Poster abstracts
Poster number 1 submitted by Tong Xiao
Novel mechanisms of androgen receptor-centered transcriptional regulatory network in regulating CD8+ T cell exhaustion and sex bias in cancer
Tong Xiao (Pelotonia Institute for Immuno-Oncology), Johanna Schafer (Roche Tissue Diagnostics), No-joon Song, Payton Weltge (Pelotonia Institute for Immuno-Oncology), Cankun Wang ( Department of Biomedical Informatics and Pelotonia Institute for Immuno-Oncology), Xue Li (Cedars-Sinai Medical Center), Qin Ma ( Department of Biomedical Informatics and Pelotonia Institute for Immuno-Oncology)
Abstract:
Sex bias in cancers arising from nonreproductive organs is known but poorly understood. We recently reported on a T cell-intrinsic role of androgen receptor (AR) in driving CD8+ T cell exhaustion which underlies the poorer tumor control in males (Kwon et al., Sci Immunol, 2022). This study aims to understand how AR regulates CD8+ tumor-infiltrating lymphocytes (TILs) by identifying its genome-wide targets. We created a CD8+ T cell-specific AR knockout (KO) mouse model by crossing E8I-cre mice with Ar-floxed mice, which we challenged with syngeneic bladder tumor MB49. We then monitored tumor growth and performed spectral flow cytometry using a T cell exhaustion panel. Further, we used Cleavage Under Targets and Tagmentation – sequencing (CUT&Tag-seq) to map the entire AR targets in CD8+ TILs. Loss of AR in CD8+ T cells significantly slowed the growth of MB49 in male but not female mice. CD8+ TILs from male CD8 AR KO mice showed reduced TOX+ TCF1- terminally exhausted subset (69%; P≤ 0.05) and TOX expression (72%; P = 0.0583) compared to controls. Similarly, TOX expression decreased by 43% in AR-deleted CD8+ T cells following chronic TCR stimulation in vitro (P ≤ 0.0001). Finally, using CUT&Tag-seq, we found that AR binds directly to promoters of multiple key transcriptional regulators of T cell exhaustion, including Tcf7 and Tox.
Through identifying the genome-wide targets of AR in CD8+ TILs, we characterized the cell-intrinsic mechanism by which AR regulates CD8+ T cell exhaustion. Our work suggests AR is a master transcriptional regulator that negatively impacts CD8+ T cell immunity, which may contribute to poorer survival in males and supports combining androgen deprivation therapy with immune checkpoint blockage for cancer treatment.
References:
Kwon, H., Schafer, J.M., Song, N.J., Kaneko, S., Li, A., Xiao, T., Ma, A., Allen, C., Das, K., Zhou, L. and Riesenberg, B., 2022. Androgen conspires with the CD8+ T cell exhaustion program and contributes to sex bias in cancer. Science immunology, 7(73), p.eabq2630.
Keywords: Sex bias, CD8+ T cell exhaustion, Anti-tumor immunity