Chapter 17 - YY1 expression and PD-1 regulation in CD8 T lymphocytes

Abstract

During the last decade we have witnessed significant milestones in the treatment of various resistant cancers with various immunotherapeutic strategies. The clinical response rates have been significant in a subset of patients. One of the mechanisms underlying the failure of a subset of cancer patients to respond to the anticancer immune CD8+ CTLs is their surface expression of an inhibitory receptor, programmed cell death 1 (PD1). The interaction of PD1 with its corresponding ligands, PDL1 or PDL2, expressed on the surface of the cancer cells, results in PD1 activation, inducing an inhibitory signaling, resulting in the inactivation of the CD8+ CTLs to perform their effector functions (e.g., cytotoxicity, proliferation, and cytokine production) and resulting in tumor cell escape and growth. The inhibition of the PD1-PDL1/2 interaction by monoclonal antibodies restored the antitumor activities of the CD8CTLs and resulted in tumor regression. Several FDA approved antibodies directed against PD1 or PDL1 have been used therapeutically with significant clinical responses. Another approach to prevent the inhibition mediated by PD1 may be by decreasing the expression of PD1 on the CD8+ CTLs. Several transcription factors have been reported that regulate PD1 expression. The transcription factor Yin Yang 1 (YY1), however, has been reported to regulate several tumor properties, including metastasis, chemoimmuneresistance, and proliferation. Therefore we examined the role of YY1 in the regulation of PD1 expression. The findings revealed that YY1 positively regulates the expression of PD1 both transcriptionally and indirectly by several crosstalk signaling pathways. We speculate that targeting YY1 may have a double sword edge by both inhibiting PD1 expression on CD8+ CTLs and restoring their antitumor activities and on the other hand by inhibiting tumor cell survival, metastasis, and resistance.