ABSTRACT
High-risk human papillomaviruses (HPVs) are causally associated with multiple human cancers. Previous studies have shown that the HPV oncoprotein E7 induces immune suppression; however, the underlying mechanisms remain unknown. To understand the mechanisms by which HPV deregulates host immune responses in the tumor microenvironment, we analyzed gene expression changes of all known chemokines and their receptors using our global gene expression data sets from human HPV-positive and -negative head/neck cancer and cervical tissue specimens in different disease stages. We report that, while many proinflammatory chemokines increase expression throughout cancer progression,
CXCL14
is dramatically downregulated in HPV-positive cancers. HPV suppression of
CXCL14
is dependent on E7 and associated with DNA hypermethylation in the
CXCL14
promoter. Using
in vivo
mouse models, we revealed that restoration of
Cxcl14
expression in HPV-positive mouse oropharyngeal carcinoma cells clears tumors in immunocompetent syngeneic mice, but not in
Rag1
-deficient mice. Further,
Cxcl14
reexpression significantly increases natural killer (NK), CD4
+
T, and CD8
+
T cell infiltration into the tumor-draining lymph nodes
in vivo
.
In vitro
transwell migration assays show that
Cxcl14
reexpression induces chemotaxis of NK, CD4
+
T, and CD8
+
T cells. These results suggest that
CXCL14
downregulation by HPV plays an important role in suppression of antitumor immune responses. Our findings provide a new mechanistic understanding of virus-induced immune evasion that contributes to cancer progression.
IMPORTANCE
Human papillomaviruses (HPVs) are causally associated with more than 5% of all human cancers. During decades of cancer progression, HPV persists, evading host surveillance. However, little is known about the immune evasion mechanisms driven by HPV. Here we report that the chemokine
CXCL14
is significantly downregulated in HPV-positive head/neck and cervical cancers. Using patient tissue specimens and cultured keratinocytes, we found that
CXCL14
downregulation is linked to
CXCL14
promoter hypermethylation induced by the HPV oncoprotein E7. Restoration of Cxcl14 expression in HPV-positive cancer cells clears tumors in immunocompetent syngeneic mice, but not in immunodeficient mice. Mice with
Cxcl14
reexpression show dramatically increased natural killer and T cells in the tumor-draining lymph nodes. These results suggest that epigenetic downregulation of
CXCL14
by HPV plays an important role in suppressing antitumor immune responses. Our findings may offer novel insights to develop preventive and therapeutic tools for restoring antitumor immune responses in HPV-infected individuals.