IN VIVO SYNGENEIC TUMOR MODELS WITH ACQUIRED RESISTANCE TO ANTI-PD-1/PD-L1 THERAPIES

• Published in: Cancer immunology research 2022-08, Vol.10 (8), p.1013-1027
• Main Authors: Denis, Morgane, Grasselly, Chloé, Choffour, Pierre-Antoine, Wierinckx, Anne, Mathe, Doriane, Chettab, Kamel, Tourette, Anne, Talhi, Nolan, Bourguignon, Aurore, Birzele, Fabian, Kress, Elsa, Jordheim, Lars Petter, Klein, Christian, Matera, Eva Laure, Dumontet, Charles
• Format: Article
• Language: English
• Subjects: Life Sciences
• ISSN: 2326-6066; 2326-6074
• DOI: 10.1158/2326-6066.CIR-21-0802

Antibodies targeting PD-1 and PD-L1 have produced durable responses in a subset of cancer patients. However, a majority of these patients will ultimately relapse due to acquired resistance. To explore the underlying mechanisms of this secondary resistance, we developed five syngeneic murine tumor variants with acquired resistance to anti-PD-1 and/or PD-L1 antibodies in vivo. Resistant in vivo models were obtained by serial treatment/reimplantation cycles of the MC38 colorectal, MB49 and MBT2 bladder, TyrNras melanoma and RENCA kidney models. Tumor immune infiltrates were characterized for wild type and resistant tumors using spectral cytometry and their molecular alterations analyzed using RNA-seq analyses. Alterations in the tumor immune microenvironment were strongly heterogeneous amongst resistant models, involving select lymphoid and/or myeloid subpopulations. Molecular alterations in resistant models included previously identified pathways as well as novel candidate genes found to be deregulated in several resistant models. Among these, Serpinf1, coding for Pigment Epithelial Derived Factor was further explored in the MC38 and the MBT2 models. Overexpression of Serpinf1 induced resistance to anti-PD-1 antibodies in the MC38 model, whereas knock-down of Serpinf1 sensitized this model as well as the primarily resistant MBT2 model. Serpinf1 overexpression was associated with increased production of free fatty acids and reduced activation of CD8+ cells, while orlistat, a compound that reduces the production of free fatty acids, reversed resistance to anti-PD-1 therapy. Our results suggest that a panel of syngeneic resistant models constitutes a useful tool to model the heterogeneity of resistance mechanisms encountered in the clinic.