Multiomics and spatial mapping characterizes human CD8⁺ T cell states in cancer

Area of Science:

• Immunology
• Oncology
• Cell Biology

Background:

• Identifying reliable biomarkers for tumor-associated CD8+ T cell dysfunction is crucial for effective cancer immunotherapy.
• Diverse hypofunctional states of CD8+ T cells exist, but their specific characteristics and clinical relevance across different tumor types are not fully understood.

Purpose of the Study:

• To characterize and differentiate diverse hypofunctional states of tumor-associated CD8+ T cells using multiomics analysis.
• To investigate the impact of tumor microenvironment (niche) on CD8+ T cell function and identify biomarkers for immunogenic versus non-immunogenic cancers.

Main Methods:

• Multiomics analysis of CD8+ T cell features across multiple patient cohorts and tumor types.
• In situ spatial mapping and ex vivo single-cell secretome analysis of glioblastoma CD8+ T cells.
• Assessment of anti-programmed cell death protein 1 (PD-1) immunotherapy and dendritic cell (DC) vaccine effects in glioblastoma.

Main Results:

• CD8+ T cells in 'supportive' tumor niches (e.g., melanoma, lung cancer) display features of tumor reactivity-driven exhaustion (CD8+ TEX) with proficient effector memory and expanded TCR repertoire.
• CD8+ T cells in 'nonsupportive' niches (e.g., glioblastoma) exhibit distinct hypofunctionality, including immature states, high wound healing signatures, and non-expanded TCR repertoires.
• Glioblastoma showed dysfunctional CD4+:CD8+ T cell interactions and negligible effector function in CD8+ T cells, with anti-PD-1 therapy exacerbating tolerogenic disparities and DC vaccines partially correcting them.

Conclusions:

• A comprehensive atlas for assessing distinct CD8+ T cell hypofunctional states in various cancer types has been established.
• Tumor niche significantly dictates CD8+ T cell state, influencing their response to immunotherapies like anti-PD-1 and DC vaccines.
• Understanding these distinct T cell states is critical for developing targeted and effective immunotherapeutic strategies for different cancers.