Ablative Tumor Radiation Can Change the Tumor Immune Cell Microenvironment to Induce Durable Complete Remissions

Abstract

Purpose The goals of the study were to elucidate the immune mechanisms that contribute to desirable complete remissions of murine colon tumors treated with single radiation dose of 30 Gy. This dose is at the upper end of the ablative range used clinically to treat advanced or metastatic colorectal, liver, and non-small cell lung tumors. Experimental design Changes in the tumor immune microenvironment of single tumor nodules exposed to radiation were studied using 21 day (>1 cm in diameter) CT26 and MC38 colon tumors. These are well-characterized weakly immunogenic tumors. Results We found that the high dose radiation transformed the immunosuppressive tumor microenvironment resulting in an intense CD8+ T cell tumor infiltrate, and a loss of myeloid derived suppressor cells (MDSCs). The change was dependent on antigen cross-presenting CD8+ dendritic cells, secretion of IFN-γ, and CD4+ T cells expressing CD40L. Anti-tumor CD8+ T cells entered tumors shortly after radiotherapy, reversed MDSC infiltration, and mediated durable remissions in an IFN-γ dependent manner. Interestingly, extended fractionated radiation regimen did not result in robust CD8+ T cell infiltration. Conclusion For immunologically sensitive tumors, these results indicate that remissions induced by a short course of high dose radiation therapy depend on the development of anti-tumor immunity that is reflected by the nature and kinetics of changes induced in the tumor cell microenvironment. These results suggest that systematic examination of the tumor immune microenvironment may help in optimizing the radiation regimen used to treat tumors by adding a robust immune response.

Stereotactic ablative radiotherapy and immunotherapy combinations: turning the future into systemic therapy?

“…23 In contrast, 10 daily 3-Gy fractions failed to lead to a robust T-cell infiltration in these tumours, resulting in poorer local control. 23 A single high dose fraction of radiation has also been shown to enhance presentation and T-cell recognition of tumour-associated antigens, 24 but in contrast this phenomenon was not seen in a melanoma model with a RT schedule at 7.5 Gy/fraction.…”

“…23 In contrast, 10 daily 3-Gy fractions failed to lead to a robust T-cell infiltration in these tumours, resulting in poorer local control. 23 A single high dose fraction of radiation has also been shown to enhance presentation and T-cell recognition of tumour-associated antigens, 24 but in contrast this phenomenon was not seen in a melanoma model with a RT schedule at 7.5 Gy/fraction. 25 As more evidence emerges, the specific hypofractionated or ablative radiation schedule required to improve the immune response may turn out to be tumour specific and be dependent on radiosensitivity and the nature and kinetics of the RTinduced ICD.…”

“…In addition to inducing double-strand DNA breaks similar to conventionally fractionated treatment regimes, 21 RT delivered at higher doses per fraction (8-10 Gy) may induce more significant vascular, stromal and antitumour immune responses within the local tumour microenvironment, 22,23 leading to increased cell death and improved efficacy.…”

Disruption of evasive immune cell microenvironment in tumors reflects immunity induced by radiation therapy

“…6,7 The goal of our recent study was to determine whether a single high dose of radiation targeted to advanced CT26 and MC38 murine subcutaneous colon tumors can induce durable complete remissions. 8 We also determined whether induction of antitumor immunity was required, and radiation induced immunity was reflected in changes in the tumor microenvironment. 8 We found that increasing the single dose of radiation resulted in an increased incidence of durable remissions, and an incidence of about 90% was achieved with 30 Gy, the maximum dose of stereotactic body radiation therapy (SBRT) used clinically.…”

“…8 We also determined whether induction of antitumor immunity was required, and radiation induced immunity was reflected in changes in the tumor microenvironment. 8 We found that increasing the single dose of radiation resulted in an increased incidence of durable remissions, and an incidence of about 90% was achieved with 30 Gy, the maximum dose of stereotactic body radiation therapy (SBRT) used clinically. Remissions were dependent on T cell immunity, since RAG-2 ¡/¡ mice lacking adaptive immune cells and mice depleted of CD4…”