Editors' ChoiceCancer Immunology

Maximizing anti-PD1 therapy

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Science Signaling  21 Jun 2016:
Vol. 9, Issue 433, pp. ec146
DOI: 10.1126/scisignal.aah3797

Immunotherapy with blocking antibodies against programmed cell death 1 (PD1) or its ligand PD-L1 (anti–PD1/PD-L1 therapy) have improved outcome in many patients with advanced cancer. Increased expression of the gene encoding PD-L1 (CD274) is a common marker for tumors that use this pathway to escape immunosurveillance. Now, Kataoka et al. add a different genetic mechanism that leads to increased PD-L1 abundance. Bioinformatic analysis of various cancer tissues revealed structural variations (SVs) in the 3′-untranslated region (3′-UTR) of CD274 that induced truncations which stabilized the mRNA encoding PD-L1. Immunohistochemistry and western blotting showed that SV-positive samples had an increased amount of functional (PD1-binding) PD-L1; notably, PD-L1 protein in these samples was detected only with N-terminal but not C-terminal PD-L1 antibodies. Introducing large deletions or inversions in the CD274 3′-UTR in the presence of actinomycin D (to inhibit new transcription) increased the amount of transcript and cell surface PD-L1 in various human and mouse cell lines. In coculture and mouse models, tumor cells expressing CD274 with a disrupted 3′-UTR had reduced viability or infiltration, respectively, of PD1-expressing T cells, and this was blocked with an anti–PD-L1 antibody. Thus detecting CD274 3′-UTR SVs could select patients that would benefit from anti–PD1/PD-L1 therapy.

Tumors are adept at resisting single-agent therapies. For patients with pancreatic ductal adenocarcinoma (PDAC), anti-PD1 therapy has been largely ineffective. Steele et al. found that combined inhibition of a chemokine receptor on pancreatic tumor-associated immune cells improved the efficacy of anti-PD1 therapy in mice. Poor prognosis in PDAC patients correlated with increased abundance of the chemokine receptor CXCR2 at the tumor border, mostly in stromal myeloid cells. The abundance of two CXCR2 ligands, CXCL2 and CXCL8, was increased in tumors compared with adjacent normal pancreas tissue. Tumors from transgenic KPC mice, a mouse model of metastatic PDAC, recapitulated the patient tumor data. Deletion of Cxcr2, pharmacological inhibition of CXCR2, or depletion of Ly6G+ cells (which include neutrophils and myeloid-derived suppressor cells) prevented metastasis and prolonged survival in KPC mice. Inhibition of CXCR2 increased the number of CD3+ T cells in pancreatic tumors in KPC mice. Combination therapy of CXCR2 inhibitors with anti-PD1 immunotherapy increased the number of tumor-infiltrating naive (CD62L+/CD44) and cytotoxic (CD8+) T cells, decreased the number of infiltrating inhibitory regulatory T cells, and improved the survival of KPC mice. Together the findings inform strategies for the use of anti–PD1/PD-L1 immunotherapy in cancer patients.

K. Kataoka, Y. Shiraishi, Y. Takeda, S. Sakata, M. Matsumoto, S. Nagano, T. Maeda, Y. Nagata, A. Kitanaka, S. Mizuno, H. Tanaka, K. Chiba, S. Ito, Y. Watatani, N. Kakiuchi, H. Suzuki, T. Yoshizato, K. Yoshida, M. Sanada, H. Itonaga, Y. Imaizumi, Y. Totoki, W. Munakata, H. Nakamura, N. Hama, K. Shide, Y. Kubuki, T. Hidaka, T. Kameda, K. Masuda, N. Minato, K. Kashiwase, K. Izutsu, A. Takaori-Kondo, Y. Miyazaki, S. Takahashi, T. Shibata, H. Kawamoto, Y. Akatsuka, K. Shimoda, K. Takeuchi, T. Seya, S. Miyano, S. Ogawa, Aberrant PD-L1 expression through 3′-UTR disruption in multiple cancers. Nature 534, 402–406 (2016). [PubMed]

C. W. Steele, S. A. Karim, J. D. G. Leach, P. Bailey, R. Upstill-Goddard, L. Rishi, M. Foth, S. Bryson, K. McDaid, Z. Wilson, C. Eberlein, J. B. Candido, M. Clarke, C. Nixon, J. Connelly, N. Jamieson, C. R. Carter, F. Balkwill, D. K. Chang, T. R. J. Evans, D. Strathdee, A. V. Biankin, R. J. B. Nibbs, S. T. Barry, O. J. Sansom, J. P. Morton, CXCR2 inhibition profoundly suppresses metastases and augments immunotherapy in pancreatic ductal adenocarcinoma. Cancer Cell 29, 832–845 (2016). [PubMed]

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