Cryoablation and immunity in non-small cell lung cancer: a new era of cryo-immunotherapy

Abstract

Despite remarkable advances in tumor response and patient survival in the past decade, systemic immunotherapies for lung cancer result in an objective response in only around half of patients treated. On the basis of this limitation, combination strategies are being investigated to improve response rates. Cryoablation has been proposed as one such technique to induce immunogenic cell death and synergize with systemic immunotherapies, including immune checkpoint inhibitors. Cryoablation has been traditionally delivered percutaneously with imaging guidance although recent technological advances allow for bronchoscopic delivery. Herein, we review the pre-clinical and clinical evidence for the use of cryoablation in non-small cell lung cancer and potential induction of anti-tumor immunity. We highlight ongoing studies involving this approach and propose areas of future investigation.

Keywords: bronchoscopy; cryoablation; cryotherapy; immune response; lung cancer.

Figure 1

Interactions between the cryoablated tumor and the adaptive and innate immune system. In the proposed mechanism of cryoimmunotherapy, cryoablated tumor cells release tumor antigens, which are taken up by immature myeloid dendritic cells (DCs). In the context of necrotic cell death and generation of inflammatory cytokines after cryoablation, DCs mature and migrate to tumor-draining lymph nodes (TDLN), where they activate tumor-specific T cells, which migrate back to the tumor site. At the same time, dying tumor cells release “danger signals” that recruit macrophages, neutrophils, and natural killer (NK) cells to the tumor site. NK cells can play a direct role in tumor cell lysis. HSP, heat shock protein, HMGB1, high mobility group box 1; MHC, major histocompatibility complex; TNF-α, tumor necrosis factor-α.

Figure 2

Proposed mechanism of synergy between cryoablation and anti–programmed cell death 1 (PD-1) monoclonal antibodies. In the tumor microenvironment after cryoablation, activated CD4-positive T cells augment immune responses through release of the proinflammatory cytokines interferon gamma (IFN-γ) and tumor necrosis factor-α (TNF-α). Activated CD8-positive T cells induce tumor cell lysis through release of granzyme B and perforin. Tumor cells can inhibit infiltrating tumor-specific T cells by up-regulating programmed death ligand 1 (PD-L1) surface expression, which binds PD-1 on the surface of activated T cells. Anti–PD-1 monoclonal antibodies block this inhibitory interaction and sustain T-cell activation.

Figure 3

Potential modalities for delivery of cryotherapy. Percutaneous cryoablation is typically delivered with image guidance (e.g., computed tomography). Bronchoscopic cryotherapy can be delivered to endoluminal lesions in proximal and segmental airways under direct visualization, as well as to more peripheral lesions with the assistance of robotic bronchoscopy. Endobronchial ultrasound guidance may allow for potential to target tumor-draining lymph nodes in the mediastinum.