Premium
Nanofitins targeting heat shock protein 110: An innovative immunotherapeutic modality in cancer
Author(s) -
Marcion Guillaume,
Hermetet François,
Neiers Fabrice,
Uyanik Burhan,
Dondaine Lucile,
Dias Alexandre M. M.,
Da Costa Laurène,
Moreau Mathieu,
Bellaye PierreSimon,
Collin Bertrand,
Gobbo Jessica,
Briand Loïc,
Seigneuric Renaud,
Kitten Olivier,
Cinier Mathieu,
Garrido Carmen
Publication year - 2021
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.33485
Subject(s) - in vivo , cancer research , in vitro , heat shock protein , immune system , tumor microenvironment , immunoprecipitation , cancer immunotherapy , colorectal cancer , antibody , cytotoxic t cell , immunotherapy , biology , cancer cell , chemistry , cancer , immunology , biochemistry , genetics , microbiology and biotechnology , gene
The presence of an inactivating heat shock protein 110 (HSP110) mutation in colorectal cancers has been correlated with an excellent prognosis and with the ability of HSP110 to favor the formation of tolerogenic (M2‐like) macrophages. These clinical and experimental results suggest a potentially powerful new strategy against colorectal cancer: the inhibition of HSP110. In this work, as an alternative to neutralizing antibodies, Nanofitins (scaffold ~7 kDa proteins) targeting HSP110 were isolated from the screening of a synthetic Nanofitin library, and their capacity to bind (immunoprecipitation, biolayer interferometry) and to inhibit HSP110 was analyzed in vitro and in vivo. Three Nanofitins were found to inhibit HSP110 chaperone activity. Interestingly, they share a high degree of homology in their variable domain and target the peptide‐binding domain of HSP110. In vitro, they inhibited the ability of HSP110 to favor M2‐like macrophages. The Nanofitin with the highest affinity, A‐C2, was studied in the CT26 colorectal cancer mice model. Our PET/scan experiments demonstrate that A‐C2 may be localized within the tumor area, in accordance with the reported HSP110 abundance in the tumor microenvironment. A‐C2 treatment reduced tumor growth and was associated with an increase in immune cells infiltrating the tumor and particularly cytotoxic macrophages. These results were confirmed in a chicken chorioallantoic membrane tumor model. Finally, we showed the complementarity between A‐C2 and an anti‐PD‐L1 strategy in the in vivo and in ovo tumor models. Overall, Nanofitins appear to be promising new immunotherapeutic lead compounds.