Viral Modulation of TLRs and Cytokines and the Related Immunotherapies for HPV-Associated Cancers

Figure 5

Interferences of HPV on CD4⁺/CD8⁺ lymphocyte responses, tumor proliferation, and apoptosis. (1) HPV is able to downregulate the Th1 response by decreasing proinflammatory cytokines. Moreover, Th2 and Treg response are stimulated by the virus because anti-inflammatory cytokines are expressed in higher amounts in tumor microenvironment. (2) Tumor cells show different mechanisms for their activation and survival. HPV (especially E6 and E7 oncogenes) promotes changes in cell cycle regulatory genes (e.g., pRb and p53), leading to tumor cell proliferation. In addition, Th2 cytokines produced by APC and T CD4⁺ cells generate a chemical microenvironment that favours tumor establishment [2]. (3) T CD8⁺ lymphocyte activities are affected by HPV infection that induces a decreased antigen presentation (MHC-I/HLA-A) and expression of TLRs and CCR7 on membrane surface of infected cells. Moreover, these cells also show upregulation of CTLA-4 and PD-1 inhibitor molecules [108].