Radiotherapy Both Promotes and Inhibits Myeloid-Derived Suppressor Cell Function: Novel Strategies for Preventing the Tumor-Protective Effects of Radiotherapy
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Author/Creator ORCID
Date
2019-04-02
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Citation of Original Publication
Ostrand-Rosenberg S, Horn LA and Ciavattone NG (2019) Radiotherapy Both Promotes and Inhibits Myeloid-Derived Suppressor Cell Function: Novel Strategies for Preventing the Tumor-Protective Effects of Radiotherapy. Front. Oncol. 9:215. doi: 10.3389/fonc.2019.00215
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Attribution 4.0 International (CC BY 4.0)
Attribution 4.0 International (CC BY 4.0)
Abstract
Cancer immunotherapies aimed at neutralizing the programmed death-1 (PD-1) immune
suppressive pathway have yielded significant therapeutic efficacy in a subset of cancer
patients. However, only a subset of patients responds to antibody therapy with either
anti-PD-1 or anti-PD-L1 antibodies. These patients appear to have so-called “hot”
tumors containing tumor-reactive T cells. Therefore, checkpoint blockade therapymay be
effective in a larger percentage of cancer patients if combined with therapeutics that also
activate tumor-reactive T cells. Radiotherapy (RT) is a prime candidate for combination
therapy because it facilitates activation of both local antitumor immunity and antitumor
immunity at non-radiated, distant sites (abscopal response). However, RT also promotes
tumor cell expression of PD-L1 and facilitates the development of myeloid-derived
suppressor cells (MDSC), a population of immune suppressive cells that also suppress
through PD-L1. This article will review how RT induces MDSC, and then describe two
novel therapeutics that are designed to simultaneously activate tumor-reactive T cells
and neutralize PD-1-mediated immune suppression. One therapeutic, a CD3xPD-L1
bispecific T cell engager (BiTE), activates and targets cytotoxic T and NKT cells to kill
PD-L1⁺ tumor cells, despite the presence of MDSC. The BiTE significantly extends the
survival time of humanized NSG mice reconstituted with human PBMC and carrying
established metastatic human melanoma tumors. The second therapeutic is a soluble
form of the costimulatory molecule CD80 (sCD80). In addition to costimulating through
CD28, sCD80 inhibits PD-1 suppression by binding to PD-L1 and sterically blocking
PD-L1/PD-1 signaling. sCD80 increases tumor-infiltrating T cells and significantly extends
survival time of mice carrying established, syngeneic tumors. sCD80 does not suppress
T cell function via CTLA-4. These studies suggest that the CD3xPD-L1 BiTE and sCD80
may be efficacious therapeutics either as monotherapies or in combination with other
therapies such as radiation therapy for the treatment of cancer.