TY - JOUR
T1 - The β-carboline Harmine improves the therapeutic benefit of anti-PD1 in melanoma by increasing the MHC-I-dependent antigen presentation
AU - Noman, Muhammad Zaeem
AU - Bocci, Irene Adelaide
AU - Karam, Manale
AU - Moer, Kris Van
AU - Bosseler, Manon
AU - Kumar, Akinchan
AU - Berchem, Guy
AU - Auclair, Christian
AU - Janji, Bassam
N1 - Funding
This work was supported by grants from the Luxembourg National Research Fund (CORE-C18/BM/12670304/COMBATIC; BRIDGES2020/BM/15412275/SMART-COMBO; BRIDGES2021/BM/16358198/TRICK-ALDH and INTER/EUROSTARS21/16896480/C2I), FNRS-Televie (7.4560.21-INCITE21; 7.4559.21-IMPACT21 and 7.4579.20-CD73), Fondation Recherche Cancer et Sang, Luxembourg (INCOM BIOM), Kriibskrank Kanner Foundation; Luxembourg (Neuroimmunotherapy II-2019); Action LION-S Vaincre le Cancer Luxembourg (AUTOKIR-2019, COMBO-KD2020 and AB-2020); Roche Pharma (2020) and Stiftelsen Cancera (2022).
PY - 2022/11/15
Y1 - 2022/11/15
N2 - Harmine is a dual-specificity tyrosine-regulated kinase 1A (DYRK1A) inhibitor that displays a number of biological and pharmacological properties. Also referred to as ACB1801 molecule, we have previously reported that harmine increases the presentation of major histocompatibility complex (MHC)-I-dependent antigen on melanoma cells. Here, we show that ACB1801 upregulates the mRNA expression of several proteins of the MHC-I such as Transporter Associated with antigen Processing TAP1 and 2, Tapasin and Lmp2 (hereafter referred to as MHC-I signature) in melanoma cells. Treatment of mice bearing melanoma B16-F10 with ACB1801 inhibits the growth and weight of tumors and induces a profound modification of the tumor immune landscape. Strikingly, combining ACB1801 with anti-PD1 significantly improves its therapeutic benefit in B16-F10 melanoma-bearing mice. These results suggest that, by increasing the MHC-I, ACB1801 can be combined with anti-PD1/PD-L1 therapy to improve the survival benefit in cancer patients displaying a defect in MHC-I expression. This is further supported by data showing that i) high expression levels of TAP1, Tapasin and Lmp2 was observed in melanoma patients that respond to anti-PD1; ii) the survival is significantly improved in melanoma patients who express high MHC-I signature relative to those expressing low MHC-I signature; and iii) high expression of MHC-I signature in melanoma patients was correlated with increased expression of CD8 and NK cell markers and overexpression of proinflammatory chemokines involved in the recruitment of CD8+ T cells.
AB - Harmine is a dual-specificity tyrosine-regulated kinase 1A (DYRK1A) inhibitor that displays a number of biological and pharmacological properties. Also referred to as ACB1801 molecule, we have previously reported that harmine increases the presentation of major histocompatibility complex (MHC)-I-dependent antigen on melanoma cells. Here, we show that ACB1801 upregulates the mRNA expression of several proteins of the MHC-I such as Transporter Associated with antigen Processing TAP1 and 2, Tapasin and Lmp2 (hereafter referred to as MHC-I signature) in melanoma cells. Treatment of mice bearing melanoma B16-F10 with ACB1801 inhibits the growth and weight of tumors and induces a profound modification of the tumor immune landscape. Strikingly, combining ACB1801 with anti-PD1 significantly improves its therapeutic benefit in B16-F10 melanoma-bearing mice. These results suggest that, by increasing the MHC-I, ACB1801 can be combined with anti-PD1/PD-L1 therapy to improve the survival benefit in cancer patients displaying a defect in MHC-I expression. This is further supported by data showing that i) high expression levels of TAP1, Tapasin and Lmp2 was observed in melanoma patients that respond to anti-PD1; ii) the survival is significantly improved in melanoma patients who express high MHC-I signature relative to those expressing low MHC-I signature; and iii) high expression of MHC-I signature in melanoma patients was correlated with increased expression of CD8 and NK cell markers and overexpression of proinflammatory chemokines involved in the recruitment of CD8+ T cells.
KW - anti-PD1 Immunotherapy
KW - DYRK1A
KW - harmine
KW - inflammatory chemokines
KW - melanoma
KW - MHC-I antigen presentation
KW - T lymphocyte and NK cells infiltration
UR - http://www.scopus.com/inward/record.url?scp=85143152821&partnerID=8YFLogxK
UR - https://pubmed.ncbi.nlm.nih.gov/36458012
U2 - 10.3389/fimmu.2022.980704
DO - 10.3389/fimmu.2022.980704
M3 - Article
C2 - 36458012
SN - 1664-3224
VL - 13
JO - Frontiers in Immunology
JF - Frontiers in Immunology
M1 - 980704
ER -