Pan-cancer mapping of single T cell profiles reveals a TCF1:CXCR6-CXCL16 regulatory axis essential for effective anti-tumor immunity
Jerby-Arnon et al. (BioRxiv) doi: 10.1101/2021.10.31.466532
T cell exhaustion
Immune checkpoint blockade
The CD8+ tumor infiltrating lymphocytes (TILs) are pivotal player in the anti-tumor immunity but are often present in dysfunctional state (Philip, M. & Schietinger, Nat. Rev. Immunol. 2021). Jerby-Arnon et al. describe a novel algorithm using single-cell RNA sequencing (scRNAseq) data set generated previously from nine different human cancers to dissect CD8+ TILs transcription program across various tumor microenvironments. Using 38,852 CD8+ T cells from 141 patients, they develop an algorithm [called Generalized Matrix Decomposition Framework (GMDF)] allowing to decipher common and cancer-specific transcriptional signatures. They found a pan-cancer dysfunctional program decoupled from T cell activation that was predictive of immune checkpoint blockade (ICB) treatment response in patients with melanoma tumors. Among the top-ranking genes of this program was CXCR6. Using different B16-tumor bearing mice models, authors confirm the CXCR6 expression on terminally dysfunctional (PD1+Tim3+) CD8+ TILs. The use of ICB treatment in mice led to an increase in CXCR6 expression, which was enhanced in Tcf7-/- mice. The authors then showed that TCF1, the transcription factor coded by tcf7 is a repressor for CXCR6. The expression of CXCR6 was associated with survival of CD8+ TILs in these animal models and depleting CXCR6 in CD8+ T cells led to a decreased control of tumor growth confirming the value of the dysfunctional state and the TCF1:CXCR6-CXCL16 axis in mediating antitumor immunity.
Levels of infiltrating CD8+ T cells is known to be associated with ICB response but a biomarker for effective ICB treatment is still lacking (Li, F. et al. EClinicalMedicine 2021; Robert, C. Nat. Commun. 2020). Thus, it would be important to know whether expression of CXCR6, alone or in combination with checkpoint inhibitors, could serve as a predictive biomarker for ICB treatment response.
Recent data in mice pointed to the role for CXCR6 expression by CD8+ TILs in tumor control (Wang, B. et al. J. Immunother. Cancer 2021; Muthuswamy R et al. J. Immunother. Cancer 2021) and Di Pilato et al. showed that CXCR6 provides signals to CD8+ TILs to accumulate around dendritic cells and receive survival signals (Di Pilato, M. et al. Cell 2021). Here the authors confirm a potential important role of CXCR6 expression in human, across 9 different tumor microenvironments. Further functional characterisation of CXCR6+ CD8 TILs would have been valuable to confirm data generated in animal models, e.g. their positioning around dendritic cells expressing IL-15.
The authors showed that CXCR6 ligand CXCL16 is expressed by myeloid cells in the tumor microenvironment. Functional data on the role of CXCL16 during tumor growth would thus be valuable.
Besides being expressed by dysfunctional CD8+ TILs, CXCR6 is important for tumor control and higher expression is observed upon ICB treatment in tumor-bearing mice. Interestingly, CXCR6 expression is regulated by TCF1, a transcription factor also implicated in CD8+ stem-like T cells renewal (Zhao, X., Shan, Q. & Xue, H. H. Rev. Immunol. 2021). Further investigations on the regulation of CXCR6 expression and the role of TCF1 during the various stage of anti-tumor immunity, from T cell priming to exhaustion or following ICB treatment in human, could grant important findings.
CD8+ T cell dysfunctions prevent efficient anti-tumor immunity. Using data set from 9 different tumor microenvironments, Jerby-Arnon et al. unravel a pan-cancer dysfunctional program predictive of ICB treatment response in human. In addition to known immune checkpoints, this dysfunctional program comprised the expression of CXCR6, an emerging marker regulated by TCF1 and associated with CD8+ stem-like T cell renewal. Thus, the authors confirm a potential important role of CXCR6 expression in human. A better understanding of the regulation of the TCF1:CXCR6 may provide both biomarkers for ICB treatment response and possibly novel tools for anti-tumor immunity.
Reviewed by Nicolas Ruffin as part of the cross-institutional journal club of the Immunology Institute of the Icahn School of Medicine, Mount Sinai, the Kennedy Institute of Rheumatology, University of Oxford and Karolinska Institute’s Center for Infectious Medicine (CIM) & Center for Molecular Medicine (CIM). Follow him on Twitter.