Differential effects of PD-1 and CTLA-4 blockade on the melanoma-reactive CD8 T cell response.
Anastasia GangaevElisa A RozemanMaartje W RohaanOlga I IsaevaDaisy PhilipsSanne PatiwaelJoost H van den BergAntoni RibasDirk SchadendorfBastian SchillingTon N M SchumacherChristian U BlankJohn B A G HaanenPia KvistborgPublished in: Proceedings of the National Academy of Sciences of the United States of America (2021)
Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) have revolutionized the treatment of melanoma patients. Based on early studies addressing the mechanism of action, it was assumed that PD-1 blockade mostly influences T cell responses at the tumor site. However, recent work has demonstrated that PD-1 blockade can influence the T cell compartment in peripheral blood. If the activation of circulating, tumor-reactive T cells would form an important mechanism of action of PD-1 blockade, it may be predicted that such blockade would alter either the frequency and/or the breadth of the tumor-reactive CD8 T cell response. To address this question, we analyzed CD8 T cell responses toward 71 melanoma-associated epitopes in peripheral blood of 24 melanoma patients. We show that both the frequency and the breadth of the circulating melanoma-reactive CD8 T cell response was unaltered upon PD-1 blockade. In contrast, a broadening of the circulating melanoma-reactive CD8 T cell response was observed upon CTLA-4 blockade, in concordance with our prior data. Based on these results, we conclude that PD-1 and CTLA-4 blockade have distinct mechanisms of action. In addition, the data provide an argument in favor of the hypothesis that anti-PD-1 therapy may primarily act at the tumor site.
Keyphrases
- peripheral blood
- end stage renal disease
- ejection fraction
- newly diagnosed
- skin cancer
- chronic kidney disease
- prognostic factors
- circulating tumor
- electronic health record
- magnetic resonance imaging
- stem cells
- basal cell carcinoma
- magnetic resonance
- big data
- computed tomography
- mesenchymal stem cells
- circulating tumor cells
- combination therapy
- replacement therapy