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  4. In an era of combinatorial immunotherapy: elucidating and targeting mechanisms of systemic immunosuppression in HPV16+ cervical cancer to improve therapeutic vaccine responses
 
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doctoral thesis

In an era of combinatorial immunotherapy: elucidating and targeting mechanisms of systemic immunosuppression in HPV16+ cervical cancer to improve therapeutic vaccine responses

Lecointre, Morgane Marie  
2025

Immunotherapy has revolutionized cancer treatment, yet many patients, including those with cervical cancers induced by high-risk human papillomaviruses such as HPV16, remain unresponsive due to immune evasion mechanisms. While the tumor microenvironment (TME) is known to inhibit immune responses, emerging evidence highlights that tumors can also induce systemic immunosuppression (SIS), which hampers T cell-mediated anti-tumor immunity in peripheral lymphoid organs. Suppressive myeloid cells, especially neutrophils, play a central role in this phenomenon, correlating with disease progression and resistance to immunotherapies. This thesis focuses on understanding and targeting SIS mechanisms in HPV16+ cervical cancer to enhance the efficacy of HPV therapeutic vaccines, a promising but largely ineffective form of immunotherapy.

The Hanahan lab previously reported that the K14-HPV16/H2b genetically engineered mouse model replicates key features of advanced cervical cancer, including SIS, which is marked by the expansion of immunosuppressive myeloid cells, particularly neutrophils, in peripheral tissues and is associated with resistance to therapeutic vaccination. We hypothesized that targeting neutrophil-mediated SIS is essential for unlocking vaccine efficacy in this cancer. To explore the molecular drivers of SIS, we performed serum proteomic profiling and single-cell RNA sequencing on key organs and identified three upregulated IL-1 superfamily cytokines â IL-1α, IL-33, and IL-36β â associated with poor outcomes in cervical cancer patients.

Mechanistically, we showed that HPV16-driven tumors release these cytokines into circulation, which promotes granulocytic myelopoiesis in the bone marrow (BM). This drives the expansion of myeloid progenitors and immunosuppressive neutrophils, which accumulate in the spleen and tumor, fostering immune evasion and limiting vaccine efficacy. Gain-of-function studies using a cancer cell line, which does not induce SIS, revealed that IL-1α, IL-33, and IL-36β are coordinately necessary and sufficient to induce neutrophil-mediated SIS. Similarly, inoculating normal mice with these cytokines expanded T cell-suppressive neutrophils in the BM and spleen, confirming their role in driving SIS. Bioinformatic analyses further showed the prevalent expression of IL-1α, IL-33, and IL-36β in human cervical cancer and other cancers, along with biomarkers of SIS.

Further functional validation has come from pharmacological inhibition of pan-IL-1 superfamily signaling using an IL1RAP antagonist, which disrupted neutrophil-mediated SIS, reducing and reprogramming neutrophils in the BM, spleen, and TME, thereby restoring CD8+ T cell proliferation capacity. Combining IL1RAP inhibition with an HPV16 E7 oncoprotein-based peptide vaccine unlocked vaccine efficacy, inducing strong E7-specific CD8+ T cell responses and a significant survival benefit which was further sustained by addition of anti-CTLA-4. Importantly, anti-CTLA-4 alone did not improve vaccine efficacy, underscoring the importance of SIS-targeting in the success of this triple combination.

Collectively, this thesis illuminates the role of IL-1 superfamily cytokines in driving HPV16-induced SIS and offers a rationale for targeting these pathways to improve therapeutic outcomes in cervical cancer. These insights may also apply to other cancers with similar immunosuppressive mechanisms, suggesting broader implications for cancer immunotherapy strategies.

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Type
doctoral thesis
DOI
10.5075/epfl-thesis-10901
Author(s)
Lecointre, Morgane Marie  
Advisors
Hanahan, Douglas  
•
De Palma, Michele  
Jury

Prof. Joachim Lingner (président) ; Prof. Douglas Hanahan, Prof. Michele De Palma (directeurs) ; Prof. Freddy Radtke, Prof. Mikäel Pittet, Prof. Karin de Visser (rapporteurs)

Date Issued

2025

Publisher

EPFL

Publisher place

Lausanne

Public defense year

2025-02-28

Thesis number

10901

Total of pages

169

Subjects

Human papillomavirus (HPV)

•

cervical cancer

•

systemic immunosuppression

•

immunosuppressive neutrophils

•

IL-1 superfamily signaling

•

anti-IL1RAP therapy

•

therapeutic peptide vaccine

•

anti-CTLA-4 immune checkpoint blockade

•

combination immunotherapy

EPFL units
CMSO  
Faculty
SV  
School
ISREC  
Doctoral School
EDMS  
Available on Infoscience
February 19, 2025
Use this identifier to reference this record
https://infoscience.epfl.ch/handle/20.500.14299/247090
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