Radiation therapy enhances systemic antitumor efficacy in PD-L1 therapy regardless of sequence of radiation in murine osteosarcoma

Abstract

Recent studies demonstrate that immune checkpoint blockade (ICB) increases the chances of the abscopal effect, an anti-tumor effect outside the radiation field in radiation therapy. However, the optimal sequence between radiation and ICB remains unclear. To investigate the impact of sequence of radiation in anti-PD-L1 antibody (P1) therapy on immune microenvironments and antitumor efficacies in local and abscopal tumors, metastatic LM8 osteosarcoma cells were inoculated into both legs of C3H mice. For irradiation, only one side leg was irradiated at 10 Gy. Then mice were divided into four groups: administrated anti-PD-L1 antibody three times (P1 monotherapy), receiving radiation 3 days prior to P1 therapy (P1+pre-Rad), and receiving concurrent radiation with P1 therapy (P1+conc-Rad). Thereafter, tumor immune microenvironment and tumor volume changes were analyzed in irradiated and unirradiated tumors. The P1+pre-Rad regimen increased the proportion of CD8+ programmed cell death 1 (PD-1)+ granzyme B (GzmB)+ reinvigorated T cells and decreased the proportion of CD8+ PD-1+ GzmB- exhausted T cells than P1+conc-Rad regimen in unirradiated tumors. Combination regimens suppressed tumor growth in irradiated tumors compared with that in P1 monotherapy. In both irradiated and unirradiated tumors, significant tumor growth suppression and prolonged overall survival were observed under both combination treatment regimens compared with P1 monotherapy. However, no distinct differences in unirradiated tumor volume and survival were observed between P1+pre-Rad and P1+conc-Rad groups. These results suggest that local irradiation is necessary to improve systemic treatment efficacy in P1 therapy regardless of sequence of local irradiation.

Immune checkpoint inhibitors in osteosarcoma: A hopeful and challenging future

“…In 2018, Xia et al (2018) first reported that in a mouse model, radiotherapy could enhance the efficacy of PD-1 inhibition on brain metastatic OS, increasing the number of CD8 + T cells in the TME. Katsuki et al (2022) alfound a similar outcome of combination therapy in a mouse OS model. Callaghan et al (2020) combined pembrolizumab with stereotactic body radiation to treat chondroblastic OS.…”

Metastasis-Related Signature for Clinically Predicting Prognosis and Tumor Immune Microenvironment of Osteosarcoma Patients

“…In the past decade, the ICB immunotherapies has achieved positive response in osteosarcoma patients [ 10 ]. However, only a small proportion of osteosarcoma patients can respond to immunotherapies, and the major reason might be the limitations in their tumor immunity status [ 15 ]. To verify whether MGR was capable of predicting the efficiency of anti-cancer immunotherapies in osteosarcoma patients, we analyzed the expression levels of immunomodulators (HAVCR2, LAG3, CTLA4, PDCD1, GZMA, NKG7, GZMM, IFNG) were significantly increased in low-risk group than high-risk group of TRAGET dataset and GSE21257 dataset.…”

Lighting Up the Fire in the Microenvironment of Cold Tumors: A Major Challenge to Improve Cancer Immunotherapy

“…This was translated in clinical settings with a case report of a patient with small-cell lung carcinoma who was treated with a combination of radiation therapy and nivolumab [ 56 ]. In murine osteosarcoma, radiotherapy could enhance antitumor efficacy of anti-PD-L1 treatment with a significant decrease in tumor growth and an improved overall survival via an increase in PD-1-positive and granzyme B-positive CD8+ T cells [ 57 ].…”