How HPV Hijacks Immune Cells to Promote Cancer Progression

Recent research from the Keck School of Medicine of USC has uncovered a new way that the human papillomavirus (HPV), specifically the HPV16 strain, contributes to cancer development. HPV16 is responsible for over half of cervical cancers and around 90% of HPV-related throat cancers. The virus employs a sophisticated mechanism to evade the immune system by reprogramming immune cells surrounding the tumor microenvironment.

In detail, the virus produces proteins E6 and E7, which stimulate nearby cells to release a signaling protein called Interleukin-23 (IL-23). This cytokine is known for its inflammatory properties but plays a detrimental role in this context by hindering the activity of T-cells—key immune cells responsible for attacking and destroying infected or abnormal cells. When IL-23 levels are elevated, T-cells are prevented from proliferating and effectively attacking the tumor, allowing the cancer to grow unchecked.

In studies involving mice, blocking IL-23 significantly enhanced the immune response against HPV-driven tumors. The researchers found that inhibiting this cytokine improved the efficacy of therapeutic vaccines designed to activate T-cells to target HPV-infected cells. Notably, antibodies that inhibit IL-23 are already FDA-approved for treating conditions like psoriasis, which could facilitate their rapid repurposing for cancer therapy.

The research further revealed that the HPV proteins E6 and E7 increase IL-23 production by upregulating a critical gene through the transcription factor KLF2, leading to heightened tumor-promoting inflammation. When IL-23 was neutralized, T-cells regained their capacity to attack and eliminate cancer cells, especially when combined with HPV-targeted vaccines, resulting in longer survival outcomes in mouse models.

This discovery not only explains some of the challenges faced by current therapeutic vaccines, which have shown limited success in clinical trials, but also suggests new treatment strategies. Combining IL-23 inhibitors with vaccines could significantly improve immune responses in patients with HPV-associated cancers. Moreover, these findings may have broader implications for other cancers involving high IL-23 levels, such as testicular and bladder cancers.

Overall, targeting IL-23 offers a promising therapeutic avenue, providing a potential means to enhance immune-based treatments and improve prognosis for HPV-related cancers. The study underscores the importance of understanding virus-host interactions at the molecular level to develop more effective cancer immunotherapies.