Bréart, Williams, and Krimm et al. showed that in human and mouse tumors, DC-expressed IL-27 strongly associated with the CTL signature. In mouse tumor models, impairing IL-27 signaling showed that IL-27 acted directly on tumor-specific CTLs in the TME to boost their abundance and function. Conversely, IL-27R agonism promoted expression of the cytolytic program in antitumor CTLs, regression of established tumors, and efficacy of PD-L1 blockade, and was well tolerated. High IL-27 levels correlated with favorable ICB responses in patients with cancer. Under ex vivo conditions of chronic antigen stimulation, IL-27 promoted human CTL function.
Contributed by Paula Hochman
ABSTRACT: Although cytotoxic CD8(+) T lymphocytes (CTLs) are essential for anti-tumour immunity, they are frequently dysfunctional in tumours(1). Cytokines that sustain CTL activity are attractive for cancer immunotherapy, but avoiding inflammatory toxicity remains a challenge for their clinical use(2). Here we show that expression of a CTL signature is strongly associated with IL27 expression in human and mouse tumours. In mice, IL-27 acts directly on tumour-specific CTLs to promote their persistence and effector function in the tumour microenvironment. Moreover, treatment with inducible IL-27 overexpression or a half-life-extended IL-27 protein in vivo is well tolerated, induces regression of established tumours, drives an enhanced cytotoxic program in anti-tumour CTLs and synergizes with PD-L1 blockade. In patients with cancer who were treated with anti-PD-1/PD-L1 therapy, high expression of IL-27 correlates with a favourable clinical response, and IL-27 supports human CTL function during chronic antigen stimulation ex vivo. Our data demonstrate that endogenous IL-27 is essential for anti-tumour immunity and that IL-27 receptor agonism can safely improve anti-tumour T cell responses alone or in combination with PD-L1 blockade.
Author Info: (1) Genentech, South San Francisco, CA, USA. (2) Genentech, South San Francisco, CA, USA. (3) Genentech, South San Francisco, CA, USA. (4) Genentech, South San Francisco, CA, USA.
Author Info: (1) Genentech, South San Francisco, CA, USA. (2) Genentech, South San Francisco, CA, USA. (3) Genentech, South San Francisco, CA, USA. (4) Genentech, South San Francisco, CA, USA. (5) Genentech, South San Francisco, CA, USA. (6) Genentech, South San Francisco, CA, USA. (7) Genentech, South San Francisco, CA, USA. (8) Genentech, South San Francisco, CA, USA. (9) Genentech, South San Francisco, CA, USA. (10) Genentech, South San Francisco, CA, USA. (11) Genentech, South San Francisco, CA, USA. (12) Genentech, South San Francisco, CA, USA. (13) Genentech, South San Francisco, CA, USA. (14) Genentech, South San Francisco, CA, USA. (15) Genentech, South San Francisco, CA, USA. (16) Genentech, South San Francisco, CA, USA. (17) Genentech, South San Francisco, CA, USA. (18) Genentech, South San Francisco, CA, USA. (19) Genentech, South San Francisco, CA, USA. (20) Genentech, South San Francisco, CA, USA. (21) Genentech, South San Francisco, CA, USA. (22) Genentech, South San Francisco, CA, USA. (23) Genentech, South San Francisco, CA, USA. (24) Genentech, South San Francisco, CA, USA. (25) Genentech, South San Francisco, CA, USA. (26) Genentech, South San Francisco, CA, USA. (27) Genentech, South San Francisco, CA, USA. (28) Genentech, South San Francisco, CA, USA. (29) Genentech, South San Francisco, CA, USA. (30) Genentech, South San Francisco, CA, USA. (31) Genentech, South San Francisco, CA, USA. (32) Genentech, South San Francisco, CA, USA. (33) Genentech, South San Francisco, CA, USA. (34) Genentech, South San Francisco, CA, USA. (35) Genentech, South San Francisco, CA, USA. (36) Genentech, South San Francisco, CA, USA. muller.soren@gene.com. (37) Genentech, South San Francisco, CA, USA. west.nathaniel@gene.com.
