CD122-selective IL2 complexes reduce immunosuppression, promote treg fragility, and sensitize tumor response to PD-L1 blockade

Justin M. Drerup, Yilun Deng, Sri Lakshmi Pandeswara, Álvaro S. Padrón, Ryan M. Reyes, Xinyue Zhang, Jenny Mendez, Aijie Liu, Curtis A. Clark, Wanjiao Chen, José R. Conejo-Garcia, Vincent Hurez, Harshita Gupta, Tyler J. Curiel

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)5063-5075
Number of pages13
JournalCancer Research
Volume80
Issue number22
DOIs
StatePublished - Nov 15 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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