Background. A combination of TLR9 agonists and an anti-PD-1 antibody has been reported to be effective in immunocompetent mice but the role of innate immunity has not yet been completely elucidated. Therefore, we investigated the contribution of the innate immune system to this combinatorial immunotherapeutic regimens using an immunodeficient mouse model in which the effector functions of innate immunity can clearly emerge without any interference from T lym-phocytes. Methods. Athymic mice xenografted with IGROV-1 human ovarian cells, reported to be sensitive to TLR9 agonist therapy, were treated with cytosine–guanine (CpG)-oligodeoxynucleo-tides (ODNs), an anti-PD-1 antibody or their combination. Results. We found that PD-1 blockade dampened CpG-ODN antitumor activity. In vitro studies indicated that the interaction between the anti-PD-1 antibody fragment crystallizable (Fc) domain and macrophage Fc receptors caused these immune cells to acquire an immunoregulatory phenotype, contributing to a decrease in the efficacy of CpG-ODNs. Accordingly, in vivo macrophage depletion abrogated the detrimental effect exerted by the anti-PD-1 antibody. Conclusion. Our data suggest that if TLR signaling is active in macro-phages, coadministration of an anti-PD-1 antibody can reprogram these immune cells towards a polarization state able to negatively affect the immune response and eventually promote tumor growth.

Macrophages impair TLR9 agonist antitumor activity through interacting with the anti-PD-1 antibody Fc domain / S. Camelliti, V. Le Noci, F. Bianchi, C. Storti, F. Arnaboldi, A. Cataldo, S. Indino, E. Jachetti, M. Figini, M.P. Colombo, A. Balsari, N. Gagliano, E. Tagliabue, L. Sfondrini, M. Sommariva. - In: CANCERS. - ISSN 2072-6694. - 13:16(2021 Aug 13), pp. 4081.1-4081.21. [10.3390/cancers13164081]

Macrophages impair TLR9 agonist antitumor activity through interacting with the anti-PD-1 antibody Fc domain

S. Camelliti
Primo
;
V. Le Noci;F. Bianchi;C. Storti;F. Arnaboldi;A. Cataldo;S. Indino;M. Figini;M.P. Colombo;A. Balsari;N. Gagliano;E. Tagliabue;L. Sfondrini
Penultimo
;
M. Sommariva
Ultimo
2021

Abstract

Background. A combination of TLR9 agonists and an anti-PD-1 antibody has been reported to be effective in immunocompetent mice but the role of innate immunity has not yet been completely elucidated. Therefore, we investigated the contribution of the innate immune system to this combinatorial immunotherapeutic regimens using an immunodeficient mouse model in which the effector functions of innate immunity can clearly emerge without any interference from T lym-phocytes. Methods. Athymic mice xenografted with IGROV-1 human ovarian cells, reported to be sensitive to TLR9 agonist therapy, were treated with cytosine–guanine (CpG)-oligodeoxynucleo-tides (ODNs), an anti-PD-1 antibody or their combination. Results. We found that PD-1 blockade dampened CpG-ODN antitumor activity. In vitro studies indicated that the interaction between the anti-PD-1 antibody fragment crystallizable (Fc) domain and macrophage Fc receptors caused these immune cells to acquire an immunoregulatory phenotype, contributing to a decrease in the efficacy of CpG-ODNs. Accordingly, in vivo macrophage depletion abrogated the detrimental effect exerted by the anti-PD-1 antibody. Conclusion. Our data suggest that if TLR signaling is active in macro-phages, coadministration of an anti-PD-1 antibody can reprogram these immune cells towards a polarization state able to negatively affect the immune response and eventually promote tumor growth.
CpG oligodeoxynucleotides (CpG-ODNs); Fc receptors; macrophages; ovarian cancer; programmed cell death 1 (PD-1); Toll-like receptor 9 (TLR9)
Settore MED/04 - Patologia Generale
Settore BIO/16 - Anatomia Umana
Settore BIO/17 - Istologia
13-ago-2021
Article (author)
File in questo prodotto:
File Dimensione Formato  
Cancers 2021.pdf

accesso aperto

Tipologia: Publisher's version/PDF
Dimensione 4.95 MB
Formato Adobe PDF
4.95 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/896284
Citazioni
  • ???jsp.display-item.citation.pmc??? 3
  • Scopus 8
  • ???jsp.display-item.citation.isi??? 7
social impact