Mapping immune activity in HPV-negative head and neck squamous cell carcinoma: a spatial multiomics analysis

Area of Science:

• Oncology
• Immunology
• Genomics
• Spatial Biology

Background:

• Head and neck squamous cell carcinoma (HNSCC) shows poor response to immunotherapy (15-25% monotherapy, 30-45% combination therapy).
• Tumor heterogeneity (intertumor and intratumor) significantly impacts HNSCC immunological activity and immunotherapy outcomes.
• Biomarkers for predicting HNSCC immunotherapy response are actively being sought at gene and protein levels.

Purpose of the Study:

• To evaluate intertumor heterogeneity using a 27-gene expression signature for stratifying HNSCC immunologic activity.
• To investigate molecular and cellular intertumor heterogeneity.
• To analyze intratumor spatial heterogeneity using spatial multiomics approaches.

Main Methods:

• Stratification of HNSCC tumors based on a 27-gene expression signature to assess immunologic activity.
• Investigation of intertumor heterogeneity at molecular and cellular levels.
• Spatial multiomics analysis to examine intratumor spatial heterogeneity within and across tumor subgroups.

Main Results:

• Immunologically active HNSCC tumors exhibit increased interferon signaling and antigen presentation machinery.
• Chemokine expression (CXCL8, CXCL9) differs between active and inactive tumors, impacting immune cell recruitment.
• Spatial analysis reveals enhanced immune cell infiltration and colocalization with tumor cells in active HNSCC, despite evidence of an immunosuppressive microenvironment and potential immune evasion via JAK-STAT3 signaling.

Conclusions:

• Spatial multiomics provides detailed insights into molecular and cellular markers differentiating immunologically active from immunosuppressive HNSCC microenvironments.
• Cell colocalization signatures, in addition to gene expression, can effectively infer HNSCC immunological activity.
• Identifying spatial heterogeneity and cell colocalization patterns can improve prediction of immunotherapy response in HNSCC.