Background: Chemotherapy is currently evaluated in order to enhance the efficacy of immune checkpoint blockade (ICB) therapy in colorectal cancer. However, the mechanisms by which these drugs could synergize with ICB remains unclear. The impact of chemotherapy on the PD-1/PD-L1 pathway and the resulting anticancer immune responses was assessed in two mouse models of colorectal cancer and validated in tumor samples from metastatic colorectal cancer patients that received neoadjuvant treatment. We demonstrated that 5-Fluorouracil plus Oxaliplatin (Folfox) drove complete tumor cure in mice when combined to anti-PD-1 treatment, while each monotherapy failed. This synergistic effect relies on the ability of Folfox to induce tumor infiltration by activated PD-1+ CD8 T cells in a T-bet dependent manner. This effect was concomitantly associated to the expression of PD-L1 on tumor cells driven by IFN-γ secreted by PD-1+ CD8 T cells, indicating that Folfox triggers tumor adaptive immune resistance. Finally, we observed an induction of PD-L1 expression and high CD8 T cell infiltration in the tumor microenvironment of colorectal cancer patients treated by Folfox regimen. Our study delineates a molecular pathway involved in Folfox-induced adaptive immune resistance in colorectal cancer. The results strongly support the use of immune checkpoint blockade therapy in combination with chemotherapies like Folfox.

Gold phosphine complexes, such as auranofin, have been recognized for decades as antirheumatic agents. Clinical trials are now underway to validate their use in anticancer or anti-HIV treatments. However, their mechanisms of action remain unclear. A challenging question is whether the gold phosphine complex is a prodrug that is administered in an inactive precursor form or rather that the gold atom remains attached to the phosphine ligand during treatment. In this study, we present two novel gold complexes, which we compared to auranofin and to their phosphonium analogue. The chosen ligand is a phosphine-based smart probe, whose strong fluorescence depends on the presence of the gold atom. The in vitro biological action of the gold complexes and the phosphonium derivative were investigated, and a preliminary in vivo study in healthy zebrafish larvae allowed us to evaluate gold complex biodistribution and toxicity. The different analyses carried out showed that these gold complexes were stable and behaved differently from phosphonium and auranofin, both in vitro and in vivo. Two-photon microscopy experiments demonstrated that the cellular targets of these gold complexes are not the same as those of the phosphonium analogue. Moreover, despite similar IC50 values in some cancer cell lines, gold complexes displayed a low toxicity in vivo, in contrast to the phosphonium salt. They are therefore suitable for future in vivo investigations.

BackgroundIdiopathic pulmonary fibrosis (IPF) is a devastating disease characterised by myofibroblast proliferation and abnormal extracellular matrix accumulation in the lungs. Transforming growth factor (TGF)-β1 initiates key profibrotic signalling involving the SMAD pathway and the small heat shock protein B5 (HSPB5). Tripartite motif-containing 33 (TRIM33) has been reported to negatively regulate TGF-β/SMAD signalling, but its role in fibrogenesis remains unknown. The objective of this study was to elucidate the role of TRIM33 in IPF.MethodsTRIM33 expression was assessed in the lungs of IPF patients and rodent fibrosis models. Bone marrow-derived macrophages (BMDM), primary lung fibroblasts and 3D lung tissue slices were isolated from Trim33-floxed mice and cultured with TGF-β1 or bleomycin (BLM). Trim33 expression was then suppressed by adenovirus Cre recombinase (AdCre). Pulmonary fibrosis was evaluated in haematopoietic-specific Trim33 knockout mice and in Trim33-floxed mice that received AdCre and BLM intratracheally.ResultsTRIM33 was overexpressed in alveolar macrophages and fibroblasts in IPF patients and rodent fibrotic lungs. Trim33 inhibition in BMDM increased TGF-β1 secretion upon BLM treatment. Haematopoietic-specific Trim33 knockout sensitised mice to BLM-induced fibrosis. In primary lung fibroblasts and 3D lung tissue slices, Trim33 deficiency increased expression of genes downstream of TGF-β1. In mice, AdCre-Trim33 inhibition worsened BLM-induced fibrosis. In vitro, HSPB5 was able to bind directly to TRIM33, thereby diminishing its protein level and TRIM33/SMAD4 interaction.ConclusionOur results demonstrate a key role of TRIM33 as a negative regulator of lung fibrosis. Since TRIM33 directly associates with HSPB5, which impairs its activity, inhibitors of TRIM33/HSPB5 interaction may be of interest in the treatment of IPF.

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International audienceTen metal-based complexes and associated ligands have been synthesized and characterized. One of the metal ligands is a coumarin-phosphine derivative, which displays tunable fluorescence properties. The fluorescence is quenched in the case of the free ligand and ruthenium and osmium complexes, whereas it is strong for the gold complexes and phosphonium derivatives. These trends were rationalized by theoretical calculations, which revealed non-radiative channels involving a dark state for the free ligands that is lower in energy than the emissive state and is responsible for the quenching of fluorescence. For the Ru-II and Os-II complexes, other non-radiative channels involving the manifold of singlet and triplet excited states may play a role. The anti-proliferative properties of all the compounds were evaluated in cancer cell lines (SW480, HCT116, MDA-MB-231 and MCF-7); higher IC50 values were obtained for gold(I) complexes, with the free ligands being only weakly cytotoxic

Two new gold(i)-BODIPY-imidazole based trackable therapeutic bimetallic complexes have been synthesized and fully characterized. They display strong antiproliferative properties on several types of cancers including colon, breast, and prostate and one of them presents a significant anti-inflammatory effect. Additionally, the two compounds could be visualised in vitro by confocal microscopy in the submicromolar range.

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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.