Single-cell spatial multiomics reveals tumor microenvironment vulnerabilities in cancer resistance to immunotherapy

Area of Science:

• Oncology
• Immunology
• Genomics

Background:

• Heterogeneous resistance to immunotherapy is a significant hurdle in cancer treatment, frequently resulting in disease progression and mortality.
• Understanding the tumor microenvironment's role in immunotherapy resistance is crucial for developing effective therapeutic strategies.

Purpose of the Study:

• To perform longitudinal multimodal single-cell analysis of tumors from metastatic melanoma patients with varying responses to immunotherapy.
• To establish a toolkit for integrating transcriptomic, cellular epitope, and spatial data for deeper tumor insights.

Main Methods:

• Utilized CITE-seq and 40-plex PhenoCycler tissue imaging for longitudinal multimodal single-cell analysis.
• Developed a multimodal integration toolkit to align transcriptomic, cellular epitope, and spatial information.
• Analyzed tumors from metastatic melanoma patients exhibiting innate resistance, acquired resistance, or response to immunotherapy.

Main Results:

• Identified an "immune-striving" tumor microenvironment characterized by peri-tumor lymphoid aggregates and reduced T-cell infiltration.
• Observed the emergence of MITF+SPARCL1+ and CENPF+ melanoma subclones post-therapy in resistant cases.
• Found that enrichment of B cell-associated signatures in lymphoid aggregates correlated with improved patient survival.

Conclusions:

• Longitudinal multimodal analysis provides critical insights into the dynamics of the tumor microenvironment during immunotherapy.
• Specific melanoma subclones and lymphoid aggregate composition are associated with immunotherapy resistance and patient outcomes.
• These findings can inform the development of novel therapeutic interventions targeting tumor-immune interactions.