Combination of radiotherapy and vaccination overcomes checkpoint blockade resistance

Abstract

The majority of cancer patients respond poorly to either vaccine or checkpoint blockade, and even to the combination of both. They are often resistant to high doses of radiation therapy as well. We examined prognostic markers of immune cell infiltration in pancreatic cancer. Patients with low CD8+ T cell infiltration and high PD-L1 expression (CD8+ TloPD-L1hi) experienced poor outcomes. We developed a mouse tumor fragment model with a trackable model antigen (SIYRYYGL or SIY) to mimic CD8+ TloPD-L1hi cancers. Tumors arising from fragments contained few T cells, even after vaccination. Fragment tumors responded poorly to PD-L1 blockade, SIY vaccination or radiation individually. By contrast, local ionizing radiation coupled with vaccination increased CD8+ T cell infiltration that was associated with upregulation of CXCL10 and CCL5 chemokines in the tumor, but demonstrated modest inhibition of tumor growth. The addition of an anti-PD-L1 antibody enhanced the effector function of tumor-infiltrating T cells, leading to significantly improved tumor regression and increased survival compared to vaccination and radiation. These results indicate that sequential combination of radiation, vaccination and checkpoint blockade converts non-T cell-inflamed cancers to T cell-inflamed cancers, and mediates regression of established pancreatic tumors with an initial CD8+ TloPD-L1hi phenotype. This study has opened a new strategy for shifting “cold” to hot tumors that will respond to immunotherapy.

Using immunotherapy to boost the abscopal effect

“…The combination of radiotherapy with anticancer vaccines and checkpoint inhibitors has been shown to overcome immunosuppression and to increase response rates in preclinical models 72 . For example, a promising strategy involving sequential combination of radiotherapy, vaccination and anti-PDL1 in a mouse model of pancreatic cancer converts non-T-cell-inflamed cancers into T cell-inflamed cancers and mediates regression of established pancreatic tumours 72 .…”

“…For example, a promising strategy involving sequential combination of radiotherapy, vaccination and anti-PDL1 in a mouse model of pancreatic cancer converts non-T-cell-inflamed cancers into T cell-inflamed cancers and mediates regression of established pancreatic tumours 72 . Other groups are also investigating the use of irradiated tumour cell vaccines as a strategy to boost therapeutic outcomes 73–75 .…”

Direct Downregulation of B-Cell Translocation Gene 3 by microRNA-93 Is Required for Desensitizing Esophageal Cancer to Radiotherapy

“…1.0 9 10 6 OE19 or OE33 cells expressing miR-93 inhibitor, BTG3 or both as well as the negative control, suspended in 200 ll total volume, were injected subcutaneously into both dorsolateral flanks of mice (n = 12/group). On both days 28 and 35 post-inoculation, a 210 kV X-ray source was utilized for target irradiation treatment, as adapted from previous procedures with modifications [9]. Briefly, IR treatment was performed with an 8 Gy dose at 2 Gy/min on the tumor position in dorsolateral flanks with other body areas of mice protected with a lead cover.…”

Targeting the PD-1 Pathway in MSI-Stable Metastatic Colorectal Cancer

“…A study examining pancreatic cancer specimens from patients demonstrated the shortest OS in the group with low CD8+ T cell infiltration and high PD-L1 expression. When murine pancreatic cancer cell lines were subcutaneously injected into mice, a pancreatic mouse model was created to mimic low CD8+ T cell infiltration and high PD-L1 expression [16]. Vaccination of such mouse model using live MC 57-SIY peptide synthesized by f-moc chemistry increased CD8+ T cell infiltration, and the addition of PD-L1 blockade to vaccination enhanced the effector function of tumorinfiltrating T cells [16].…”

“…When murine pancreatic cancer cell lines were subcutaneously injected into mice, a pancreatic mouse model was created to mimic low CD8+ T cell infiltration and high PD-L1 expression [16]. Vaccination of such mouse model using live MC 57-SIY peptide synthesized by f-moc chemistry increased CD8+ T cell infiltration, and the addition of PD-L1 blockade to vaccination enhanced the effector function of tumorinfiltrating T cells [16]. Providing CD8+ T cell infiltration into tumor with low mutational load was essential to elicit a synergistic immune response with immunotherapies, which was demonstrated in a phase IIA study of 2 nd line metastatic pancreatic cancer patients.…”