Postdoctoral Fellowship Center for Advanced Studies and Technologies (CAST), “G. d’Annunzio” University of Chieti Chieti, Abruzzi, Italy
Disclosure(s):
Maria Tredicine, PhD: No financial relationships to disclose
Introduction/Rationale: PD-1 inhibition has revolutionized cancer therapy. However, despite the initial success of immune checkpoint inhibitors (ICIs) across several cancer types, this approach remains ineffective for most patients. Studies indicate that T cell exhaustion (Tex) is epigenetically encoded, and PD-1 blockade can only partially restore T cell activity. Chronic, non-resolving inflammation fosters an immunosuppressive tumor microenvironment (TME) that promotes T cell exhaustion and contributes to immunotherapy resistance. Our goal is to promote the resolution of inflammation through the administration of D-series resolvins (RvDs) to restore leukocyte antitumor activity and reverse immunosuppression and immunotherapy resistance within the TME.
Methods: We employed in vitro and in vivo models of HPV-positive head and neck cancer (HNC). Activated CD8⁺ T cells, isolated from human peripheral blood, were co-cultured with either tumor cell lines or primary tumor cells derived from patient biopsies. Cultures were stimulated with RvD5, a pro-resolving lipid mediator that promotes the resolution of inflammation. Syngeneic and NGS mouse models were treated with RvD5, anti-PD-1, and/or anti-CTLA-4 immunotherapies. Samples were analyzed by flow cytometry, cytokine profiling, lipidomics, bulk RNA sequencing, and single-cell RNA sequencing.
Results: We found that RvD5 reduced PD-1 expression on T cells and PD-L1 expression on cancer cells, thereby restoring T cell antitumor functions by delaying their differentiation into Tex. In vivo, RvD5 inhibited tumor growth. Notably, when combined with anti-PD-1 therapy, RvD5 enhanced tumor response rates, suggesting that shifting cancer-associated inflammation toward resolution can improve ICI efficacy.
Conclusion: Thus, RvD5 suppresses tumor growth by dampening inflammation and delaying T cell exhaustion within the TME. By reshaping CD8⁺ T cell responses, RvDs may represent a promising therapeutic strategy to strengthen antitumor immunity and overcome resistance to immunotherapy.
