Imaging Memory T-Cells Stratifies Response to Adjuvant Metformin Combined with αPD-1 Therapy.
Julian L GoggiSiddesh V HartimathShivashankar KhanapurBoominathan RamasamyZan Feng ChinPeter ChengHui Xian ChinYou Yi HwangEdward G RobinsPublished in: International journal of molecular sciences (2022)
The low response rates associated with immune checkpoint inhibitor (ICI) use has led to a surge in research investigating adjuvant combination strategies in an attempt to enhance efficacy. Repurposing existing drugs as adjuvants accelerates the pace of cancer immune therapy research; however, many combinations exacerbate the immunogenic response elicited by ICIs and can lead to adverse immune-related events. Metformin, a widely used type 2 diabetes drug is an ideal candidate to repurpose as it has a good safety profile and studies suggest that metformin can modulate the tumour microenvironment, promoting a favourable environment for T cell activation but has no direct action on T cell activation on its own. In the current study we used PET imaging with [ 18 F]AlF-NOTA-KCNA3P, a radiopharmaceutical specifically targeting K V 1.3 the potassium channel over-expressed on active effector memory T-cells, to determine whether combining PD1 with metformin leads to an enhanced immunological memory response in a preclinical colorectal cancer model. Flow cytometry was used to assess which immune cell populations infiltrate the tumours in response to the treatment combination. Imaging with [ 18 F]AlF-NOTA-KCNA3P demonstrated that adjuvant metformin significantly improved anti-PD1 efficacy and led to a robust anti-tumour immunological memory response in a syngeneic colon cancer model through changes in tumour infiltrating effector memory T-cells.
Keyphrases
- working memory
- type diabetes
- early stage
- pet imaging
- flow cytometry
- high resolution
- stem cells
- dendritic cells
- regulatory t cells
- cardiovascular disease
- squamous cell carcinoma
- adipose tissue
- drug delivery
- photodynamic therapy
- cell therapy
- young adults
- drug induced
- mass spectrometry
- cancer therapy
- metabolic syndrome
- pet ct
- smoking cessation
- genetic diversity