Noninvasive in vivo deoxycytidine kinase (dCK)-PET identifies tumor-draining lymph nodes upon immune checkpoint inhibitor therapy

TL;DR

This study shows that PET imaging with [18F]FAC and [18F]CFA can detect immune cell activation in tumor-draining lymph nodes during immunotherapy, offering a noninvasive way to monitor treatment response.

Contribution

The study introduces [18F]FAC and [18F]CFA as novel radiotracers for noninvasive monitoring of immune activation in tumor-draining lymph nodes during immunotherapy.

Findings

Activated T cells and macrophages show significantly higher [18F]FAC uptake in vitro.

CIT induces increased [18F]FAC uptake in tumor-draining lymph nodes in preclinical and clinical settings.

Ex vivo analysis confirms elevated [18F]FAC uptake in T cells from CIT-treated tumor-draining lymph nodes.

Abstract

Efficient application of immunotherapy necessitates advanced whole-body imaging techniques to monitor sites of immune cell activation. Deoxycytidine kinase (dCK), a key enzyme in the deoxynucleotide salvage pathway, is upregulated in proliferating immune cells and can be targeted by the radiotracers [18F]FAC (preclinical) and [18F]CFA (clinical), allowing for noninvasive monitoring of immune activation in lymphatic organs via positron emission tomography (PET). In this study, we aimed to assess the efficacy of [18F]FAC in detecting immune activation upon immune checkpoint inhibitor therapy (CIT). In vitro, activated T cells and macrophages exhibited significantly higher [18F]FAC uptake compared to their naïve counterparts. In vivo, preclinical [18F]FAC-PET/MRI revealed a CIT-induced significant increase in [18F]FAC uptake in tumor-draining lymph nodes (TDLNs) compared to contralateral lymph nodes, independent of tumor responsiveness. This phenomenon was absent in TDLNs of sham-treated experimental mice. Ex vivo cell sorting further confirmed elevated [18F]FAC uptake in T cells from TDLNs following CIT. Consistently, [18F]CFA-PET/CT imaging in metastatic melanoma patients demonstrated CIT-induced enhanced regional LN uptake. Together, these findings establish a strong correlation between CIT-induced immune activation and [18F]FAC/[18F]CFA uptake, underscoring the critical role of TDLNs in cancer immuotherapy. The radiotracers [18F]FAC and [18F]CFA provide valuable tools for noninvasive monitoring of immune cell activation, potentially unveiling tumor-microenvironment-related resistance mechanisms and advancing the utility of PET imaging in immunotherapy monitoring and patient stratification.

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