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

Mohamed Shanavas; Soi-Cheng Law; Mark Hertzberg; Rodney J Hicks; John F Seymour; Zhixiu Li; Lilia Merida de Long; Karthik Nath; Muhammed B Sabdia; Jay Gunawardana; Maher K Gandhi; Colm Keane

doi:10.1002/cti2.1351

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

Clin Transl Immunology. 2021 Oct 27;10(11):e1351. doi: 10.1002/cti2.1351. eCollection 2021.

Authors

Mohamed Shanavas^{1

2}, Soi-Cheng Law¹, Mark Hertzberg³, Rodney J Hicks⁴, John F Seymour⁵, Zhixiu Li⁶, Lilia Merida de Long¹, Karthik Nath¹, Muhammed B Sabdia¹, Jay Gunawardana¹, Maher K Gandhi^{1

7}, Colm Keane^{1

7}

Affiliations

¹ Mater Research University of Queensland Brisbane QLD Australia.
² Department of Haematology Mater Hospital Brisbane QLD Australia.
³ Department of Haematology Prince of Wales Hospital and University of NSW Randwick NSW Australia.
⁴ Department of Cancer Imaging Peter MacCallum Cancer Centre East Melbourne Melbourne VIC Australia.
⁵ Department of Haematology Peter MacCallum Cancer Centre Royal Melbourne Hospital & University of Melbourne Parkville VIC Australia.
⁶ Centre for Genomics and Personalised Health School of Biomedical Sciences, Faculty of Health Translational Research Institute Queensland University of Technology (QUT) Woolloongabba QLD Australia.
⁷ Department of Haematology Princess Alexandra Hospital Brisbane QLD Australia.

Abstract

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 TCRβ 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.

Keywords: TCR repertoire; immunotherapy; interim PET; lymphoma.