Submitted by Livia Harriman on Fri, 02/12/2022 - 10:44
An IL-2 variant that is more tolerant of the acidic tumour environment improves immunotherapy in mice with melanoma.
Researchers have created a variant of human IL-2 that can overcome challenges it experiences in the low-pH environment of tumours, boosting its ability to promote CD8 T cell and natural killer (NK) cell functions during cancer immunotherapy. The mutated cytokine’s in vivo efficacy was established in mice with melanoma.
IL-2 immunotherapy has less impact on the tumour microenvironment, which typically has a low pH near 6. This acidity impairs IL-2’s ability to bind to the IL-2Rα receptor chain and subsequently blocks the cytokine’s capacity to encourage CD8 T cell and NK cell responses.
The new study by Silvia Gaggero and colleagues looks to make IL-2 therapy more effective under acidic conditions. To do so, they screened for IL-2 variants with mutations that would enable better receptor binding in acidic environments. They identified one such variant, called Switch-2, with higher binding affinity in low pH environments. They then showed that the Switch-2 IL-2 variant could activate CD8 T cells and NK cells in mouse models of melanoma.
“By exploiting directed evolution, we improved the tissue-specific activity, efficacy and systemic toxicity profile of IL-2, defining Switch-2 as a potential new immunotherapy for cancer, alone or in combination with checkpoint blockade or adoptive cell therapy,” -the authors write.
They also note that since IL-2 is not the only cytokine responsive to pH nor the only one being explored for cancer immunotherapy, the techniques could potentially be used to support the development of acid-tolerant variants of other cytokines used in cancer treatments.
This work was jointly led by Suman MITRA (INSERM Lille), Ignacio Moraga (University of Dundee), and Rahul Roychoudhuri (University of Cambridge).
The published paper is available here.
About our author
Dr Rahul Roychoudhuri
Rahul Roychoudhuri is an Associate Professor at the University of Cambridge Department of Pathology and Director of Studies in Pathology at St Catherine’s College. He is the Theme Lead in Infection and Immunity at the School of the Biological Sciences.
Find out more about Rahul here.
Keep up with Rahul on Twitter @RoychoudhuriLab