1052P - Pan-cancer, multi-omic analysis of 'hot' and 'cold' tumors reveals immunotherapy relevant signatures

Background

The tumor microenvironment (TME) influences cancer progression and the efficacy of immune checkpoint inhibitors (ICIs). 'Hot' tumors, characterized by significant immune cell infiltration, are more responsive to ICIs than 'cold' tumors, which exhibit minimal immune activity. This comprehensive pan-cancer, multi-omic study aims to discern the molecular signatures differentiating 'hot' and 'cold' tumors that could inform immunotherapy strategies.

Methods

We analyzed 3413 freshly frozen tumor samples from colorectal, non-small cell lung, liver, breast, and ovarian cancers. 'Hot' and 'cold' categorization was based on immune profiles from RNA-Seq data. We integrated genomic, transcriptomic, proteomic, and phospho-proteomic data, alongside single-cell RNA-Seq resources, to identify patterns and features associated with the 'hot' cancer phenotypes within and across cancer types.

Results

Our analysis identified hundreds of gene expression commonalities across ‘hot’ cancer molecular subtypes, above and beyond known ICI targets such as CTLA-4, PD-L1 and LAG3. These could be further refined into specific modules based on co-expression analysis, that were associated with distinct proteomic and phospho-proteomic features. Single-cell analysis further refined these results to reveal specific B and T cell regulators in 'hot' tumors that displayed variation across cancer types, suggesting distinct underlying regulatory mechanisms of this pan-cancer phenomenon.

Conclusions

The multi-omic approach adopted in this study revealed known and novel molecular features that discriminate 'hot' and 'cold' tumors. Furthermore, through scRNA-Seq integration with bulk datasets they can be differentiated through immune-cell type specificity. By delineating similarities and differences in ‘hot’ tumor subtypes, these findings warrant further investigation into their roles in the TME and could have significant implications for the development of precision immunotherapy strategies.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

J. Woodsmith: Financial Interests, Institutional, Member of Board of Directors: Indivumed. All other authors have declared no conflicts of interest.