Abstract 4200: Characterization of acquired resistant models to therapies targeting the PD-1/PD-L1 axis demonstrates model-dependent mechanisms

• Published in: Cancer research (Chicago, Ill.) Ill.), 2022-06, Vol.82 (12_Supplement), p.4200-4200
• Main Authors: Denis, Morgane, Grasselly, Chloé, Choffour, Pierre-Antoine, Wierinckx, Anne, Mathé, Doriane, Chettab, Kamel, Tourette, Anne, Talhi, Nolan, Birzele, Fabian, Kress, Elsa, Jordheim, Lars Petter, Klein, Christian, Matera, Eva-Laure, Dumontet, Charles
• Format: Article
• Language: English
• ISSN: 1538-7445; 1538-7445
• DOI: 10.1158/1538-7445.AM2022-4200

The underlying mechanisms of acquired resistance to the immune checkpoint inhibitory (ICI) PD-1 and PD-L1 antibodies remain largely unknown and need to be further explored. In this study, we established and analyzed robust ICI resistance in in vivo models in order to identify new mechanisms and genes involved in acquired resistance. Resistant in vivo models were obtained by serial treatment/reimplantation cycles in immunocompetent mice bearing MC38, MB49, MBT2, TyrNRas or RENCA tumors. Spectral cytometry was applied to characterize modifications in the tumor immune microenvironment. RNAseq analyses were performed to identify differences in gene expression profiles between sensitive parental models compared to their resistant counterparts. Alterations in the tumor immune microenvironment were highly heterogeneous amongst resistant models, and are thus considered representative for the diversity expected in patients. Each resistant model displayed multiple modifications in the tumor immune infiltrate in comparison to the respective wild type model, involving selected lymphoid and/or myeloid subpopulations. For instance, in anti-PD-1 and anti-PD-L1 resistant MC38 models, we observed a remarkable increase of FoxP3+CD4+ T cells while CD8+ Tem cells were decreased in anti PD-1 resistant models. We also found that the type 2 macrophage content was increased in the anti PD-1 resistant MB49 model. Gene profiling analyses demonstrated the variability associated with acquisition of a resistance phenotype. Alterations of pathways previously reported to be associated with resistance to ICIs were observed in some of our models while other genes appeared to be highly de-regulated in several models. For instance, in the anti PD-L1 resistant MBT2 model many signaling pathways were found to be up-regulated, such as HIF1α, TGFβ, and ERK/MAPK signaling. Several therapeutic combinations, in particular targeting alternative immune checkpoints, were found to reverse the resistance phenotype in selected models. Moreover, in accordance with flow cytometry results, in the anti PD-1 resistant MC38 model we observed a significant delay in tumor growth when a TNFR1 antibody was combined with a PD-1 antibody (p