Antigen Selection Shapes the T-cell Repertoire in Chronic Lymphocytic Leukemia

Abstract

Purpose: The role of antigen(s) in shaping the T-cell repertoire in chronic lymphocytic leukemia, although relevant for understanding malignant cell interactions with cognate T cells, is largely unexplored.Experimental Design: Here we profiled the T-cell receptor b chain gene repertoire in 58 chronic lymphocytic leukemia patients, focusing on cases assigned to well-characterized subsets with stereotyped clonotypic B-cell receptor immunoglobulins, therefore those cases most evidently selected by antigen (subsets #1, #2, and #4).Results: Remarkable repertoire skewing and oligoclonality were observed, and differences between subsets were noted regarding both T-cell receptor b chain gene usage and the extent of clonality, with subset #2 being the least oligoclonal. Longitudinal analysis of subset #4 cases revealed that although the repertoire may fluctuate over time, certain clonotypes persist, thus alluding to persistent antigenic stimulation. Shared ("stereotyped") clonotypes were found between different patients, reflecting selection by common antigenic elements. Cross-comparison of our dataset with public databases showed that some T-cell clonotypes may have expanded secondary to common viral infections; however, the majority of clonotypes proved to be disease-specific.Conclusions: Overall, the T-cell receptor b chain repertoire in chronic lymphocytic leukemia is likely shaped by antigen selection and the implicated antigenic elements may concern epitopes that also select the malignant B-cell progenitors or, more intriguingly, chronic lymphocytic leukemia-derived epitopes.

Ibrutinib Therapy Increases T Cell Repertoire Diversity in Patients with Chronic Lymphocytic Leukemia

“…In these areas, CLL cells are interspersed with T cells, which co-localize with Ki67 + proliferating CLL cells, suggesting that T cells provide help to the CLL cells for promoting their expansion (4–6). PB T cell numbers in untreated CLL patients are elevated and oligoclonal (4, 7), and emerging data indicate that these CLL T cells expand in an antigen-dependent fashion, in a process that resembles normal adaptive immune responses to antigen (8–10). Prior studies reported about T cell repertoire skewing and oligoclonality in CLL patients based on flow cytometric analysis, spectratyping (9, 11–13), and T cell receptor beta sequencing (10).…”

“…PB T cell numbers in untreated CLL patients are elevated and oligoclonal (4, 7), and emerging data indicate that these CLL T cells expand in an antigen-dependent fashion, in a process that resembles normal adaptive immune responses to antigen (8–10). Prior studies reported about T cell repertoire skewing and oligoclonality in CLL patients based on flow cytometric analysis, spectratyping (9, 11–13), and T cell receptor beta sequencing (10). TCRαβ diversity is generated by random rearrangements of V and J segments in the TCRα gene and V, D, and J segments in the TCRβ gene, concurrent with non-templated nucleotide insertions and deletions at the junctions (N-region); the resulting NDN region along with short segments of the flanking V and J genes comprise the complementarity-determining regions 3 (CDR3) of the TCR, which is primarily responsible for recognition of antigenic peptides (14).…”

Spatiotemporal homogeneity and distinctness of the T‐cell receptor β‐chain repertoires in Epstein–Barr virus‐associated primary and metastatic nasopharyngeal carcinomas

“…In combination with the tumor‐shared and organ‐specific clonotypes with their frequencies, the TCR beta overlap rates and genetic distance between the initial primary NPCs and the subsequently developed distant metastatic tumors in the same patient after chemoradiotherapy were still up to 17.5–45.5% and close to 1.2–4.7, respectively, in contrast to the relatively long genetic distance from 27.4 to 32,518.6 between different NPCs. Our results demonstrated that a few common subsets of T‐cell clones of TILs found in primary NPCs were persistently juxtaposed to distant metastatic NPC cells regardless of anatomic location, physiological microenvironment and developmental time of metastasis (Table ) and were not matched to any known T‐cell clones specific to EBV, other viruses or neoantigens in the public databases despite the persistent presence of EBV in metastatic epithelial cancer cells …”

“…We next compared the 302,452 in‐frame TCR beta CDR3 amino acid sequences from the EBV‐associated NPC‐infiltrating lymphocytes against the public database sequences . Only 18 of the sequences were found to have identical matches to the known CD8 + T‐cell clones corresponding to EBV infection and were specific for the epitopes of BZLF1 or BMLF1 of the EBV lytic proteins in 32 patients (38%) (Table ).…”

Problems of Cancer Treatment. Part I. Theory of Treatment Based on Known Mechanisms of Anticancer Immunological Responses

“…Their very early stages remain unknown but considering behaviour of cells in one of leukaemias (chronic B-cell laukaemia) [90,146], certain hypotheses can be suggested. Normal B lymphocytes of CD19 + CD5 + subpopulation continuously produce antibodies and in that function require no activation by T lymphocytes.…”