{"doi":"10.1136/jitc-2023-sitc2023.0916","title":"916 Making their own off switch: Fgl2 produced by antigen-specific CD8+T cells tempers the CD8+T-cell response via apoptosis of FcγRIIB+CD8+T cells","abstract":"

Background

Effector CD8+ T-cell tumor infiltration is a critical factor to immunotherapeutic success. Our lab recently discovered that FcγRIIB, the sole inhibitory IgG-Fc receptor, is upregulated on effector-like memory CD8+ T cells at the tumor in mice and humans1–3 and signaling through FcγRIIB regulates CD8+ T cells in a cell-intrinsic manner. We discovered that fibrinogen-like protein 2 (Fgl2) binds FcγRIIB and induces FcγRIIB-mediated cell death, but the source of Fgl2 was unknown. Here, we investigate the possibility that CD8+ T cells produce Fgl2 in an auto-regulatory feedback loop.

Methods

In vivo mouse studies utilized the B16-OVA and B16-F10 melanoma mouse models. For melanoma patient tumor-infiltrating lymphocyte (TIL) studies, melanoma tumor tissues were collected (IRB #00095411), deidentified, and distributed by the Cancer Tissue and Pathology shared resource of Winship Cancer Institute of Emory University. Publicly available single-cell RNA-sequencing human data was analyzed using the BBrowser2 platform.4 5

Results

Here, we show that CD8+ T cells can express and produce Fgl2 upon activation in mice and humans compared to unstimulated controls (p<0.01). To determine the clinical relevance of Fgl2 on CD8+ T cells, we analyzed two publicly available datasets of melanoma patient TIL.6 7 We found that Fgl2 is expressed on patient CD8+ TIL (p<0.0001), upregulated on activated vs. naïve CD8+ TIL (p<0.0001), and that this expression is correlated with decreased patient survival (p<0.05). To determine the isolated impact of Fgl2 from CD8+ T cells, a conditional knockout model was generated wherein only the tumor-specific CD8+ T cells lack Fgl2. B16-challenged mice given Fgl2-deficient tumor-specific CD8+ T cells exhibited enhanced antitumor response as measured by increased persistence (p<0.01), decreased exhaustion (p<0.01), and decreased tumor size (p<0.05) compared to mice given WT tumor-specific CD8+ T cells. Increased persistence of Fgl2-/- tumor-specific CD8+ T cells was underpinned by a decrease in apoptosis of FcγRIIB+ CD8+ T cells, as Fgl2-/- CD8+ T cells possessed a higher frequency of FcγRIIB+ CD8+ T cells compared to WT CD8+ T cells (p<0.05).

Conclusions

These data support the immunosuppressive role of Fgl2 in dysregulating the T-cell antitumor response and highlight the clinical importance of the FcγRIIB-Fgl2 pathway on CD8+ T cells. Furthermore, these data demonstrate a regulatory signaling axis whereby effector-like memory CD8+ T cells produce their own off-switch. The discovery of this pathway opens several potential avenues to manipulate the expression and signaling of this axis to increase patient treatment options.

Acknowledgements

Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number F31CA271764. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

References

Morris AB, Farley CR, Pinelli DF, Adams LE, Cragg MS, Boss JM, Scharer CD, Fribourg M, Cravedi P, Heeger PS, Ford ML. Signaling through the Inhibitory Fc Receptor FcgammaRIIB Induces CD8(+) T Cell Apoptosis to Limit T Cell Immunity. Immunity 2020;52:136–150 e136. 10.1016/j.immuni.2019.12.006. Morris AB, Pinelli DF, Liu D, Wagener M, Ford ML. Memory T cell-mediated rejection is mitigated by FcγRIIB expression on CD8(+) T cells. Am. J. Transplant. 2020;20:2206–2215. 10.1111/ajt.15837. Farley CR, Morris AB, Tariq M, Bennion KB, Potdar S, Kudchadkar R, Lowe MC, Ford M","journal":"Regular and Young Investigator Award Abstracts","year":2023,"id":413370,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9506,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":522327,"name":"Danya Liu","orcid":"0000-0001-6103-6486","position":1,"is_corresponding":false},{"id":1195045,"name":"Abdelhameed Dawood","orcid":null,"position":2,"is_corresponding":false},{"id":314036,"name":"Megan M. Wyatt","orcid":"0000-0003-1316-260X","position":3,"is_corresponding":false},{"id":1195046,"name":"Mosalah S Abdel-Hakeem","orcid":null,"position":4,"is_corresponding":false},{"id":314041,"name":"Chrystal M. Paulos","orcid":"0000-0002-0784-2601","position":5,"is_corresponding":false},{"id":270266,"name":"Mandy L. Ford","orcid":"0000-0001-6736-4421","position":6,"is_corresponding":false},{"id":695465,"name":"Kelsey B. Bennion","orcid":"0000-0001-5735-991X","position":0,"is_corresponding":true}],"reference_count":9,"raw_metadata":null,"created_at":"2026-07-19T01:21:57.641539Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}