Editors' ChoiceCancer

Resisting the antitumor immune response

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Science Translational Medicine  23 Dec 2015:
Vol. 7, Issue 319, pp. 319ec218
DOI: 10.1126/scitranslmed.aad9010

Cytotoxic T lymphocytes have the ability to find, target, and kill tumor cells. In recent years, scientists have undertaken a major effort to learn to control these T cells to treat cancer. Melanoma, in particular, has proven to be a tumor amenable to T cell–mediated immunotherapy, possibly because of its high somatic mutation burden, which generates many aberrant, potentially immunogenic peptide sequences. Researchers have developed various methods to manipulate T cells to target melanoma cells. Although some of these strategies have achieved considerable success, it is unclear why some patients respond to T cell–mediated tumor killing whereas in others, tumors appear to be intrinsically resistant.

Now Peng and colleagues have determined that loss of PTEN mediates the resistance of melanoma to T cell–mediated tumor killing. PTEN is a lipid phosphatase that negatively regulates PI3K signalling, a central signalling pathway in normal and cancer cells. PTEN is a well-established tumor suppressor gene in a variety of cancers including melanoma. Peng et al. used in vitro and in vivo models as a starting point, and observed that loss of PTEN inhibited T cell–mediated tumor killing in a variety of assays and readouts. As a putative mechanism underlying PTEN-mediated immune resistance, the authors identified alterations in expression and production of immune modulators. Importantly, evidence for PTEN mediating immune resistance was also found in patients suffering from melanoma. Last, the authors made the therapeutically promising observation that inhibition of PI3K signalling boosted the efficacy of immunostimulants, anti–PD-1 and anti–CTLA4 antibodies, in a mouse model of PTEN-deficient melanoma.

Although this probably represents one of many ways in which tumors evade immune attacks, the findings of Peng et al. define a specific mechanism for immune resistance of melanoma. It is conceivable that the same mechanism may also operate in other types of cancers in which PTEN is frequently mutated. In the meantime, targeting PI3K signalling to boost T cell–mediated tumor killing merits further investigation.

W. Peng et al., Loss of PTEN promotes resistance to T cell–mediated immunotherapy. Cancer Discov. 10.1158/2159-8290.CD-15-0283 (2015). [Full Text]

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