Editors' ChoiceProstate Cancer

Unraveling the role of immune accessory molecules

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Science Translational Medicine  12 Aug 2015:
Vol. 7, Issue 300, pp. 300ec136
DOI: 10.1126/scitranslmed.aad0224

Once alone at center stage, T cells now share the cancer–immunotherapy limelight with accessory molecules that modulate T cell signaling. Checkpoint therapies such as with an antibody targeting programmed cell death-1 (anti–PD-1), for example, have shown recent successes in clinical trials and have gained approval as standard of care therapies for some cancers. As successful immunotherapies often employ combinations of engineered cells, drugs, and biologics, the characterization of new immunomodulatory targets remains a priority. Now, Kreymborg et al. ablate certain accessory molecules in mice to explore their impact on tumors.

B7-H3 and B7-H4 are cosignaling modulators of T cell responses that are overexpressed in various tumor types. Despite hypotheses that these molecules are potential tumor targets for immunotherapy, their role in tumor development and progression has been elusive. In the new work, a spontaneous prostate cancer model was used to compare tumor burden between wild-type and B7-H3– or B7-H4–deficient mice. B7-H3–deficient mice displayed dramatically increased tumor burden compared with wild-type mice, while B7-H4 knockdown did not affect tumor burden. Concurrent with the enhanced tumor burden in B7-H3–deficient mice was an increase in the number of regulatory T cell (Treg) along with elevated proliferation rates of these cells in the tumor microenvironment. Transcripts of the Treg-associated inhibitory cytokines transforming growth factor–β and interleukin -10 were also increased in tumors from B7-H3–deficient mice compared with wild-type mouse tumors. These significant results suggest a previously unrecognized role for B7-H3 in regulating Treg responses in the tumor microenvironment. Although further mechanistic studies are needed to clarify the role of B7-H3 in tumor development, the results of this study set the stage for further consideration of B7-H3 as an immunomodulatory target for cancer therapy.

K. Kreymborg et al., Ablation of B7-H3 but not B7-H4 results in highly increased tumor burden in a murine model of spontaneous prostate cancer. Cancer Immunol. Res. 10.1158/2326-6066.CIR-15-0100 (2015). [Full Text]

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