The Impact of TCR Affinity on T-Cell Dysfunction and Immunotherapeutic Reprogramming in Solid Tumors
Technical Report,01 Jul 2018,30 Jun 2019
Memorial Sloan Kettering Cancer Research Center New York United States
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Although tumor-specific CD8 T cells are found in human tumors, cancers progress, indicating that these T cells are dysfunctional yet the regulatory mechanisms underlying tumor-specific T cell dysfunction remain poorly defined. T cell-mediated immune responses are triggered by T cell receptor TCR binding to peptide-major histocompatibility complex pMHC. In acute infections, affinity of TCRpMHC interaction is a critical determinant of T cell expansion and effector function. However, little is known about how tumor antigen affinity impacts T cell differentiation and dysfunction in progressing tumors. To investigate the functional and molecular programs determined by affinity, we generated an in vivo tumor model expressing altered peptide ligands APL derived from SV40 large T antigen epitope I TAG and recognized by TAG-specific transgenic CD8 T cells TCRTAG with varying functional avidity. While affinity did not impact T cell activation and differentiation in tumor draining lymph nodes, it drove distinct functional and molecular programs at the tumor site. Interestingly, key transcription factors and effector molecules were regulated by signal strength, preserving a cell-intrinsic functional program in T cells with low-affinity interactions. In contrast, certain hallmarks of T cell dysfunction, including the expression of inhibitory receptors e.g. PD1 and LAG3, were affinity-independent, revealing that even very weak TCR ligations can induce a typical exhaustion phenotype. Ongoing studies will define the transcriptional and epigenetic programs underlying the distinct dysfunctional T cell states in tumors driven by TCR signal strength.
- Medicine and Medical Research