WT mice. At day 38 p.i. of cells a reduced tumour weight was evident in KO mice. This was accompanied by a decreased proportion of CD4+CD25+FoxP3+ regulatory T cells in TDLN of KO compared to WT mice. Tumour-bearing KO mice showed a better survival compared to WT mice. CONCLUSIONS: H4R-mediated mechanisms may modulate the immune tumour microenvironment, promoting an immunosuppressive milieu. Results suggest that H4R could be explored as an immunotherapeutic target with potential benefit in combination with immunotherapy. Further preclinical and clinical studies are necessary to confirm this hypothesis.
BACKGROUND: The histamine H4 receptor (H4R) is preferentially expressed in immune cells and is a potential therapeutic target for inflammatory and autoimmune diseases. This study aimed at further exploring the role of H4R in the immunobiology of breast cancer. METHODS: We used wild type (WT) and H4R deficient mice (KO) to evaluate whether H4R genotypes show a different distribution of T cell subsets in spleens, tumours and tumour draining lymph nodes (TDLN) in a syngeneic ErbB2-positive breast cancer model developed orthotopically with LM3 cells and its impact on tumour growth. RESULTS: The presence of tumours had a differential impact on the distribution of T cells in TDLN from KO mice compared to WT ones. At day 21 post-inoculation (p.i.) of cells, despite no significant changes in the tumour weight, TDLN from KO mice showed a significantly increased proportion of CD8+ T cells compared to WT mice. At day 38 p.i. of cells a reduced tumour weight was evident in KO mice. This was accompanied by a decreased proportion of CD4+CD25+FoxP3+ regulatory T cells in TDLN of KO compared to WT mice. Tumour-bearing KO mice showed a better survival compared to WT mice. CONCLUSIONS:H4R-mediated mechanisms may modulate the immune tumour microenvironment, promoting an immunosuppressive milieu. Results suggest that H4R could be explored as an immunotherapeutic target with potential benefit in combination with immunotherapy. Further preclinical and clinical studies are necessary to confirm this hypothesis.
Entities:
Keywords:
Antitumour immunity; Breast cancer; Histamine H4 receptor; T regulatory cells
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