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754 TIGIT-PVR is a key immune checkpoint and therapeutic target in HPV-positive head and neck squamous cell carcinomas
  1. Xiuning Le1,
  2. Minghao Dang1,
  3. Venkatesh Hegde1,
  4. Bo Jiang1,
  5. Ravaen Slay1,
  6. Weihong Xiao1,
  7. Keiko Akagi1,
  8. Joseph Fresquez1,
  9. Kathrina Marcelo1,
  10. Qianyun Luo1,
  11. Pragya Sinha1,
  12. Ananta Yanamandra1,
  13. Diana Bell1,
  14. Michelle Williams1,
  15. Edwin Parra Cuentas1,
  16. Ryan Goepfert1,
  17. Stephen Lai1,
  18. Neil Gross1,
  19. Amit Agrawal2,
  20. Alexandre Reuben1,
  21. Jeffrey Myers1,
  22. Michael Curran1,
  23. Jagannadha Sastry1,
  24. Linghua Wang1 and
  25. Maura Gillison1
  1. 1MD Anderson Cancer Center, Houston, TX, United States
  2. 2The Ohio State University Medical Center, Columbus, United States


Background Human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HPV+ HNSCC) is a disease that has moderate response to anti-PD-1/L1 immune checkpoint blockade, with the response rates less than 20% and median progression-free survival less than 3 months. A greater understanding of tumor intrinsic and extrinsic factors that restrict anti-tumor immunity in the tumor immune microenvironment (TIME) is needed to identify other immune checkpoints to enhance therapeutic efficacy.

Methods Two cohorts (TCGA n=72 and a separate cohort n=84) of surgically resected, treatment-naïve HPV+ HNSCC with RNA-seq were analyzed to understand the immune features. In addition, single-cell RNA-seq and TCR-seq were performed on 18 cases to further delineate the immune molecules' interactions. An immune-competent murine HPV+ HNSCC model was used to preliminarily evaluate the therapeutic efficacy.

Results In two bulk-sequenced HPV+ HNSCC cohorts, TIGIT ligands PVR and NECTIN2 were found to associate with an epithelial-to-mesenchymal gene expression signature, suppression of IFNα and IFNγ signaling, a stromal-enriched or immune-excluded TIME, and poor survival. Single-cell RNA-seq of over 72,000 cells of HPV+ HNSCC revealed that the PVR/NECTIN ligand TIGIT was highly prevalent in T-cells (34%), significantly higher than PD1- (20%, p<0.01). There is an enrichment of cell-cell interactions mediated by TIGIT-PVR/NECTIN2 in the TIME of HPV+HNSCC versus normal tonsil. TIGIT was the most differentially upregulated immune checkpoint on clonally expanded CD8+T-cells and was abundant on antigen-experienced, tissue-resident memory CD8+T-cell and T-regulatory subsets. TIGIT ligands PVR, NECTIN1, and NECTIN2 were abundant on mature regulatory dendritic cells (DCs), immunosuppressive plasmacytoid (p)DCs, and macrophages, respectively. TIGIT and PD-1 co-blockade in the mEER syngeneic murine model significantly reduced tumor growth, improved survival, restored effector function of HPV16E7-specific CD8+T cells, natural killer cells, and DCs, and conferred tumor re-challenge protection.

Conclusions TIGIT-PVR/NECTIN receptors/ligands are more abundant than PD-1/L1 in the TIME of HPV+ HNSCC. Co-blockade of TIGIT and PD-1 immune checkpoints enhanced anti-tumor efficacy in a CD8+ T-cell-dependent manner and conferred long-term immune protection in a murine model. Our study nominates TIGIT as a therapeutic target for HPV+ HNSCC.

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