Noninvasive Imaging of Immune Responses to Gauge Efficacy of Immunotherapy

Background and Aim: Immunotherapy using checkpoint-blockingantibodies against targets such as CTLA-4 and PD-1 can cure melanomaand non-small cell lung cancer in a subset of patients. The presence ofCD8+ T cells in the tumor correlates with improved survival. We aimedto develop a method to monitor the dynamics of CD8+ T cells in thetumor microenvironment in response to treatment to identify patterns ofresponse in responders and nonresponders.Methods: In this study, we report on how immuno-positron emissiontomography (immuno-PET) can visualize tumors by the detection ofinfiltrating lymphocytes. We also show how the longitudinal observationof individual animals distinguish responding tumors from those that do notrespond to therapy. In this line, we capitalized on the use of 89Zr-labeledPEGylated single-domain antibody fragments (VHHs) specific for CD8 totrack the presence of intratumoral CD8+ T cells in the immunotherapysusceptibleB16 melanoma model in response to checkpoint blockade.Results: The 89Zr-labeled PEGylated anti-CD8 VHH was found to be ableto detect the thymus and the secondary lymphoid structures as well as theintratumoral CD8+ T cells. Our data revealed that the animals respondedto CTLA-4 therapy displayed a homogeneous distribution of the anti-CD8+ PET signal throughout the tumor. However, more heterogeneousinfiltration of CD8+ T cells were found to correlate with faster tumorgrowth and worse responses. To support the validity of these observations,we exploited two different transplantable breast cancer models, in whichthe yielding results conformed with predictions based on the antimelanomaresponse. We also explored the dynamics and distributionof intratumoral CD8+ T cells and CD11b+ myeloid cells in responseto anti-PD-1 treatment in the anti-PD-1-responsive MC38 colorectalmouse adenocarcinoma model. Responders and nonresponders showedconsistent differences in the distribution of CD8+ and CD11b+ cells. PD-1treatment mobilized CD8+ T cells from the tumor periphery to a morecentral location. Only those tumors fully infiltrated by CD8+ T cells wenton to show a complete response. All tumors contained CD11b+ myeloidcells from the outset, followed by recruitment of additional CD11b+ cells.As tumors grew, the distribution of intratumoral CD11b+ cells becamemore heterogeneous. Shrinkage of tumors in responders correlated withan increase in the CD11b+ population in the center of the tumor.Conclusion: The changes in the distribution of CD8+ and CD11b+ cells asassessed by PET served as biomarkers to gauge the efficacy of checkpointblockade treatments. It may thus be possible to use immuno-PET andmonitor antitumor immune responses as a prognostic tool to predictpatient responses to checkpoint therapies.

کلیدواژه ها:

Immunotherapy ، Checkpoint blockade ، Immuno-PET ، single domain antibodies