Study shows how HPV reprograms immune cells to help cancer grow

A team from the Norris Cancer Center at the Keck School of Medicine (USC) has shown how human papillomavirus type 16 (HPV16) helps tumors evade immune surveillance. Two oncoproteins of the virus, E6 and E7, cause cells in the microenvironment to secrete interleukin-23 (IL-23). This signal inhibits T cells from killing infected and cancer cells. In a mouse model, blocking IL-23 significantly enhanced the effect of a therapeutic HPV vaccine, prolonging survival compared to either strategy alone.

Background of the study

Human papillomavirus (HPV), especially the HPV16 strain, is the main driver of cervical cancer and a significant proportion of oropharyngeal tumors. The preventive vaccine Gardasil-9 reliably protects, but only before infection, so therapeutic vaccines are being actively developed for those already infected and sick, the purpose of which is to train T cells to recognize viral antigens (E6/E7) and destroy the tumor. Their clinical effectiveness is still limited and variable, which forces us to look for the causes of "immune inhibition" directly in the tumor microenvironment and ways to bypass it.

HPV-positive tumors have well-described immune evasion mechanisms: E6/E7 oncoproteins rewire host cell signaling pathways, shift cytokine balances, and promote a “cold” microenvironment—with low cytotoxic T cell activity and a predominance of suppressive populations. E6/E7 has previously been shown to enhance proinflammatory but immunosuppressive signals (such as IL-6) and dampen parts of the innate response; the new USC work focuses on the role of IL-23 as a key link through which E6/E7 “reprogram” surrounding cells and weaken T cell pressure on the tumor. It is this “E6/E7 → ↑IL-23 → T cell inhibition” circuit that may explain why therapeutic vaccines do not work to their full potential.

A practically important detail: the IL-23 axis is already drug-available. Monoclonal antibodies to the p19 subunit of IL-23 (guzelkumab, tildrakizumab, rizankizumab) and to p40 (ustekinumab, IL-12/23) have long been used in psoriasis and other immune-inflammatory diseases, have clear dosing regimens and a safety profile. This creates a “shortcut” to testing combination strategies in oncology: a therapeutic vaccine against HPV + IL-23 blockade to remove the local immune brake in the tumor.

From a clinical perspective, the next step is obvious: to confirm in humans that IL-23 inhibition truly “unties the hands” of vaccine-induced T cells and improves control of HPV-associated tumors (cervix, oropharynx). The USC authors explicitly point to such a plan and emphasize that preliminary results were obtained in cell systems and mice; therefore, early-phase trials with inclusion biomarkers (IL-23 levels, E6/E7 signatures) and well-thought-out endpoints (T-cell infiltration, clinical response, survival) are needed. In a broader perspective, the IL-23 axis may also be relevant for a subset of non-HPV tumors where this cytokine is elevated, but this will require separate validation.

Why is this important?

HPV16 is the main carcinogenic strain of the virus: it is responsible for more than half of cervical cancer cases and about 90% of HPV-associated throat tumors. The preventive vaccination Gardasil-9 provides excellent protection - but only before infection. Therefore, the world is actively testing therapeutic vaccines (for those already infected and sick), the purpose of which is to train T-cells to recognize E6/E7 proteins and attack the tumor. Their effectiveness is still uneven - a new study explains one of the reasons and suggests a combination: vaccine + IL-23 blocker.

How it works (the mechanism in three steps)

1. Viral proteins E6/E7 → IL-23 release. The tumor and the surrounding cells are “rewired” to a pro-inflammatory but immunosuppressive mode.
2. IL-23 → T-cell inhibition. T-cells proliferate and cytotoxicate worse - the tumor grows.
3. IL-23 blockade → vaccine ‘free play’. Antibodies to IL-23 restore functionality to T cells; in mice, the combination with the vaccine is stronger than either method alone.

What exactly was shown

The researchers implanted HPV16 tumors into mice and administered a therapeutic vaccine, inducing specialized T cells against viral antigens. In a test tube, adding IL-23 reduced the ability of these T cells to divide and kill their target. In live models, neutralizing IL-23 increased the number of killer T cells in the tumor; the combination with the vaccine elicited a more powerful immune response and longer survival than either approach alone. In parallel, the scientists tracked how exactly E6/E7 boosts IL-23 by analyzing RNA and chromatin.

Translation into clinical language

The good news: IL-23 inhibitors are already FDA-approved (for psoriasis, etc.), which speeds up the path to clinical trials in oncology - in combination with therapeutic HPV vaccines. The logic is simple: the vaccine creates "sharpened" T cells, and anti-IL-23 prevents the tumor from turning them off. The authors are already developing their own vaccine candidate and are planning to test the combination.

Context and boundaries

This is preclinical: cell systems and mice. Before humans, there are steps on safety and trial design (doses, patient selection, inclusion biomarkers). However, independent news reports emphasize: the mechanism of IL-23 as a "brake" on T cells in HPV tumors looks convincing, and the combination strategy is reasonable.

Who is this especially relevant for?

• Patients with HPV-associated cervical and oropharyngeal cancers where the E6/E7 → IL-23 signature pathway is expressed.
• Those participating or planning to participate in therapeutic HPV vaccine trials (combinations with anti-IL-23 may be the next wave).
• Potentially - some non-HPV tumors (eg some bladder or testicular tumors) where IL-23 is elevated, but this remains to be tested.

What will be important in future research

• Clinical trial design: selection of endpoints (T-cell infiltration, viral clearance, tumor response), vaccine → anti-IL-23 or vice versa regimens.
• Selection biomarkers: IL-23 levels, E6/E7 expression, hot/cold tumor transcriptional signatures.
• Combinations broader than vaccines: anti-PD-1/PD-L1, local adjuvants, radiation therapy - how to correctly combine synergies.
• Immunosuppression risks: control of infections and exacerbations associated with IL-23 inhibitors with long-term use.

In short: what to take with you

• HPV16 “re-educates” the tumor microenvironment via IL-23, turning off anti-tumor T cells.
• IL-23 blockade in mice enhances the action of a therapeutic HPV vaccine and prolongs survival.
• A fast track to the clinic is emerging: IL-23 inhibitors are already on the market (in other indications).
• The next step is combination clinical trials in humans.

Source: Keck School of Medicine, USC press release (August 19, 2025).