Pre-Malignant Immune Suppressive Environment Is Dependent on HPV16E7-Rb Interaction Induced Epithelium Hyperplasia
Paula Kuo1*, Kelvin Tuong1, Graham Leggatt1, Stephen Mattarollo1, Ian Frazer1*
1Diamantina Institute, University of Queensland
Persistent high-risk Human Papilloma Virus (HPV-16 and 18) infection is associated with cancer development. Understanding the immune response involved in the precancerous environment will aid the development of therapeutic vaccine against chronic HPV infection. Mice transgenic for epidermal expression of HPV16 viral oncoprotein E7 (K14E7) mimic chronic HPV infection, displaying epidermal hyperplasia and suppressed immune response with increased lymphocytic infiltrate. However, when the E7-Rb interaction was disrupted (K14E7xRb9), these mice display normoplastic skin and have no discernible immune dysfunction. Thus, we hypothesize that hyperplasia, rather than E7 oncoprotein expression, is a major determinant of immunosuppression in HPV16E7 transgenic mice. We show that K14E7xRb9 and wild-type C57BL/6 mice, in contrast to K14E7 mice, have limited immune cell infiltrate and low levels of cytokine secretion. Expression of co-inhibitory markers such as CTLA4 and PD-1 are significantly lower on lymphocytes found in K14E7xRb9 and C57BL/6 skin when compared with K14E7 skin. To uncover the potential ‘hyperplasia-dependent’ signals that recruit lymphocytes to skin, RNA sequencing was performed. We identified chemokine signaling pathways as a specific consequence of hyperplasia. Concordantly, chemokines including CXCL9, 10, 13, CCL17 and 22 are up-regulated in the HPV16 E7-expressing hyperplastic skin but not in C57BL/6 and K14E7xRb9 skin. Furthermore, we show that K14E7 skin environment preferentially recruits T cells in vitro in a CXCL9 and CXCL10-dependent manner. Taken together, the data suggest that the expression of immune checkpoint molecules and lymphocyte recruitment signals occur as a consequence of HPV-associated hyperplasia rather than the expression of viral oncoprotein. Hyperplasia-dependent factors could potentially serve as targets for therapeutic vaccine development against chronic HPV infection.
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