Angioimmunoblastic T-cell lymphoma with predominant CD8+ tumor-infiltrating T-cells is a distinct immune pattern with an immunosuppressive microenvironment

Abstract

BackgroundAngioimmunoblastic T-cell lymphoma (AITL) has a rich tumor microenvironment (TME) that typically harbors plenty of CD4+tumor infiltrating lymphocytes, (TIL)-T-cells (so called common AITL). Nonetheless, AITL with large numbers of CD8+TIL-Ts that outnumber CD4+cells have been observed (CD8-predominant AITL). However, detailed comparison of CD8-predominant AITL and common AITL are still lacking.MethodsWe compared clinicopathological features, TIL subsets, TME T cell receptor-β (TRB), and immunoglobulin heavy chain (IGH) repertoires, and gene expression profiles in six CD8-predominant and 12 common AITLs using case-control matching (2014 to 2019).ResultsComparing with common AITLs, CD8-predominant AITLs showed more frequent edema (P = 0.011), effusion (P = 0.026), high elevated plasma EBV-DNA (P = 0.008), and shorter survival (P = 0.034). Moreover, they had more pronounced eosinophil increase (P = 0.004) and a higher Ki67 index (P = 0.041). Flow cytometry revealed an inverted CD4/CD8 ratio in TIL-Ts and lower TIL-B proportions (P = 0.041). TRB repertoire metrics deteriorated, including lower productive clones (P = 0.014) and higher clonality score (P = 0.019). The IGH repertoire was also narrowed, showing a higher proportion of the top 10 clones (P = 0.002) and lower entropy (P = 0.027). Gene expression analysis showed significant enrichment for upregulated negative regulation of immune system processes and downregulated T-cell activation and immune cell differentiation.ConclusionOur findings demonstrated that CD8-predominant AITL is a distinct immune pattern of AITL characterized by anti-tumor immunity impairment and an immunosuppressive microenvironment. These characteristics can interpret its severe clinical manifestations and poor outcomes.

High CD8+tumor-infiltrating lymphocytes indicate severe exhaustion and poor prognosis in angioimmunoblastic T-cell lymphoma

“…CD8 + TILs can exert anti-tumor functions ( 11 ) through several pathways such as the release of GZMA and GZMB, Fas-Fas ligand pathway-mediated apoptosis ( 14 , 15 ), and secretion of inflammatory cytokines like IFN-γ ( 16 ) and TNF-α ( 17 ). We previously found that an increase in CD8 + TILs had a negative impact on the prognosis of AITL at the protein level ( 3 , 4 ), and hypothesized that CD8 + TILs are exhausted in AITL. Intriguingly, Pritchett et al.…”

“…On the other hand, there were obvious deficiencies in the biological function of CD8 + TILs in the high CTL group, characterized by the dysregulated expression of genes related to metabolism, mitochondria, and effector function in CD8 + TILs, suggesting a disturbance in normal metabolic processes ( 27 ), mitochondrial dysfunction, and deficiency in energetic adaptations ( 28 , 29 ). Further, several chemokines were enriched in the high-CTL group, which could recruit M2 macrophages ( 30 ) and Tregs ( 31 ), thereby enhancing immune suppression in the TME ( 4 ) and aggravating the exhaustion of CD8 + TILs. In summary, exhausted CD8 + TILs in the high CTL group exhibited abnormal biological changes in addition to high IC expression, suggesting a more severe degree of CD8 + TILs exhaustion in the high CTL group than in the low CTL group, eventually resulting in tumor proliferation ( 32 ) and poor prognosis.…”

Precise diagnosis and treatment for peripheral T-cell lymphomas: From pathogenic mechanisms to innovative approaches

“…278 Accordingly, the survival and proliferation of these malignant T FH cells are highly dependent on their collaboration with GCB cells. 279 Intriguingly, TET2-mutated GCB cells were discovered in the LME, which undergo independent clonal evolution and support the growth of T FH -like tumor cells via the CD40-CD40LG axis in ACH-related TFH lymphoma, angioimmunoblastic type. 96 These genetically aberrant B-cells exhibit a global shift in phenotypes, marked by a decreased expression of CD73 and CXCR5, which are critical molecules for B-cell homing and germinal center formation.…”

Pathobiology of nodal peripheral T-cell lymphomas: current understanding and future directions

“…62,63 Reactive CD8 + cells are variably abundant and may outnumber the CD4 + neoplastic cells. 64 The large B-cell immunoblasts are positive for CD20, PAX5 and CD79a, often CD30, and may also sometimes co-express CD15. They are usually, but not always, infected by EBV (positive for EBV-encoded RNA [EBER] and latent membrane protein 1 [LMP-1]).…”