Hyperthermia combined with immune checkpoint inhibitor therapy: Synergistic sensitization and clinical outcomes

Abstract

Background: Within the field of oncotherapy, research interest regarding immunotherapy has risen to the point that it is now seen as a key application. However, inherent disadvantages of immune checkpoint inhibitors (ICIs), such as their low response rates and immune-related adverse events (irAEs), currently restrict their clinical application. Were these disadvantages to be overcome, more patients could derive prolonged benefits from ICIs. At present, many basic experiments and clinical studies using hyperthermia combined with ICI treatment (HIT) have been performed and shown the potential to address the above challenges. Therefore, this review extensively summarizes the knowledge and progress of HIT for analysis and discusses the effect and feasibility.

Methods: In this review, we explored the PubMed and clinicaltrials.gov databases, with regard to the searching terms "immune checkpoint inhibitor, immunotherapy, hyperthermia, ablation, photothermal therapy".

Results: By reviewing the literature, we analyzed how hyperthermia influences tumor immunology and improves the efficacy of ICI. Hyperthermia can trigger a series of multifactorial molecular cascade reactions between tumors and immunization and can significantly induce cytological modifications within the tumor microenvironment (TME). The pharmacological potency of ICIs can be enhanced greatly through the immunomodulatory amelioration of immunosuppression, and the activation of immunostimulation. Emerging clinical trials outcome regarding HIT have verified and enriched the theoretical foundation of synergistic sensitization.

Conclusion: HIT research is now starting to transition from preclinical studies to clinical investigations. Several HIT sensitization mechanisms have been reflected and demonstrated as significant survival benefits for patients through pioneering clinical trials. Further studies into the theoretical basis and practical standards of HIT, combined with larger-scale clinical studies involving more cancer types, will be necessary for the future.

Keywords: hyperthermia; immune checkpoint inhibitor; synergistic sensitization; tumor immunosuppression.

FIGURE 1

Schematic of the mechanisms of PD‐L1/PD‐1 and CTLA‐4 inhibitors. ①: The tumor antigens are taken up and processed by APC and presented to CD4+T cells and CD8+T cells. ②: The activation and proliferation of CD8+T cells can be triggered by APC through the combination of MHC‐I and TCR; CD4+T cells stimulated by APC promote this process. Meanwhile, CD28 and CTLA‐4 on T cells competitively bind to the B7 ligand expressed on APC; the former can facilitate the activation and proliferation of CD8+T, while for the latter the opposite is true. This immunosuppression can be antagonized by CTLA‐4 inhibitors. ③: Immune killing by increased and activated CD8+T cells elicits more antigens, which achieves positive feedback. The overexpression of PD‐L1 in immunosuppressive tumor cells can impede the immunopotency of CTL; PD‐1/PD‐L1 inhibitors could remit this.

FIGURE 2

Guided by seven heat effects, a battery of lethal and sublethal biologic alterations in tumor cells interact with immunocytes to induce the generation of DAMP. The number of immune‐activated subtypes and the tumor‐killing potency of NK cells is greatly augmented in the TME under DAMP.