Nanofitins targeting heat shock protein 110: An innovative immunotherapeutic modality in cancer. Issue 12 (4th March 2021)

• Record Type: Journal Article
• Authors: Marcion, Guillaume; Hermetet, François; Neiers, Fabrice; Uyanik, Burhan; Dondaine, Lucile; Dias, Alexandre M. M.; Da Costa, Laurène; Moreau, Mathieu; Bellaye, Pierre‐Simon; Collin, Bertrand; Gobbo, Jessica; Briand, Loïc; Seigneuric, Renaud; Kitten, Olivier; Cinier, Mathieu; Garrido, Carmen
• Is Part Of: International journal of cancer. Volume 148:Issue 12(2021)
• Page Start: 3019
• Page End: 3031
• Publication Date: 2021-03-04
• Subjects: anticancer‐targeted therapy -- HSP110 -- Nanofitins -- small peptide molecules; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.33485
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract: 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. Abstract : What's new? Inactivating HSP110 mutations in colorectal cancers have been correlated with excellent prognosis and revealed the ability of HSP110 to favor the formation of tolerogenic macrophages. As an alternative to neutralizing antibodies, here the authors selected Nanofitins (scaffold ~7 kDa‐proteins) able to target HSP110 with subnanomolar affinity. The highest‐affinity Nanofitin, A‐C2, was shown to accumulate within the tumor and reduce tumor growth in vivo through a mechanism involving macrophages. The results also demonstrated A‐C2 complementarity with PD‐L1 checkpoint inhibitors, an immunotherapeutic approach currently in use. Altogether, this work shows the potential of Nanofitins as therapeutic lead compounds.