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Spotlight

Radiotherapy and immune checkpoint blockade: potential interactions and future directions David C. Binder1, Yang-Xin Fu1,2*, and Ralph R. Weichselbaum2,3* 1

Department of Pathology, University of Chicago, Chicago, IL 60637, USA The Ludwig Center for Metastasis Research, University of Chicago, Chicago, IL 60637, USA 3 Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL 60637, USA 2

Combining radiation and immune checkpoint blockade provides synergistic antitumor responses in animal models and a small subset of patients. New preclinical data have provided mechanistic insight into this treatment interaction and identification of therapeutic targets to optimize this approach. Over the past 15 years, inhibitory receptors on T cells have become recognized for their capacity to abrogate tumorspecific T cell responses in preclinical and clinical trials. Programmed death 1 (PD-1) and cytotoxic T-lymphocyteassociated protein 4 (CTLA-4) are the best characterized inhibitory receptors. As T cells become activated, CTLA-4 expression increases which inhibits their proliferation capacity and effector function. CTLA-4 is also essential for suppression of effector T cell responses by Foxp3+ CD4+ regulatory T cells (Treg). PD-1-mediated inhibition of cytotoxic T cell responses occurs in tumors as: (i) T cells experience chronic antigen stimulation, resulting in persistent PD-1 upregulation; (ii) T cells secrete interferon-g (IFN-g) upon antigen recognition, which leads to programmed death-ligand 1 (PD-L1) upregulation on cancer and tumor stromal cells; and finally (iii) T cells lose effector function through negative PD-1/PD-L1 interactions (Figure 1). The realization that inhibitory receptors suppress anti-tumor T cell responses motivated the development of CTLA-4, PD-1, and PD-L1 checkpoint blocking antibodies. These antibodies have provided impressive durable responses in a subset of patients, with the most consistent responses observed treating advanced melanoma, bladder cancer, and non-small cell lung cancer [1–3]. Postow et al. recently reported phase I randomized results demonstrating that dual blockade of PD-1 and CTLA-4 provides improved responses in patients with untreated metastatic melanoma compared to standard of care CTLA-4 blockade (complete response rate of 22% versus 0%) [1]. This complete response rate also compares favorably to previous studies treating melanoma with monotherapy PD-1 blockade [2], in which responders have pretreatment tumor tissue with colocalization of T cells and PD-L1 expression [3].

Corresponding author: Binder, D.C. ([email protected]). Keywords: cancer; immunotherapy; radiation. * These authors are co-senior authors. 1471-4914/ ß 2015 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.molmed.2015.05.007

To increase the number of patients that respond to checkpoint blocking antibodies, it was proposed that checkpoint blockade should be combined with ablative radiation. Radiation, initially thought to immunosuppressive, was recently considered to be a promising candidate for such combination based on its capacity to induce not only cancer cell death but also mobilize immune responses for tumor control [4]. One proposed mechanism by which radiation induces adaptive immunity is by activating a Type I IFN pathway in dendritic cells that licenses dendritic cells, already presenting tumor-specific antigenic peptides, to effectively prime tumor-specific T cells [5]. Radiation-mediated IFN induction occurs when dendritic cells ‘pick up’ cancer cell DNA, resulting in activation of the cytosolic STING (Stimulator of IFN genes) DNA sensing pathway [6]. Thus, radiation seems to increase cancer cell killing and DNA release, with a resulting enhancement in dendritic cell-mediated T cell priming. Based on the immunostimulatory properties of radiation, preclinical and clinical studies combining radiation with checkpoint blockade were undertaken. Preclinical studies combining anti-CTLA-4 with radiation demonstrated promising local tumor control and abscopal responses [7], meaning nonirradiated metastatic lesions also regressed as a result of a presumed systemic antitumor immune response. In a recent Phase I clinical trial, Twyman-Saint Victor et al. reported that hypofractionated radiation to single lesions followed by antiCTLA-4 treatment can provide responses to unirradiated lesions, but this effect is restricted to 36% of patients with overall median progression-free survival still less than 4 months [8]. To identify biomarkers associated with this clinical response to radiation and anti-CTLA-4, TwymanSaint Victor et al. analyzed pretreatment melanoma tissue from patients treated in their trial. They discovered that responses to treatment were restricted to patients with melanoma cancer cells that expressed low levels of PD-L1 [8]. Despite the small number of patients analyzed, these data suggested that PD-1/PD-L1 interactions mediate treatment resistance which was consistent with their mouse findings demonstrating that ‘knocking out’ PD-L1 on cancer cells restores preclinical responses to radiation and anti-CTLA-4 [8]. The important role of PD1/PD-L1 interactions for suppressing T cell responses following radiotherapy was consistent with the findings of Deng et al. in which radiation was discovered to consistently upregulate PD-L1 expression on cancer cells, dendritic cells, and macrophages [9]. Consistent with Trends in Molecular Medicine xx (2015) 1–3

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Figure 1. Mechanisms of PD-1/PD-L1-mediated tumor immunosuppression. T cells encounter chronic antigen stimulation in tumors resulting in PD-1 upregulation. The tumor microenvironment can express high PD-L1 levels by (i) intrinsic cancer cell expression, (ii) T cell-secreted cytokine, and/or (iii) radiation-induced inflammation. When high PD-1-expressing T cells encounter PD-L1 in the tumor, T cells become dysfunctional with loss of cytokine production and lysis capacity. Suppressive PD-1/PD-L1 interactions can be blocked with antibody, reversing or preventing T cell dysfunction. T cells can now target cancer or tumor stromal cells for destruction.

this observation, combining radiation with anti-PD-L1 resulted in CD8+ T cell-dependent eradication of 2 weekestablished preclinical tumors nonresponsive to monotherapy anti-PD-L1 or radiation [9] (Figure 1). To determine how to best combine radiation and checkpoint blockade, Twyman-Saint Victor et al. compared treatment efficacy of different immune checkpoint and radiation combinations in mice. The most effective regimen, in terms of survival and complete response rate, was trimodal antiPD-L1 or anti-PD-1, anti-CTLA-4, and radiation [8]. Each treatment modality was found to provide nonredundant immune activation: anti-CTLA-4 inhibits suppressive regulatory T cells and increases the CD8/TReg ratio; radiation broadens or diversifies the T cell receptor (TCR) repertoire; and PD-1 blockade prevents or reverses T cell exhaustion [8]. Collectively, these data demonstrate the promise of combining radiation with dual checkpoint blockade. While the next wave of clinical trials evaluate radiation and dual checkpoint blockade, preclinical studies should further investigate how to optimize this therapeutic approach. One promising approach is to use STING agonists, now recognized as potent vaccine adjuvant to prime cytotoxic T cells, for enhancing dendritic cell-mediated T cell priming that is important for TCR diversification. Intratumoral injection of STING agonist 20 30 -cGAMP has been shown to amplify radiation-mediated adaptive immune responses and tumor regression [6], but no study has combined these STING agonists with both radiation and checkpoint blockade. As a second approach, therapeutic 2

vaccination may be favorably combined with radiation and checkpoint blockade. Vaccination followed by radiation and checkpoint blockade has potential to ‘home’ vaccinegenerated T cells into tumors and enhance/maintain their effector function. Finally, radiation and immune checkpoint blockade may be used in adoptive T cell therapy protocols, specifically by inducing T cell responses in tumors with no baseline T cell infiltration. When functional tumor-infiltrating T cells can be isolated from surgical tissue and re-expanded ex vivo, re-infusing or adoptively transferring these T cells into the same individual can provide impressive tumor responses against large melanoma tumor burden [10]. In conclusion, combination radiation and checkpoint blockade has the potential to synergize with many other immunotherapeutic modalities and future studies should investigate these next-generation combinations. Acknowledgments This work was in part supported by Graduate Training in Growth and Development grant T32 HD009007 to D.C.B., US National Institutes of Health grants CA141975 and CA134563 to Y-X.F., Ludwig Foundation grant to R.R.W., and generous gifts from the Foglia Foundation to Y-X.F. and R.R.W.

References 1 Postow et al. (2015) Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N. Engl. J. Med. 372, 2006–2017 2 Topalian, S.L. et al. (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366, 2443–2454

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Spotlight 3 Tumeh et al. (2014) PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515, 568–571 4 Lee, Y. et al. (2009) Therapeutic effects of ablative radiation on local tumor require CD8+ T cells: changing strategies for cancer treatment. Blood 114, 589–595 5 Burnette, B. et al. (2011) The efficacy of radiotherapy relies upon induction of type I interferon-dependent innate and adaptive immunity. Cancer Res. 71, 2488–2496 6 Deng, L. et al. (2014) STING-dependent cytosolic DNA sensing promotes radiation-induced type I interferon-dependent antitumor immunity in immunogenic tumors. Immunity 41, 843–852

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7 Demaria, S. et al. (2005) Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer. Clin. Cancer Res. 11, 728–734 8 Twyman-Saint Victor, C.A. et al. (2015) Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 520, 373–377 9 Deng, L. et al. (2014) Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J. Clin. Invest. 124, 687–695 10 Restifo, N.P. et al. (2012) Adoptive immunotherapy for cancer: harnessing the T cell response. Nat. Rev. Immunol. 12, 269–281

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Radiotherapy and immune checkpoint blockade: potential interactions and future directions.

Combining radiation and immune checkpoint blockade provides synergistic antitumor responses in animal models and a small subset of patients. New precl...
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