1036P - Large-scale cellular profiling of 1283 cancer patients reveals a NK cell-mediated immunosuppressive tumor microenvironment in immunotherapy resistance

Background

Immune checkpoint inhibitors (ICIs) have shown remarkable anti-tumor effects in several types of cancer. However, ICIs treatment failures can still be observed in many patients. The tumor microenvironment (TME) serves as the soil of tumor that can decisively influence the treatment outcomes of ICIs. The distinctive roles and cell-cell communications related to ICIs response remain to be elucidated.

Methods

By ultilizing deconvolution in bulk RNA sequencing and single-cell RNA sequencing data, we summarize over 1000 patients receiving ICIs treatment across eight tumor types to elucidate the role of distinct TME cell population at different states in determining ICIs response and their potential as markers or therapeutic targets.

Results

We discover that the ICIs response could be characterized by the immune-related transcriptomic profiles before treatment. Based on this finding, we reveal that the proficient-inflamed TME with enriched favorable immune cells and strengthened positive interactions is a hallmark of ICIs responders, while a competitive cell community with activated mediating cells linking favorable and unfavorable cells is observed in non-responders. In addition, we find that the association of tumor mutation burden with ICIs response might depend on proficient-inflamed cell subtypes in TME. In network analysis, we uncover that the SERPING1+ Natural Killer (NK) cells play as the mediator between the proficient-inflamed and deficient-inflamed cellular network. Furthermore, by using single-cell RNA sequencing data, we confirm the altered ligand-receptor pairs and signaling pathways between responders and non-responders of this NK cell subtype, which could serve as molecular targets to sensitize ICIs.

Conclusions

This study represents a tissue-agnostic immunological profile of cell states and interactions in TME with potential molecular targets that could decide immunotherapy outcome and be used to develop the next-generation biomarkers and therapeutic targets to improve tumor immunotherapy.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The Sixth Affiliated Hospital, Sun Yat-sen University.

Funding

National Natural Science Foundation of China, Natural Science Foundation of Guangdong Province.

Disclosure

All authors have declared no conflicts of interest.