Stereotactic Radiation Therapy Augments Antigen-Specific PD-1–Mediated Antitumor Immune Responses via Cross-Presentation of Tumor Antigen

Cancer Immunology Research - Tập 3 Số 4 - Trang 345-355 - 2015
Andrew B. Sharabi1,2, Christopher J. Nirschl2, Christina M. Kochel2, Thomas R. Nirschl2, Brian J. Francica2, Esteban Velarde1, Theodore L. DeWeese1,2,3, Charles G. Drake2,3,4
11Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.
22Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
33The Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland.
44Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Tóm tắt

AbstractThe immune-modulating effects of radiotherapy (XRT) have gained considerable interest recently, and there have been multiple reports of synergy between XRT and immunotherapy. However, additional preclinical studies are needed to demonstrate the antigen-specific nature of radiation-induced immune responses and elucidate potential mechanisms of synergy with immunotherapy. Here, we demonstrate the ability of stereotactic XRT to induce endogenous antigen-specific immune responses when it is combined with anti–PD-1 checkpoint blockade immunotherapy. Using the small animal radiation research platform (SARRP), image-guided stereotactic XRT delivered to B16-OVA melanoma or 4T1-HA breast carcinoma tumors resulted in the development of antigen-specific T cell– and B cell–mediated immune responses. These immune-stimulating effects of XRT were significantly increased when XRT was combined with either anti–PD-1 therapy or regulatory T cell (Treg) depletion, resulting in improved local tumor control. Phenotypic analyses of antigen-specific CD8 T cells revealed that XRT increased the percentage of antigen-experienced T cells and effector memory T cells. Mechanistically, we found that XRT upregulates tumor-associated antigen–MHC complexes, enhances antigen cross-presentation in the draining lymph node, and increases T-cell infiltration into tumors. These findings demonstrate the ability of XRT to prime an endogenous antigen-specific immune response and provide an additional mechanistic rationale for combining radiation with PD-1 blockade in the clinic. Cancer Immunol Res; 3(4); 345–55. ©2014 AACR.

Từ khóa


Tài liệu tham khảo

Canman, 1998, Activation of the ATM kinase by ionizing radiation and phosphorylation of p53, Science, 281, 1677, 10.1126/science.281.5383.1677

Hall, 2011, Radiobiology for the radiologist, 7th ed

Hallahan, 1991, Tumor necrosis factor gene expression is mediated by protein kinase C following activation by ionizing radiation, Cancer Res, 51, 4565

Hara, 1998, Ionizing radiation activates c-Jun NH2-terminal kinase (JNK/SAPK) via a PKC-dependent pathway in human thyroid cells, Biochem Biophys Res Commun, 244, 41, 10.1006/bbrc.1998.8210

Li, 1998, Ionizing radiation and short wavelength UV activate NF-kappaB through two distinct mechanisms, Proc Natl Acad Sci U S A, 95, 13012, 10.1073/pnas.95.22.13012

Zeng, 2013, Immune modulation and stereotactic radiation: improving local and abscopal responses, Biomed Res Int, 2013, 658126, 10.1155/2013/658126

Garnett, 2004, Sublethal irradiation of human tumor cells modulates phenotype resulting in enhanced killing by cytotoxic T lymphocytes, Cancer Res, 64, 7985, 10.1158/0008-5472.CAN-04-1525

Lugade, 2005, Local radiation therapy of B16 melanoma tumors increases the generation of tumor antigen-specific effector cells that traffic to the tumor, J Immunol, 174, 7516, 10.4049/jimmunol.174.12.7516

Matsumura, 2010, Up-regulation of the pro-inflammatory chemokine CXCL16 is a common response of tumor cells to ionizing radiation, Radiat Res, 173, 418, 10.1667/RR1860.1

Morel, 1998, g-Ray irradiation induces B7.1 costimulatory molecule neoexpression in various murine tumor cells.pdf, Cancer Immunol Immunother, 46, 277, 10.1007/s002620050488

Parker, 2013, Characterization of direct radiation-induced immune function and molecular signaling changes in an antigen presenting cell line, Clin Immunol, 148, 44, 10.1016/j.clim.2013.03.008

Reits, 2006, Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy, J Exp Med, 203, 1259, 10.1084/jem.20052494

Stone, 1979, Effect of host immune capability on radiocurability and subsequent transplantability of a murine fibrosarcoma.pdf, J Natl Cancer Inst, 63, 1229

Lee, 2009, Therapeutic effects of ablative radiation on local tumor require CD8+ T cells: changing strategies for cancer treatment, Blood, 114, 589, 10.1182/blood-2009-02-206870

Gupta, 2012, Radiotherapy promotes tumor-specific effector CD8+ T cells via dendritic cell activation, J Immunol, 189, 558, 10.4049/jimmunol.1200563

Burnette, 2011, The efficacy of radiotherapy relies upon induction of type i interferon-dependent innate and adaptive immunity, Cancer Res, 71, 2488, 10.1158/0008-5472.CAN-10-2820

Takeshima, 2010, Local radiation therapy inhibits tumor growth through the generation of tumor-specific CTL: its potentiation by combination with Th1 cell therapy, Cancer Res, 70, 2697, 10.1158/0008-5472.CAN-09-2982

Couzin-Frankel, 2013, Breakthrough of the year 2013. Cancer immunotherapy, Science, 342, 1432, 10.1126/science.342.6165.1432

Drake, 2014, Breathing new life into immunotherapy: review of melanoma, lung and kidney cancer, Nat Rev Clin Oncol, 11, 24, 10.1038/nrclinonc.2013.208

Pardoll, 2012, The blockade of immune checkpoints in cancer immunotherapy, Nat Rev Cancer, 12, 252, 10.1038/nrc3239

Nirschl, 2013, Molecular pathways: coexpression of immune checkpoint molecules: signaling pathways and implications for cancer immunotherapy, Clin Cancer Res, 19, 4917, 10.1158/1078-0432.CCR-12-1972

Wolchok, 2013, Nivolumab plus ipilimumab in advanced melanoma, N Engl J Med, 369, 122, 10.1056/NEJMoa1302369

Hodi, 2010, Improved survival with ipilimumab in patients with metastatic melanoma, N Engl J Med, 363, 711, 10.1056/NEJMoa1003466

Brahmer, 2012, Safety and activity of anti-PD-L1 antibody in patients with advanced cancer, N Engl J Med, 366, 2455, 10.1056/NEJMoa1200694

Pardoll, 2012, Immunotherapy earns its spot in the ranks of cancer therapy, J Exp Med, 209, 201, 10.1084/jem.20112275

Formenti, 2013, Combining radiotherapy and cancer immunotherapy: a paradigm shift, J Natl Cancer Inst, 105, 256, 10.1093/jnci/djs629

Kalbasi, 2013, Radiation and immunotherapy: a synergistic combination, J Clin Invest, 123, 2756, 10.1172/JCI69219

Schaue, 2012, Maximizing tumor immunity with fractionated radiation, Int J Radiat Oncol Biol Phys, 83, 1306, 10.1016/j.ijrobp.2011.09.049

Postow, 2012, Immunologic correlates of the abscopal effect in a patient with melanoma, N Engl J Med, 366, 925, 10.1056/NEJMoa1112824

Golden, 2013, An abscopal response to radiation and ipilimumab in a patient with metastatic non–small cell lung cancer, Cancer Immunol Res, 1, 365, 10.1158/2326-6066.CIR-13-0115

Demaria, 2004, Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated, Int J Radiat Oncol Biol Phys, 58, 862, 10.1016/j.ijrobp.2003.09.012

Chakravarty, 1999, Flt3-ligand administration after radiation therapy prolongs survival in a murine model of metastatic lung cancer, Cancer Res, 59, 6028

Dewan, 2009, Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody, Clin Cancer Res, 15, 5379, 10.1158/1078-0432.CCR-09-0265

Wong, 2008, High-resolution, small animal radiation research platform with x-ray tomographic guidance capabilities, Int J Radiat Oncol Biol Phys, 71, 1591, 10.1016/j.ijrobp.2008.04.025

Wada, 2013, Combined treatment effects of radiation and immunotherapy: studies in an autochthonous prostate cancer model, Int J Radiat Oncol Biol Phys, 87, 769, 10.1016/j.ijrobp.2013.07.015

Zeng, 2013, Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas, Int J Radiat Oncol Biol Phys, 86, 343, 10.1016/j.ijrobp.2012.12.025

Deng, 2014, Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice, J Clin Invest, 124, 687, 10.1172/JCI67313

Dovedi, 2014, Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade, Cancer Res, 74, 5458, 10.1158/0008-5472.CAN-14-1258

Ackerman, 2005, Access of soluble antigens to the endoplasmic reticulum can explain cross-presentation by dendritic cells, Nat Immunol, 6, 107, 10.1038/ni1147

Porgador, 1997, Localization, quantitation, and in situ detection of specific peptide-MHC class I complexes using a monoclonal antibody, Immunity, 6, 715, 10.1016/S1074-7613(00)80447-1

Messaoudi, 1999, The mode of ligand recognition by two peptide:MHC class I-specific monoclonal antibodies, J Immunol, 163, 3286, 10.4049/jimmunol.163.6.3286

Sotomayor, 2001, Cross-presentation of tumor antigens by bone marrow-derived antigen-presenting cells is the dominant mechanism in the induction of T-cell tolerance during B-cell lymphoma progression, Blood, 98, 1070, 10.1182/blood.V98.4.1070

Karttunen, 1992, Detection of rare antigen-presenting cells by the lacZ T-cell activation assay suggests an expression cloning strategy for T-cell antigens, Proc Natl Acad Sci U S A, 89, 6020, 10.1073/pnas.89.13.6020

DeWeese, 2011, Molecular determinants of radiation response, 276

Seder, 2003, Similarities and differences in CD4+ and CD8+ effector and memory T cell generation, Nat Immunol, 4, 835, 10.1038/ni969

Pilon-Thomas, 2010, Blockade of programmed death ligand 1 enhances the therapeutic efficacy of combination immunotherapy against melanoma, J Immunol, 184, 3442, 10.4049/jimmunol.0904114

Hirano, 2005, Blockade of B7-H1 and PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity, Cancer Res, 65, 1089, 10.1158/0008-5472.1089.65.3

Galon, 2006, Type, density, and location of immune cells within human colorectal tumors predict clinical outcome, Science, 313, 1960, 10.1126/science.1129139

Loi, 2013, Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02–98, J Clin Oncol, 31, 860, 10.1200/JCO.2011.41.0902

Fukunaga, 2004, CD8+ tumor-infiltrating lymphocytes together with CD4+ tumor-infiltrating lymphocytes and dendritic cells improve the prognosis of patients with pancreatic adenocarcinoma, Pancreas, 28, e26, 10.1097/00006676-200401000-00023

Clemente, 1996, Prognostic value of tumor infiltrating lymphocytes in the vertical growth phase of primary cutaneous melanoma, Cancer, 77, 1303, 10.1002/(SICI)1097-0142(19960401)77:7<1303::AID-CNCR12>3.0.CO;2-5

Thông tin
Thông tin xuất bản

Cancer Immunology Research

Tập 3 Số 4

345-355

Thông tin tác giả