CD122-selective IL-2 complexes reduce immunosuppression, promote Treg fragility, and sensitize tumor response to PD-L1 blockade

• Published in: Cancer research (Chicago, Ill.) Ill.), 2020-09, Vol.80 (22), p.5063-5075
• Main Authors: Drerup, Justin M., Deng, Yilun, Pandeswara, Sri Lakshmi, Padrón, Álvaro S., Reyes, Ryan M., Zhang, Xinyue, Mendez, Jenny, Liu, Aijie, Clark, Curtis A., Chen, Wanjiao, Conejo-Garcia, José R., Hurez, Vincent, Gupta, Harshita, Curiel, Tyler J.
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-20-0002

The IL-2 receptor (IL-2R) is an attractive cancer immunotherapy target that controls immunosuppressive T regulatory cells (Tregs) and anti-tumor T cells. Here we used IL-2Rβ-selective IL-2/anti-IL-2 complexes (IL-2c) to stimulate effector T cells preferentially in the orthotopic mouse ID8agg ovarian cancer (OC) model. Despite strong tumor rejection, IL-2c unexpectedly lowered the tumor microenvironmental CD8 + /Treg ratio. IL-2c 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. IL-2c also reduced Treg-mediated, high-affinity IL-2R signaling needed for optimal Treg functions, a likely mechanism for reduced Treg suppression. Effector T cell IL-2R signaling was simultaneously improved, suggesting that IL-2c 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 IL-2c generated complete tumor regressions and protective immune memory not achieved by either monotherapy. Similar anti-PD-L1 augmentation of IL-2c and degradation of Treg functions were seen in subcutaneous B16 melanoma. Thus, IL-2c 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.