Background Achieving robust responses with adoptive cell therapy for the treatment of the highly lethal pancreatic ductal adenocarcinoma (PDA) has been elusive. We previously showed that T cells engineered to express a mesothelin-specific T cell receptor (TCR Msln) accumulate in autochthonous PDA, mediate therapeutic antitumor activity, but fail to eradicate tumors in part due to acquisition of a dysfunctional exhausted T cell state. Methods Here, we investigated the role of immune checkpoints in mediating TCR engineered T cell dysfunction in a genetically engineered PDA mouse model. The fate of engineered T cells that were either deficient in PD-1, or transferred concurrent with antibodies blocking PD-L1 and/or additional immune checkpoints, were tracked to evaluate persistence, functionality, and antitumor activity at day 8 and day 28 post infusion. We performed RNAseq on engineered T cells isolated from tumors and compared differentially expressed genes to prototypical endogenous exhausted T cells. Results PD-L1 pathway blockade and/or simultaneous blockade of multiple coinhibitory receptors during adoptive cell therapy was insufficient to prevent engineered T cell dysfunction in autochthonous PDA yet resulted in subclinical activity in the lung, without enhancing anti-tumor immunity. Gene expression analysis revealed that ex vivo TCR engineered T cells markedly differed from in vivo primed endogenous effector T cells which can respond to immune checkpoint inhibitors. Early after transfer, intratumoral TCR engineered T cells acquired a similar molecular program to prototypical exhausted T cells that arise during chronic viral infection, but the molecular programs later diverged. Intratumoral engineered T cells exhibited decreased effector and cell cycle genes and were refractory to TCR signaling. Conclusions Abrogation of PD-1 signaling is not sufficient to overcome TCR engineered T cell dysfunction in PDA. Our study suggests that contributions by both the differentiation pathways induced during the ex vivo T cell engineering process and intratumoral suppressive mechanisms render engineered T cells dysfunctional and resistant to rescue by blockade of immune checkpoints.
|Original language||English (US)|
|Journal||Journal for ImmunoTherapy of Cancer|
|State||Published - Feb 24 2022|
Bibliographical noteFunding Information:
Funding MRR is supported by NIH T32 AI007313 and the Dennis W. Watson fellowship. ALB was supported by an American Association of Immunologists (AAI) postdoctoral fellowship. IMS received support from the American Cancer Society Institutional Research Grant (124166-IRG-58-001-55-IRG65), Randy Shaver Cancer Research Fund, and pilot awards from the Masonic Cancer Center (University of Minnesota Medical School). Support was also provided by the National Cancer Institute, CA255039 and CA249393 (IMS), CA018029 and CA033084 (PDG), and CA161112 and CA224193 (SRH), and Pancreatic Cancer Action Network, 16-65-GREE (PDG), 17-85-HING (SRH), 17-20-25-STRO (IMS), and 19-35-STRO (IMS). PDG is also supported by a Stand up to Cancer Lustgarten grant as well as received support from Juno Therapeutics, a Celgene company.
- cell engineering
- tumor microenvironment
- Immune Checkpoint Inhibitors/pharmacology
- Pancreatic Neoplasms/drug therapy
PubMed: MeSH publication types
- Research Support, Non-U.S. Gov't
- Journal Article
- Research Support, N.I.H., Extramural