Editors' ChoiceCancer Immunology

Overcoming immunotherapy resistance

Sci. Signal.  16 Feb 2016:
Vol. 9, Issue 415, pp. ec32
DOI: 10.1126/scisignal.aaf4542

Tumor cells can suppress T cell activation and thus impair anticancer immunosurveillance. Immunotherapies targeting this interaction, such as antibodies that block the binding of an inhibitory receptor PD-1 on T cells to its ligand PD-L1 on tumor cells, have had promising results in patients, but resistance frequently occurs (see Rizvi and Chan). Peng et al. found that loss of the lipid phosphatase PTEN, which is common in various cancers, contributes to immunotherapy resistance in melanoma. Knocking down PTEN in a melanoma cell line reduced T cell–mediated lysis of the cells in cocultures and when T cells and the cancer cells were introduced into mice, suggesting that PTEN loss may impair T cell–mediated antitumor responses. PTEN abundance in melanoma samples from patients correlated with decreased infiltration of CD8+ T cells and reduced abundance of T cell effector molecules in the tumors and decreased therapeutic efficacy of PD-1–blocking antibodies in the patients. Curiously, PTEN loss did not correlate with changes in the tumor cell–surface abundance of PD-L1, but it did correlate with decreased expression of inflammation-related genes and a gene necessary for autophagy and increased abundance of inhibitory cytokines, as well as increased activation of the phosphoinositide 3-kinase (PI3K) pathway. Genetically engineering the PTEN-deficient melanoma cells to enhance autophagy improved T cell–mediated toxicity in cocultures, and inhibiting PI3Kβ improved the efficacy of PD-1–blocking antibodies against PTEN-deficient tumor cells in T cell cocultures and in mice. The results indicate new targets to explore to overcome immunotherapy resistance in PTEN-deficient tumors.

W. Peng, J. Q. Chen, C. Liu, S. Malu, C. Creasy, M. T. Tetzlaff, C. Xu, J. A. McKenzie, C. Zhang, X. Liang, L. J. Williams, W. Deng, G. Chen, R. Mbofung, A. J. Lazar, C. A. Torres-Cabala, Z. A. Cooper, P.-L. Chen, T. N. Tieu, S. Spranger, X. Yu, C. Bernatchez, M.-A. Forget, C. Haymaker, R. Amaria, J. L. McQuade, I. C. Glitza, T. Cascone, H. S. Li, L. N. Kwong, T. P. Heffernan, J. Hu, R. L. Bassett Jr., M. W. Bosenberg, S. E. Woodman, W. W. Overwijk, G. Lizée, J. Roszik, T. F. Gajewski, J. A. Wargo, J. E. Gershenwald, L. Radvanyi, M. A. Davies, P. Hwu, Loss of PTEN promotes resistance to T cell–mediated immunotherapy. Cancer Discov. 6, 202–216 (2016). [PubMed]

N. A. Rizvi, T. A. Chan, Immunotherapy and oncogenic pathways: The PTEN connection. Cancer Discov. 6, 128–129 (2016). [PubMed]