Download This Paper
Preprints with The Lancet is a collaboration between The Lancet Group of journals and SSRN to facilitate the open sharing of preprints for early engagement, community comment, and collaboration. Preprints available here are not Lancet publications or necessarily under review with a Lancet journal. These preprints are early-stage research papers that have not been peer-reviewed. The usual SSRN checks and a Lancet-specific check for appropriateness and transparency have been applied. The findings should not be used for clinical or public health decision-making or presented without highlighting these facts. For more information, please see the FAQs.
Chronic TCR-MHC (Self)-Interactions Limit the Functional Potential of TCR Affinity-Increased CD8 T Lymphocytes
64 Pages Posted: 11 Jun 2019
More...Abstract
Affinity-optimized T cell receptor (TCR)-engineered lymphocytes targeting tumor antigens can mediate potent antitumor responses in cancer patients, but also bear substantial risks for off-target toxicities. Identifying adverse events in relation to enhanced TCR-pMHC affinity is therefore becoming essential to improve and ensure the safety of candidate TCRs for clinical trials. Here, we describe a central role of HLA-A2 expression per se in predisposing redirected HLA-A2/NY-ESO-1-specific CD8 T cells to chronic activation followed by T cell hyporesponsiveness, depending on TCR affinity. HLA-A2pos but not HLA-A2neg CD8 T cells engineered with increased-affinity TCRs displayed TCR/CD3 downmodulation and impaired TCR signaling, even in the absence of cognate antigen. The observed strong T cell activation was associated to enhanced upregulation of c-CBL and multiple inhibitory receptors, and preceded TCR affinity-mediated functional hyporesponsiveness. This stepwise activation-to-hyporesponsive state did not involve the PD-1/PDL-1 regulatory axis, but was recapitulated once affinity-increased HLA-A2neg T cells were chronically exposed to HLA-A2pos-expressing target cells. Collectively, our observations indicate that sustained interactions between affinity-increased TCRs and self-MHC molecules directly adjust the functional potential of T cells, independently of specific peptide. Such TCR-MHC (self)-interactions have potential implications for the design of affinity-improved TCRs for adoptive T cell-based therapies.
Funding: This study was sponsored and supported by the Department of Oncology (University of Lausanne), the ISREC Foundation (Switzerland), and the Swiss National Science Foundation (310030-159417, 310030-179280).
Declaration of Interest: The authors report no conflict of interest.
Ethical Approval: Human peripheral blood cells were obtained from healthy donors of the Interregional Blood Transfusion SRC Ltd. All blood donors had previously completed the Swiss National Medical questionnaire to verify that they fulfilled the criteria for blood donation and provided written informed consent for the use of blood samples in medical research after anonymization.
Keywords: human, immunotherapy, preclinical testing, CD8 T cells, NY-ESO-1 tumor antigen, TCR engineered, TCR affinity optimization, TCR-A2 (self)-interactions, TCR/CD3 complex, T cell signaling, T cell functionality
Suggested Citation: Suggested Citation