Barriers to Radiation-Induced In Situ Tumor Vaccination

Abstract

The immunostimulatory properties of radiation therapy (RT) have recently generated widespread interest due to preclinical and clinical evidence that tumor-localized RT can sometimes induce antitumor immune responses mediating regression of non-irradiated metastases (abscopal effect). The ability of RT to activate antitumor T cells explains the synergy of RT with immune checkpoint inhibitors, which has been well documented in mouse tumor models and is supported by observations of more frequent abscopal responses in patients refractory to immunotherapy who receive RT during immunotherapy. However, abscopal responses following RT remain relatively rare in the clinic, and antitumor immune responses are not effectively induced by RT against poorly immunogenic mouse tumors. This suggests that in order to improve the pro-immunogenic effects of RT, it is necessary to identify and overcome the barriers that pre-exist and/or are induced by RT in the tumor microenvironment. On the one hand, RT induces an immunogenic death of cancer cells associated with release of powerful danger signals that are essential to recruit and activate dendritic cells (DCs) and initiate antitumor immune responses. On the other hand, RT can promote the generation of immunosuppressive mediators that hinder DCs activation and impair the function of effector T cells. In this review, we discuss current evidence that several inhibitory pathways are induced and modulated in irradiated tumors. In particular, we will focus on factors that regulate and limit radiation-induced immunogenicity and emphasize current research on actionable targets that could increase the effectiveness of radiation-induced in situ tumor vaccination.

Keywords: abscopal effect; adenosine; hypoxia; immunotherapy; macrophages; radiation therapy; transforming growth factor-β; tumor microenvironment.

Figure 1

Immunosuppressive pathways enhanced by RT in the TME that limit RT-induced in situ vaccination. (A) DCs are recruited to the tumor and activated following RT-mediated induction of ICD and subsequent release of DAMPs in the TME [including ATP, depicted in (E)]. After uptake of TAAs that are released from dying tumor cells DCs become activated and migrate to tumor-draining lymph nodes where they cross-present the antigens to naïve T cells. The activated TAA-specific CD8⁺ T cells proliferate, acquire effector function, and infiltrate the irradiated tumor and abscopal sites where they eliminate tumor cells. However, RT promotes not only immune stimulation but also contributes to a suppressive TME that counteracts the newly initiated immune response. (B) Hypoxic regions within tumors have reduced sensitivity to RT and a suppressive TME that can be exacerbated following RT. RT upregulates transcription of HIF-1α resulting in expression of a series of genes that promote immunosuppression, by inducing Treg proliferation, M2 polarization of TAMs, and MDSC activation. (C) C–C chemokine receptor type 2 (CCR2)-expressing monocytes are recruited to the tumor due to increased CCL2 levels following RT. In the tumor, monocytes then differentiate to TAMs. RT can also directly modulate TAMs through induction of CSF1 causing mobilization, proliferation, and polarization of TAMs to an M2 phenotype. (D) RT activates latent TGFβ within the tumor that causes conversion of CD4⁺ T cells to Tregs, and polarization of TAMs and TANs to an M2 and N2 phenotype, respectively. (E) Tumor cells undergoing radiation-induced ICD release ATP, which is rapidly catabolized into adenosine in the TME by ectoenzymes CD39 and CD73 expressed on tumor cells, stromal cells, and immune cells. Local accumulation of extracellular adenosine suppresses DCs and effector T cells while promoting proliferation of Tregs and a more suppressive phenotype in TAMs. DC, dendritic cell; ICD, immunogenic cell death; RT, radiation therapy; DAMPs, danger-associated molecular patterns; TAA, tumor-associated antigens; TME, tumor microenvironment; pMHC-1, peptide-loaded major histocompatibility class I complex; TCR, T cell receptor; HIF-1α, hypoxia-inducible factor-1α; VEGFA, vascular endothelial growth factor A; CTLA-4, cytotoxic T lymphocyte-associated protein 4; PD-1, programmed cell death protein-1; TIM-3, T-cell immunoglobulin and mucin-domain containing-3; LAG-3, lymphocyte-activation gene 3; Treg, regulatory T cell; TGFβ, transforming growth factor β; TAM, tumor-associated macrophage; MDSC, myeloid-derived suppressor cell; CSF1, colony-stimulating factor 1; TAN, tumor-associated neutrophil; ATP, adenosine triphosphate.