Immune Profiles Linked to Response and Resistance in Endometrial Cancer Treatment
A biomarker analysis of a phase 2 trial evaluating the immune checkpoint inhibitor nivolumab with or without the multi-tyrosine kinase inhibitor cabozantinib in recurrent endometrial cancer identified immune signatures linked to clinical outcomes and treatment resistance.
Antiangiogenic agents combined with immune checkpoint inhibitors have become the standard of care for recurrent endometrial cancer following platinum-based chemotherapy. However, mechanisms of response and resistance to these therapies remain poorly understood. This study aimed to identify biomarkers associated with clinical outcomes in patients treated with nivolumab alone or in combination with cabozantinib.
Researchers conducted multidimensional immune monitoring using peripheral blood samples from 75 evaluable patients enrolled in a randomized phase 2 trial. Immune signatures were assessed using Olink proteomics, mass cytometry, tumor antigen-specific enzyme-linked immunosorbent assay (ELISA), and whole-exome tumor sequencing.
The results revealed distinct immune signatures associated with cabozantinib use, including increased plasma heme oxygenase-1 and reductions in vascular endothelial growth factor receptor 2, interleukin-12, and circulating plasmacytoid dendritic cells. Prior immunotherapy exposure and carcinosarcoma histology did not adversely affect clinical benefit or biomarker profiles. Tumors with high copy-number alterations showed increased plasma granzymes in response to combination treatment.
Poor overall and progression-free survival were associated with higher baseline levels of myeloid-related markers, including chemokine ligand 23 and macrophage colony-stimulating factor. In contrast, patients with favorable outcomes had elevated activated T-cell markers, including plasma inducible T-cell costimulator ligand and CD28, as well as spontaneous autoantibody titers to the tumor antigen NY-ESO-1. Patients who experienced severe adverse events had higher baseline levels of neutrophil-derived markers such as C-X-C motif chemokine ligand 1.
“Overall, this study highlights potential resistance and response mechanisms to nivolumab plus cabozantinib and suggests prioritizing combination treatment in patients with activated T-cell immunogenicity profiles while exploring future combinatorial therapies targeting myeloid populations to overcome resistance,” the authors concluded.
Reference
Roudko V, Del Valle DM, Radkevich E, et al. Immunological biomarkers of response and resistance to treatment with cabozantinib and nivolumab in recurrent endometrial cancer. J Immunother Cancer. 2025;13(2):e010541. doi:10.1136/jitc-2024-010541