Protective Cytotoxic Clonal T-Cells in Myeloma Have the Characteristics of Telomere-Independent Senescence Rather Than an Exhausted or Anergic Phenotype: Implications for Immunotherapy

摘要: Dysfunctional T-cells associated with human tumors can be identified utilizing multi-parameter flow cytometry and studied for intracellular signalling checkpoints using phospho-flow or time-of-flight mass spectrometry. Whether tumor-induced hypo-responsive in patients myeloma are anergic, exhausted senescent has not yet been determined. Anergic low cytokine production induce tolerance to protect the host from autoimmune disease. T-cell exhaustion is usually chronic viral infection such as CMV but also some cancers. Both anergic express PD-1, LAG-3, Tim-3, CD160 CD28. Hypo-responsive melanoma have phenotype of which reactivated targeted immune check point blockade, resulting clinical benefit. Senescent accumulate an oligoclonal manner ageing antigen exposure. Senescence characterised by telomere shortening, expression CD57, KLRG-1, absence However, all cells shortened telomeres independent senescence involving p21-p53 p16-pRb pathways secretory (SASP) described. The aim this study was determine whether identify targetable restore function. Cytotoxic clones (CD57+ CD28- TCRVβ restricted) determined BetaMark analysis were present 51% (n=264), protective (OS χ2=6.2; p<0.01) maintain high secretion. CFSE proliferation assays sorted demonstrated a significant lack after stimulation MACS iBeads (n=12; p<0.0001). They failed respond vitro cytokines IL- 2, IL-12, IL-15 OX40. In contrast, proliferative group long term survivors whom universally suggesting that impaired may reversible. Geneset enrichment mRNA Affymetrix U133 plus 2.0 arrays pleiotropic dysfunction multiple involved T cell inactivation. Utilizing techniques we reduced phosphorylated ERK levels clonal vs non-clonal (n=8; p<0.002) well elevated Smad2/3 (n=10; p<0.02) Bcl-xL (n=7; p<0.04) .These findings suggest pathway, proliferation, suppressed, TGFβ pathway activated dysfunctional survival advantage due apoptotic resistance. normal SHP-2 ZAP-70 suggested there no defect upstream TCR signaling. Clonal lacked CD28, CTLA-4, Tim-3 therefore neither nor anergic. assessment qPCR T/S ratios length age significantly less than autologous CD57+TCR-Vβ- cells. had p38 TNF-α inhibiting p38/MAPK pathway. The cytotoxic characteristics telomere-independent senescence. suggests hypo-responsiveness induced telomeres, potentially reversible, though nature might require targeting pathways. PD-1 CTLA-4 checkpoint blockade would unable reverse dysfunction. Disclosures No relevant conflicts interest declare.