Unlocking the combination: potentiation of radiation-induced antitumor responses with immunotherapy

Abstract

There is increasing evidence of the potential for radiation therapy to generate antitumor immune responses. The mechanisms of this immune-activating potential include actions on tumor cells such as immunogenic cell death and phenotypic change. Radiation modulates tumor cell surface expression of cell death receptors, tumor-associated antigens and adhesion molecules. This process of immunomodulation sensitizes tumor cells to immune-mediated killing. Radiation also affects immune compartments, including antigen-presenting cells, cytotoxic T lymphocytes and humoral immunity, leading to specific antitumor immune responses. Recognizing the importance of immunity as a potentiator of response to radiation leads to rational augmentation of antitumor immunity by combining radiation and immunotherapy. Targeted immunotherapy manipulates the immune system in a way that best synergizes with radiation. This article discusses the ability of radiation monotherapy to induce antitumor immunity, with a focus on the effect of radiation on antigen-presenting cells and cytotoxic T lymphocytes. We define two important responses generated by tumor cells, immunogenic cell death and immunomodulation, both of which are radiation dose-dependent. In conclusion, we describe the translation of several combination therapies from the preclinical to the clinical setting and identify opportunities for further exploration.

FIG. 1

Molecular determinants of radiation effects. Immune-relevant characteristics of radiation-induced necrosis, ICD and IM, as well as real and potential immunotherapeutic interventions.

FIG. 2

Phenotypic changes in tumor cells postirradiation increase sensitivity to T-cell lysis. Panel A: Expression of upregulated Fas on tumor cells postirradiation is maintained for >11 days. C57BL/6 mice were injected with MC38-CEA⁺ tumor cells subcutaneously, 14 days later, tumors were subjected to EBRT (8 Gy). Tumors were surgically removed at several time points after RT and analyzed for Fas expression by flow cytometry and immunohistochemistry. Panel B: Irradiation of tumor cells in vivo enhances efficacy of vaccine therapy. CEA-transgenic mice were injected with MC38-CEA⁺ tumor cells subcutaneously. As indicated, mice received no treatment; were vaccinated with rV-CEA/TRICOM on day 8 (closed triangles) followed by boosting with rF-CEA/TRICOM on days 15, 22 and 29 (gray triangles); subjected to fractionated EBRT (2 Gy) in situ on days 11, 12, 13 and 14 (open inverted triangles); or were vaccinated on day 8 (closed triangles) and subjected to fractionated EBRT. A subset of mice from each treatment group had tumors surgically removed at day 21 post-tumor transplant. Tumors were then stained with CEA and Fas antibodies. Inset panels: % Fas⁺ cells (mean fluorescence intensity). Taken from ref. (34). Panel C: Irradiation increases human tumor cell sensitivity to antigen-specific CTL killing. CEA⁺ human tumor cells were mock irradiated (gray bar) or irradiated with 10 Gy (black bar) and re-cultured for 72 h, then coincubated with HLA-A2-restricted CEA-specific CTLs. All cell lines were both CEA⁺ and HLA-A2⁺. Taken from ref. (33).

FIG. 3

Combination therapy with anti-CTLA-4 and palliative radiation. Panel A: Patient presented with metastatic melanoma, received anti-CTLA-4, progressed and received palliative RT for a paraspinal mass. Improvement was seen in irradiated mass as well as metastatic lesion outside the radiation field. Induction of antigen-specific T- and B-cell responses were also seen. Adapted from ref. (43). Panel B: Proposed mechanism of action for anti-CTLA-4 and RT-induced primary immune responses. Panel C: Further expansion of RT-induced tumor-specific T cells.

FIG. 4

Impact of high-dose ablative RT on tumor microenvironment. High-dose ablative RT given in lattice (2 vertices) to the tumor induces bystander/abscopal effect, endothelial-cell death coupled with immune activation. The underlying radiobiological mechanisms for improved outcome with high-dose hypofractionated RT may be multifactorial, including differential effects on tumor endothelium and cancer stem cells. Complex immunologic pathways may be linked to high-dose radiation-induced mechanisms. All of these pathways may be affected by bystander/abscopal factors released by the tumor after high dose spatially fractionated RT. Taken from ref. (65).

FIG. 5

Combination therapy with vaccine and palliative radionuclide. Panel A: Irradiation modulates tumor-cell phenotype and increases immune recognition. Irradiation can cause: 1. upregulation of chemokines and adhesion molecules that signal T cells to traffic to areas of tumor; 2. upregulation of MHC molecules and TAAs, facilitating T-cell recognition of tumor; and 3. upregulation of Fas and downregulation of Tregs, facilitating tumor-specific CTL killing. Taken from ref. (3). Panel B: Effect of ¹⁵³Sm-EDTMP on sensitivity of human prostate cancer cells to antigen-specific CTL killing. LNCaP cells were exposed to 0, 25 or 50 Gy of ¹⁵³Sm-EDTMP. Cells were harvested 72 h after exposure and incubated with PSA- or MUC-1-specific T cells. Taken from ref. (58).