Research ArticleCancer

Triple-modality therapy maximizes antitumor immune responses in a mouse model of mesothelioma

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Science Translational Medicine  14 Apr 2021:
Vol. 13, Issue 589, eabd9882
DOI: 10.1126/scitranslmed.abd9882

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A triple threat for mesothelioma

Treatment options for mesothelioma are still lacking, although immunotherapies have shown promise when combined with conventional therapies such as radiation and surgical resection. Here, Murakami et al. investigated a triple-modality therapy for a mouse model of mesothelioma. The authors treated mice with a combination of subablative radiotherapy, an interleukin-15 superagonist, and a glucocorticoid-induced tumor necrosis factor receptor–related protein (GITR) agonist. The authors showed that this combination treatment extended survival in mice and was associated with durable antitumor immune responses. The benefit conferred by triple therapy was further enhanced by tumor resection surgery. These data support the development of combination therapies for patients with mesothelioma.

Abstract

Malignant pleural mesothelioma (MPM) is an intractable disease with an extremely poor prognosis. Our clinical protocol for MPM of subablative radiotherapy (RT) followed by radical surgery achieved better survival compared to other multimodal treatments, but local relapse and metastasis remain a problem. This subablative RT elicits an antitumoral immune response that is limited by the immunosuppressive microenvironment generated by regulatory T (Treg) cells. The antitumor effect of immunotherapy to simultaneously modulate the immune activation and the immune suppression after subablative RT has not been investigated in MPM. Herein, we demonstrated a rationale to combine interleukin-15 (IL-15) superagonist (IL-15SA) and glucocorticoid-induced tumor necrosis factor receptor–related protein (GITR) agonist (DTA-1) with subablative RT in mesothelioma. IL-15SA boosted the systemic expansion of specific antitumoral memory CD8+ T cells that were induced by RT in mice. Their effect, however, was limited by the up-regulation and activation of Treg cells in the radiated tumor microenvironment. Hence, selective depletion of intratumoral Treg cells through DTA-1 enhanced the benefit of subablative RT in combination with IL-15SA. The addition of surgical resection of the radiated tumor in combination with IL-15SA and DTA-1 maximized the benefit of RT and was accompanied by a reproducible abscopal response in a concomitant tumor model. These data support the development of clinical trials in MPM to test such treatment options for patients with locally advanced or metastatic tumors.

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