Caffeine-enhanced anti-tumor activity of anti-PD1 monoclonal antibody.

Tej, Gullanki Naga Venkata Charan; Neogi, Kaushik; Nayak, Prasanta Kumar

Tej, Gullanki Naga Venkata Charan; Neogi, Kaushik; Nayak, Prasanta Kumar.

Afiliación

Tej GNVC; Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi, Uttar Pradesh, India.
Neogi K; Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi, Uttar Pradesh, India.
Nayak PK; Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi, Uttar Pradesh, India. Electronic address: pknayak.phe@iitbhu.ac.in.

Int Immunopharmacol ; 77: 106002, 2019 Dec.

Article en En | MEDLINE | ID: mdl-31711939

RESUMEN

Antibodies targeting PD1 receptor have emerged as a promising therapeutic strategy against multiple types of solid cancers. However, relatively low complete response rates observed with anti-PD1 mAb monotherapy emphasizes the importance of testing new immunotherapeutic combinations. The production of extracellular adenosine in solid tumors was recently identified as a major immunosuppressive pathway, targeting this pathway would enhance the therapeutic activity of anti-PD1 mAbs. In this study, we evaluated the anti-tumor activity and mechanism of action of caffeine and anti-PD1 mAb combination therapy against carcinogen- and cell line-induced tumors. Our results demonstrate that combination therapy enhanced the anti-tumor activity and prolonged overall survival period against 3-MCA-induced tumors. In addition, combination therapy showed a significant anti-tumor activity against B16F10 melanoma tumors. We found that combination therapy showed additive increase in infiltration of CD4+ and CD8+ T lymphocytes into the B16F10 melanoma tumors. On the other hand, combination therapy showed significant decrease in infiltration of CD4+CD25+ T regulatory cells. We further investigated whether the observed anti-tumor effect of caffeine and anti-PD1 mAb combination therapy is mediated through the release of cytokines. We found that caffeine and anti-PD1 mAb combination therapy significantly increased intra-tumoral TNF-α and IFN-Î³ levels. Our work suggests that administration of caffeine and anti-PD1 mAb harness the therapeutic potential of effector T cells in vivo possibly due to combined blockade of PD1 and adenosine-A2A receptor pathway. This study provides the scientific basis for testing combination regimens of caffeine and anti-PD1 mAbs for sustained tumor control in cancer patients.

Asunto(s)

Anticuerpos Monoclonales/farmacología; Antineoplásicos/farmacología; Cafeína/farmacología; Melanoma/tratamiento farmacológico; Animales; Linfocitos T CD4-Positivos/efectos de los fármacos; Linfocitos T CD4-Positivos/metabolismo; Linfocitos T CD8-positivos/efectos de los fármacos; Linfocitos T CD8-positivos/metabolismo; Línea Celular Tumoral; Terapia Combinada/métodos; Femenino; Inmunosupresores/farmacología; Inmunoterapia/métodos; Interferón gamma/metabolismo; Melanoma/metabolismo; Ratones; Ratones Endogámicos C57BL; Factor de Necrosis Tumoral alfa/metabolismo

Palabras clave

Adenosine-A2A receptor pathway; Anti-PD1 mAb; Anti-tumor immune response; Caffeine; Cytotoxic T lymphocytes; PD-1 pathway

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Cafeína / Melanoma / Anticuerpos Monoclonales / Antineoplásicos Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Int Immunopharmacol Asunto de la revista: ALERGIA E IMUNOLOGIA / FARMACOLOGIA Año: 2019 Tipo del documento: Article País de afiliación: India Pais de publicación: Países Bajos

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