Cryoablation triggers type I interferon-dependent antitumor immunity and potentiates immunotherapy efficacy in lung cancer.

ABSTRACT

BACKGROUND: Cryoablation is a minimally invasive option for patients with medically inoperable non-small cell lung cancer (NSCLC) and can trigger abscopal immune-regulatory effects. However, it remains unclear how cryoablation affects the host-level immune response in NSCLC. In this study, we investigated the local and systemic immunological effects of cryoablation and the potential of combining cryoablation with programmed cell death protein 1 (PD-1) blockade to boost immunotherapy efficacy in NSCLC. METHODS: We first investigated systemic immunological effects induced by cryoablation in patients with early-stage NSCLC. Subsequently, we explored cryoablation-induced antitumor immunity and the underlying biological mechanisms using KP (Kras G12D/+, Tp53 -/-) mutant lung cancer cell allograft mouse models. Moreover, the synergistic efficacy of cryoablation and PD-1 blockade was explored in both mouse models and patients with unresectable NSCLC. RESULTS: We found that cryoablation significantly increased circulating CD8+ T cell subpopulations and proinflammatory cytokines in patients with early-stage NSCLC. In lung cancer cell allograft mouse models, we demonstrated that cryoablation resulted in abscopal growth inhibition of contralateral, non-ablated tumors. Integrated analysis of bulk, single-cell RNA and T cell receptor (TCR) sequencing data revealed that cryoablation reprogrammed the intratumoral immune microenvironment and increased CD8+ T cell infiltration with higher effector signature, interferon (IFN) response, and cytolytic activity. Mechanistically, cryoablation promoted antitumor effect through the STING-dependent type I IFN signaling pathway, and type I IFN signaling blockade attenuated this antitumor effect. We also found that the combination of PD-1 blockade with cryoablation further inhibited tumor growth compared with either treatment alone in an allograft mouse model. Moreover, the combination therapy induced notable tumor suppression and CD8+ T cell infiltration in patients with unresectable NSCLC. CONCLUSIONS: Our results provide mechanistic insights into how cryoablation triggers the antitumor immune effect in lung cancer, thereby potentiating programmed cell death ligand 1 (PD-L1)/PD-1 blockade efficacy in the clinical treatment of NSCLC.