Highly prevalent colorectal cancer-infiltrating LAP⁺ Foxp3⁻ T cells exhibit more potent immunosuppressive activity than Foxp3⁺ regulatory T cells.
Although elevated CD4⁺Foxp3⁺ regulatory T cell (Treg) frequencies within tumors are well documented, the functional and phenotypic characteristics of CD4⁺Foxp3⁺ and CD4⁺Foxp3⁻ T cell subsets from matched blood, healthy colon, and colorectal cancer require in-depth investigation. Flow cytometry revealed that the majority of intratumoral CD4⁺Foxp3⁺ T cells (Tregs) were Helios⁺ and expressed higher levels of cytotoxic T-lymphocyte antigen 4 (CTLA-4) and CD39 than Tregs from colon and blood. Moreover, ∼30% of intratumoral CD4⁺Foxp3⁻ T cells expressed markers associated with regulatory functions, including latency-associated peptide (LAP), lymphocyte activation gene-3 (LAG-3), and CD25. This unique population of cells produced interleukin-10 (IL-10) and transforming growth factor-β (TGF-β), and was ∼50-fold more suppressive than Foxp3⁺ Tregs. Thus, intratumoral Tregs are diverse, posing multiple obstacles to immunotherapeutic intervention in colorectal malignancies.
Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK.
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Scurr
Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK.
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Ladell
Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK.
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Besneux
Department of Pathology, University Hospital of Wales, Cardiff, UK.
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Christian
Department of Pathology, University Hospital of Wales, Cardiff, UK.
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Hockey
Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK.
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Smart
Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK.
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Bridgeman
Department of Surgery, University Hospital of Wales, Cardiff, UK.
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Hargest
Department of Surgery, University Hospital of Wales, Cardiff, UK.
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Phillips
Department of Surgery, University Hospital of Wales, Cardiff, UK.
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Davies
Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK.
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Price
Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK.
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Gallimore
Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK.
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Godkin
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D016130:Immunophenotyping; D060889:Inducible T-Cell Co-Stimulator Protein / Q000378:metabolism; D039001:Integrin alpha Chains / Q000378:metabolism; D016753:Interleukin-10 / Q000096:biosynthesis; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010641:Phenotype; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D000093322:Lymphocyte Activation Gene 3 Protein
D015703:Antigens, CD; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D060889:Inducible T-Cell Co-Stimulator Protein; D039001:Integrin alpha Chains; D016212:Transforming Growth Factor beta; C091367:alpha E integrins; D016753:Interleukin-10; D000093322:Lymphocyte Activation Gene 3 Protein; C000720326:Lag3 protein, human