TIGIT is a key inhibitory checkpoint receptor in lymphoma.

Autor:	Godfrey J; Hematology, City of Hope Comprehensive Cancer Center, Duarte, California, USA., Chen X; Comprehensive Cancer Center, University of Chicago, Chicago, Illinois, USA., Sunseri N; Comprehensive Cancer Center, University of Chicago, Chicago, Illinois, USA., Cooper A; Comprehensive Cancer Center, University of Chicago, Chicago, Illinois, USA., Yu J; Comprehensive Cancer Center, University of Chicago, Chicago, Illinois, USA., Varlamova A; BostonGene, Waltham, Massachusetts, USA., Zarubin D; BostonGene, Waltham, Massachusetts, USA., Popov Y; BostonGene, Waltham, Massachusetts, USA., Jacobson C; BostonGene, Waltham, Massachusetts, USA., Postovalova E; BostonGene, Waltham, Massachusetts, USA., Xiang Z; BostonGene, Waltham, Massachusetts, USA., Nomie K; BostonGene, Waltham, Massachusetts, USA., Bagaev A; BostonGene, Waltham, Massachusetts, USA., Venkataraman G; Comprehensive Cancer Center, University of Chicago, Chicago, Illinois, USA., Zha Y; Comprehensive Cancer Center, University of Chicago, Chicago, Illinois, USA., Tumuluru S; Comprehensive Cancer Center, University of Chicago, Chicago, Illinois, USA., Smith SM; Comprehensive Cancer Center, University of Chicago, Chicago, Illinois, USA., Kline JP; Comprehensive Cancer Center, University of Chicago, Chicago, Illinois, USA jkline@medicine.bsd.uchicago.edu.
Jazyk:	angličtina
Zdroj:	Journal for immunotherapy of cancer [J Immunother Cancer] 2023 Jun; Vol. 11 (6).
DOI:	10.1136/jitc-2022-006582
Abstrakt:	Background: PD-1 checkpoint blockade therapy (CBT) has greatly benefited patients with select solid tumors and lymphomas but has limited efficacy against diffuse large B-cell lymphoma (DLBCL). Because numerous inhibitory checkpoint receptors have been implicated in driving tumor-specific T cell dysfunction, we hypothesized that combinatorial CBT would enhance the activity of anti-PD-1-based therapy in DLBCL. T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) is a coinhibitory receptor expressed on dysfunctional tumor-infiltrating T cells, and TIGIT blockade has demonstrated encouraging activity in combination with PD-1 blockade in murine tumor models and in clinical studies. However, the degree to which TIGIT mediates T cell dysfunction in DLBCL has not been fully explored. Results: Here, we demonstrate that TIGIT is broadly expressed on lymphoma-infiltrating T cells (LITs) across a variety of human lymphomas and is frequently coexpressed with PD-1. TIGIT expression is particularly common on LITs in DLBCL, where TIGIT + LITs often form distinct cellular communities and exhibit significant contact with malignant B cells. TIGIT + /PD-1 + LITs from human DLBCL and murine lymphomas exhibit hypofunctional cytokine production on ex vivo restimulation. In mice with established, syngeneic A20 B-cell lymphomas, TIGIT or PD-1 mono-blockade leads to modest delays in tumor outgrowth, whereas PD-1 and TIGIT co-blockade results in complete rejection of A20 lymphomas in most mice and significantly prolongs survival compared with mice treated with monoblockade therapy. Conclusions: These results provide rationale for clinical investigation of TIGIT and PD-1 blockade in lymphomas, including DLBCL. Competing Interests: Competing interests: ST, JY, XC, NS and AC have no conflicts of interest to disclose. JG receives research support from Merck and Secura Bio. SMS has served as a consultant for Morphosys/Incyte, Janssen, BMS, Karyopharm, TGTX, and Celgene, and has research funding from FortySeven, TG Therapeutics, Pharmacyclics, Acerta, Karyopharm, Portola, Celgene, Novartis, Genentech/Roche, and Epizyme. JPK receives research support from Merck, Secura Bio, and iTeos, has served on a Speakers Bureau for Kite/Gilead, and has served on advisory boards for Verastem, Seattle Genetics, MorphoSys, and Karyopharm. Arina Varlamova, Dmitry Zarubin, Yuriy Popov, Connor A. Jacobson, Ekaterina Postovalova, Zhongmin Xiang, Krystle Nomie, and Aleksander Bagaev are employees of BostonGene. (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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