Mechanisms underlying the resistance of human papillomavirus-infected or -transformed cells to Th1 immunity

Abstract

HPV has evolved mechanisms to resist immune attack. I

showed that HPV impaired necroptosis induced by IFNγ and TNFα by

down-regulation of RIPK3 expression. Methyltransferase inhibitor DZNeP

restored the expression of RIPK3 in HPV+ keratinocytes, and increased the necroptosis in HPV+ keratinocytes. Simultaneously, hrHPV effectively inhibited IFNγ/TNFα-mediated arrest of cell growth by down-regulating IFITM1. Then I studied HPV associated oropharyngeal squamous cell cancer (OPSCC). The OPSCC infiltrating HPV specific CD4+ Tcells produce cytokines such as IFNγ and TNFα. I found that HPV16-positive tumor cells lacked expression of RIPK3, which were not sensitive to the necroptosis induced by IFNγ /TNFα. I also showed that a combination of IFNγ and TNFα with cisplatin synergized in killing tumor cells. Last but not least I showed that combination of the clinically applied EGFR inhibitor Cetuximab and IFNγ/TNFα increased gene expression of multiple cytokines, including CXCL9, CXCL10 and CCL5, which may attract more lymphocytes to the tumor site. By using the inhibitors of the targets downstream of EGFR, I found that JNK and MEK1 played major role in mediating the suppression of CCL5, CXCL9 and CXCL10 expression.