CD122-Selective IL2 Complexes Reduce Immunosuppression, Promote Treg Fragility, and Sensitize Tumor Response to PD-L1 Blockade.

Autor:	Drerup JM; Department of Cell Systems and Anatomy, The Graduate School of Biomedical Sciences, University of Texas Health San Antonio, Texas.; Department of Medicine, University of Texas Health San Antonio, Texas., Deng Y; Department of Medicine, University of Texas Health San Antonio, Texas., Pandeswara SL; Department of Medicine, University of Texas Health San Antonio, Texas., Padrón ÁS; Department of Medicine, University of Texas Health San Antonio, Texas., Reyes RM; Department of Microbiology, Immunology and Molecular Genetics, The Graduate School of Biomedical Sciences, University of Texas Health San Antonio, Texas., Zhang X; Sun Yat-sen University, Guangzhou, Guangdong, P.R.China., Mendez J; Department of Medicine, University of Texas Health San Antonio, Texas., Liu A; Department of Medicine, University of Texas Health San Antonio, Texas., Clark CA; Department of Medicine, University of Texas Health San Antonio, Texas.; Department of Microbiology, Immunology and Molecular Genetics, The Graduate School of Biomedical Sciences, University of Texas Health San Antonio, Texas., Chen W; Xiangya Medical School, Changsha, Hunan, China., Conejo-Garcia JR; Department of Immunology, Moffitt Cancer Center, Tampa, Florida., Hurez V; Department of Medicine, University of Texas Health San Antonio, Texas., Gupta H; Department of Medicine, University of Texas Health San Antonio, Texas., Curiel TJ; Department of Medicine, University of Texas Health San Antonio, Texas. curielt@uthscsa.edu.; Department of Microbiology, Immunology and Molecular Genetics, The Graduate School of Biomedical Sciences, University of Texas Health San Antonio, Texas.; Mays Family Cancer Center, University of Texas Health San Antonio, Texas.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2020 Nov 15; Vol. 80 (22), pp. 5063-5075. Date of Electronic Publication: 2020 Sep 18.
DOI:	10.1158/0008-5472.CAN-20-0002
Abstrakt:	The IL2 receptor (IL2R) is an attractive cancer immunotherapy target that controls immunosuppressive T regulatory cells (Treg) and antitumor T cells. Here we used IL2Rβ-selective IL2/anti-IL2 complexes (IL2c) to stimulate effector T cells preferentially in the orthotopic mouse ID8agg ovarian cancer model. Despite strong tumor rejection, IL2c unexpectedly lowered the tumor microenvironmental CD8 + /Treg ratio. IL2c reduced tumor microenvironmental Treg suppression and induced a fragile Treg phenotype, helping explain improved efficacy despite numerically increased Tregs without affecting Treg in draining lymph nodes. IL2c also reduced Treg-mediated, high-affinity IL2R signaling needed for optimal Treg functions, a likely mechanism for reduced Treg suppression. Effector T-cell IL2R signaling was simultaneously improved, suggesting that IL2c inhibits Treg functions without hindering effector T cells, a limitation of most Treg depletion agents. Anti-PD-L1 antibody did not treat ID8agg, but adding IL2c generated complete tumor regressions and protective immune memory not achieved by either monotherapy. Similar anti-PD-L1 augmentation of IL2c and degradation of Treg functions were seen in subcutaneous B16 melanoma. Thus, IL2c is a multifunctional immunotherapy agent that stimulates immunity, reduces immunosuppression in a site-specific manner, and combines with other immunotherapies to treat distinct tumors in distinct anatomic compartments. SIGNIFICANCE: These findings present CD122-targeted IL2 complexes as an advancement in cancer immunotherapy, as they reduce Treg immunosuppression, improve anticancer immunity, and boost PD-L1 immune checkpoint blockade efficacy in distinct tumors and anatomic locations. (©2020 American Association for Cancer Research.)
Databáze:	MEDLINE
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