4.5 Article

Intratumoral T-cell receptor repertoire is predictive of interim PET scan results in patients with diffuse large B-cell lymphoma treated with rituximab/cyclophosphamide/doxorubicin/prednisolone/vincristine (R-CHOP) chemoimmunotherapy

期刊

CLINICAL & TRANSLATIONAL IMMUNOLOGY
卷 10, 期 11, 页码 -

出版社

WILEY
DOI: 10.1002/cti2.1351

关键词

immunotherapy; interim PET; lymphoma; TCR repertoire

资金

  1. Mater foundation Betty McGrath Fellowship
  2. National Health and Medical Research Council Early Career Fellowship
  3. Princess Alexandra Hospital Award
  4. Cancer Australia/Cancer Cure Grant [1161139]
  5. Australian Government

向作者/读者索取更多资源

This study found that clonally expanded intratumoral TCR repertoires are associated with iPET(+) and that the blood can be used to track tumor-associated antigen-specific clonotypes. The diversity of TCR repertoire, relationships between intratumoral and circulating repertoire, and phenotypes of expanded clonotypes were explored in patients with high-risk DLBCL. The majority of shared clonotypes were CD8(+) PD-1(HI) T cells, and CD8(+) T cells had the largest clonal expansions in tumor and blood.
Objectives. A diverse intratumoral T-cell receptor (TCR) repertoire is associated with improved survival in diffuse large B-cell lymphoma (DLBCL) treated with rituximab/cyclophosphamide/doxorubicin/prednisolone/vincristine (R-CHOP) chemoimmunotherapy. We explored the impact of intratumoral TCR repertoire on interim PET (iPET) done after four cycles of R-CHOP, the relationships between intratumoral and circulating repertoire, and the phenotypes of expanded clonotypes. Methods. We sequenced the third complementarity-determining region of TCR beta in tumor samples, blood at pre-therapy and after four cycles of R-CHOP in 35 patients enrolled in ALLGNHL21 trial in high-risk DLBCL. We correlated the TCR diversity metrics with iPET status, gene expression profiles and HLA-class I genotypes. We then sequenced the FACS-sorted peripheral blood T cells in six patients, and pentamer-sorted EBV-specific CD8(+) T cells in one patient from this cohort. Results. Compared with iPET(-) patients, the intratumoral TCR repertoire in iPET(+) patients was characterised by higher cumulative frequency of abundant clonotypes and higher productive clonality. There was a variable overlap between circulating and intratumoral repertoires, with the dominant intratumoral clonotypes more likely to be detected in the blood. The majority of shared clonotypes were CD8(+) PD-1(HI) T cells, and CD8(+) T cells had the largest clonal expansions in tumor and blood. In a patient with EBV+ DLBCL, EBV-specific intratumoral clonotypes were trackable in the blood. Conclusion. This study demonstrates that clonally expanded intratumoral TCR repertoires are associated with iPET(+) and that the blood can be used to track tumor-associated antigen-specific clonotypes. These findings assist the rationale design and therapeutic monitoring of immunotherapeutic strategies in DLBCL.

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