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Lin L, Kane N, Kobayashi N, et al. High-dose per Fraction Radiotherapy Induces Both Antitumor Immunity and Immunosuppressive Responses in Prostate Tumors. Clin Cancer Res. 2020;27(5):1505-1515doi: 10.1158/1078-0432.CCR-20-2293.
Lin, L., Kane, N., Kobayashi, N., Kono, E. A., Yamashiro, J. M., Nickols, N. G., & Reiter, R. E. (2021). High-dose per Fraction Radiotherapy Induces Both Antitumor Immunity and Immunosuppressive Responses in Prostate Tumors. Clinical cancer research : an official journal of the American Association for Cancer Research, 27(5), 1505-1515. https://doi.org/10.1158/1078-0432.CCR-20-2293
Lin, Lin, et al. "High-dose per Fraction Radiotherapy Induces Both Antitumor Immunity and Immunosuppressive Responses in Prostate Tumors." Clinical cancer research : an official journal of the American Association for Cancer Research vol. 27,5 (2021): 1505-1515. doi: https://doi.org/10.1158/1078-0432.CCR-20-2293
Lin L, Kane N, Kobayashi N, Kono EA, Yamashiro JM, Nickols NG, Reiter RE. High-dose per Fraction Radiotherapy Induces Both Antitumor Immunity and Immunosuppressive Responses in Prostate Tumors. Clin Cancer Res. 2021 Mar 01;27(5):1505-1515. doi: 10.1158/1078-0432.CCR-20-2293. Epub 2020 Nov 20. PMID: 33219015.
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Clin Cancer Res. 2021 Mar 01;27(5):1505-1515. doi: 10.1158/1078-0432.CCR-20-2293. Epub 2020 Nov 20.

High-dose per Fraction Radiotherapy Induces Both Antitumor Immunity and Immunosuppressive Responses in Prostate Tumors.

Clinical cancer research : an official journal of the American Association for Cancer Research

Lin Lin, Nathanael Kane, Naoko Kobayashi, Evelyn A Kono, Joyce M Yamashiro, Nicholas G Nickols, Robert E Reiter

Affiliations

  1. Department of Urology, University of California, Los Angeles, Los Angeles, California.
  2. Department of Radiation Oncology, University of California, Los Angeles, Los Angeles, California.
  3. Radiation Oncology Service, VA Greater Los Angeles, Los Angeles, California.
  4. Department of Urology, University of California, Los Angeles, Los Angeles, California. [email protected].

PMID: 33219015 DOI: 10.1158/1078-0432.CCR-20-2293

Abstract

PURPOSE: The use of high-dose per fraction radiotherapy delivered as stereotactic body radiotherapy is a standard of care for prostate cancer. It is hypothesized that high-dose radiotherapy may enhance or suppress tumor-reactive immunity. The objective of this study was to assess both antitumor and immunosuppressive effects induced by high-dose radiotherapy in prostate cancer coclinical models, and ultimately, to test whether a combination of radiotherapy with targeted immunotherapy can enhance antitumor immunity.

EXPERIMENTAL DESIGN: We studied the effects of high-dose per fraction radiotherapy with and without anti-Gr-1 using syngeneic murine allograft prostate cancer models. The dynamic change of immune populations, including tumor-infiltrating lymphocytes (TIL), T regulatory cells (Treg), and myeloid-derived suppressive cells (MDSC), was evaluated using flow cytometry and IHC.

RESULTS: Coclinical prostate cancer models demonstrated that high-dose per fraction radiotherapy induced a rapid increase of tumor-infiltrating MDSCs and a subsequent rise of CD8 TILs and circulating CD8 T effector memory cells. These radiation-induced CD8 TILs were more functionally potent than those from nonirradiated controls. While systemic depletion of MDSCs by anti-Gr-1 effectively prevented MDSC tumor infiltration, it did not enhance radiotherapy-induced antitumor immunity due to a compensatory expansion of Treg-mediated immune suppression.

CONCLUSIONS: In allograft prostate cancer models, high-dose radiotherapy induced an early rise of MDSCs, followed by a transient increase of functionally active CD8 TILs. However, systemic depletion of MDSC did not augment the antitumor efficacy of high-dose radiotherapy due to a compensatory Treg response, indicating blocking both MDSCs and Tregs might be necessary to enhance radiotherapy-induced antitumor immunity.

©2020 American Association for Cancer Research.

References

  1. Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–23. - PubMed
  2. Herbst RS, Baas P, Kim D-W, Felip E, Pérez-Gracia JL, Han Ji-Y, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387:1540–50. - PubMed
  3. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti–PD-1 antibody in cancer. N Engl J Med. 2012;66:2443–54. - PubMed
  4. Beer TM, Kwon ED, Drake CG, Fizazi K, Logothetis C, Gravis G, et al. Randomized, double-blind, phase III trial of ipilimumab versus placebo in asymptomatic or minimally symptomatic patients with metastatic chemotherapy-naive castration-resistant prostate cancer. J Clin Oncol. 2017;35:40–7. - PubMed
  5. Abida W, Cheng ML, Armenia J, Middha S, Autio KA, Vargas HA, et al. Analysis of the prevalence of microsatellite instability in prostate cancer and response to immune checkpoint blockade. JAMA Oncol. 2019;5:471–8. - PubMed
  6. Yi-Mi W, Cieslik M, Lonigro RJ, Vats P, Reimers MA, Cao X, et al. Inactivation of CDK12 delineates a distinct immunogenic class of advanced prostate cancer.. Cell. 2018;173:1770–82. - PubMed
  7. Graff JN, Alumkal JJ, Drake CG, Thomas GV, Redmond WL, Farhad M, et al. Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer. Oncotarget. 2016;7:52810–7. - PubMed
  8. Cabel L, Loir E, Gravis G, Lavaud P, Massard C, Albiges L, et al. Long-term complete remission with Ipilimumab in metastatic castrate-resistant prostate cancer: case report of two patients. J Immunother Cancer. 2017;5:1–6. - PubMed
  9. Slovin SF, Higano CS, Hamid O, Tejwani S, Harzstark A, Alumkal JJ, et al. Ipilimumab alone or in combination with radiotherapy in metastatic castration-resistant prostate cancer: results from an open-label, multicenter phase I/II study. Ann Oncol. 2013;24:1813–21. - PubMed
  10. Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell. 2017;168:707–73. - PubMed
  11. Gannot G, Richardson AM, Rodriguez-Canales J, Pinto PA, Merino MJ, Chuaqui RF, et al. Decrease in CD8+ lymphocyte number and altered cytokine profile in human prostate cancer. Am J Cancer Res. 2011;1:120–7. - PubMed
  12. Sfanos KS, Bruno TC, Maris CH, Xu L, Thoburn CJ, DeMarzo AM, et al. Phenotypic analysis of prostate-infiltrating lymphocytes reveals T H17 and Treg skewing. Clin Cancer Res. 2008;14:3254–61. - PubMed
  13. Ness N, Andersen S, Khanehkenari MR, Nordbakken CV, Valkov A, Paulsen E-E, et al. The prognostic role of immune checkpoint markers programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) in a large, multicenter prostate cancer cohort. Oncotarget. 2017;8:26789–801. - PubMed
  14. Gao J, Ward JF, Pettaway CA, Shi LZ, Subudhi SK, Vence LM, et al. VISTA is an inhibitory immune checkpoint that is increased after ipilimumab therapy in patients with prostate cancer. Nat Med. 2017;23:551–5. - PubMed
  15. Idorn M, Køllgaard T, Kongsted P, Sengeløv L, Thor Straten P. Correlation between frequencies of blood monocytic myeloid-derived suppressor cells, regulatory T cells and negative prognostic markers in patients with castration-resistant metastatic prostate cancer. Cancer Immunol Immunother. 2014;63:1177–87. - PubMed
  16. Liauw SL, Connell PP, Weichselbaum RR. New paradigms and future challenges in radiation oncology: an update of biological targets and technology. Sci Transl Med. 2013;5:173sr2. - PubMed
  17. Demaria S, Golden EB, Formenti SC. Role of local radiation therapy in cancer immunotherapy. JAMA Oncol. 2015;1:1325–32. - PubMed
  18. Sharabi AB, Lim M, DeWeese TL, Drake CG. Radiation and checkpoint blockade immunotherapy: radiosensitisation and potential mechanisms of synergy. Lancet Oncol. 2015;16:e498–e509. - PubMed
  19. Deng L, Liang H, Xu M, Yang X, Burnette B, Arina A, et al. STING-dependent cytosolic DNA sensing promotes radiation-induced type I interferon-dependent antitumor immunity in immunogenic tumors. Immunity. 2014;41:543–852. - PubMed
  20. Muroyama Y, Nirschl TR, Kochel CM, Lopez-Bujanda Z, Theodros D, Mao W, et al. Stereotactic radiotherapy increases functionally suppressive regulatory T cells in the tumor microenvironment. Cancer Immunol Res. 2017;5:992–1004. - PubMed
  21. Xu J, Escamilla J, Mok S, David J, Priceman S, West B, et al. CSF1R signaling blockade stanches tumor-infiltrating myeloid cells and improves the efficacy of radiotherapy in prostate cancer. Cancer Res. 2013;73:2782–94. - PubMed
  22. Filatenkov A, Baker J, Mueller AMS, Kenkel J, Ahn G-O, Dutt S, et al. Ablative tumor radiation can change the tumor immune cell microenvironment to induce durable complete remissions. Clin Cancer Res. 2015;21:3727–39. - PubMed
  23. Straub JM, New J, Hamilton CD, Lominska C, Shnayder Y, Thomas SM. Radiation-induced fibrosis: mechanisms and implications for therapy. J Cancer Res Clin Oncol. 2015;141:1985–94. - PubMed
  24. Nickols NG, Ganapathy E, Nguyen C, Kane N, Lin L, Diaz-Perez S, et al. The intraprostatic immune environment after stereotactic body radiotherapy is dominated by myeloid cells. Prostate Cancer Prostatic Dis. 2020. - PubMed
  25. Liang H, Deng L, Hou Y, Meng X, Huang X, Rao E, et al. Host STING-dependent MDSC mobilization drives extrinsic radiation resistance. Nat Commun. 2017;8:1–10. - PubMed
  26. Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol. 2009;9:162–74. - PubMed
  27. Condamine T, Ramachandran I, Youn J-I, Gabrilovich DI. Regulation of tumor metastasis by myeloid-derived suppressor cells. Annu Rev Med. 2015;66:97–110. - PubMed
  28. Rodriguez PC, Ernstoff MS, Hernandez C, Atkins M, Zabaleta J, Sierra R, et al. Arginase I-producing myeloid-derived suppressor cells in renal cell carcinoma are a subpopulation of activated granulocytes. Cancer Res. 2009;69:1553–60. - PubMed
  29. Srivastava MK, Sinha P, Clements VK, Rodriguez P, Ostrand-Rosenberg S. Myeloid-derived suppressor cells inhibit T-cell activation by depleting cystine and cysteine. Cancer Res. 2010;70:68–77. - PubMed
  30. Ugel S, De Sanctis F, Mandruzzato S, Bronte V. Tumor-induced myeloid deviation: when myeloid-derived suppressor cells meet tumor-associated macrophages. J Clin Invest. 2015;125:3365–76. - PubMed
  31. Tavazoie MF, Pollack I, Tanqueco R, Ostendorf BN, Reis BS, Gonsalves FC, et al. LXR/ApoE activation restricts innate immune suppression in cancer. Cell. 2018;172:825–40. - PubMed
  32. Wang G, Lu X, Dey P, Deng P, Wu CC, Jiang S, et al. Targeting YAP-dependent MDSC infiltration impairs tumor progression. Cancer Discov. 2016;6:80–95. - PubMed
  33. Kumar V, Donthireddy L, Marvel D, Condamine T, Wang F, Lavilla-Alonso S, et al. Cancer-associated fibroblasts neutralize the anti-tumor effect of CSF1 receptor blockade by inducing PMN-MDSC infiltration of tumors. Cancer Cell. 2017;32:654–68. - PubMed
  34. Hossain DMS, Pal SK, Moreira D, Duttagupta P, Zhang Q, Won H, et al. TLR9-targeted STAT3 silencing abrogates immunosuppressive activity of myeloid-derived suppressor cells from prostate cancer patients. Clin Cancer Res. 2015;21:3771–82. - PubMed
  35. Lu X, Horner JW, Paul E, Shang X, Troncoso P, Deng P, et al. Effective combinatorial immunotherapy for castration-resistant prostate cancer. Nature. 2017;543:728–32. - PubMed
  36. Lopez-Bujanda Z, Drake CG. Myeloid-derived cells in prostate cancer progression: phenotype and prospective therapies. J Leukoc Biol. 2017;102:393–406. - PubMed
  37. King CR, Freeman D, Kaplan I, Fuller D, Bolzicco G, Collins S, et al. Stereotactic body radiotherapy for localized prostate cancer: pooled analysis from a multi-institutional consortium of prospective phase II trials. Radiother Oncol. 2013;109:217–21. - PubMed
  38. Baley PA, Yoshida K, Qian W, Sehgal I, Thompson TC. Progression to androgen insensitivity in a novel in vitro mouse model for prostate cancer. J Steroid Biochem Mol Biol. 1995;52:403–13. - PubMed
  39. Li J, Lee Y, Li Y, Jiang Yu, Lu H, Zang W, et al. Co-inhibitory molecule B7 superfamily member 1 expressed by tumor-infiltrating myeloid cells induces dysfunction of anti-tumor CD8+ T cells. Immunity. 2018;48:773–86. - PubMed
  40. Schaue D, Ratikan JA, Iwamoto KS, McBride WH. Maximizing tumor immunity with fractionated radiation. Int J Radiat Oncol Biol Phys. 2012;83:1306–10. - PubMed
  41. Chetram MA, Don-Salu-Hewage AS, Hinton CV. ROS enhances CXCR4-mediated functions through inactivation of PTEN in prostate cancer cells. Biochem Biophys Res Commun. 2011;410:195–200. - PubMed
  42. Kumar V, Patel S, Tcyganov E, Gabrilovich DI. The nature of myeloid-derived suppressor cells in the tumor microenvironment. Trends Immunol. 2016;37:208–22. - PubMed
  43. Youn Je-In, Kumar V, Collazo M, Nefedova Y, Condamine T, Cheng P, et al. Epigenetic silencing of retinoblastoma gene regulates pathologic differentiation of myeloid cells in cancer. Nat Immunol. 2013;14:211–20. - PubMed
  44. Corzo CA, Condamine T, Lu L, Cotter MJ, Youn Je-In, Cheng P, et al. HIF-1α regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. J Exp Med. 2010;207:2439–53. - PubMed
  45. Centuori SM, Trad M, LaCasse CJ, Alizadeh D, Larmonier CB, Hanke NT, et al. Myeloid-derived suppressor cells from tumor-bearing mice impair TGF-β-induced differentiation of CD4 + CD25 + FoxP3 + Tregs from CD4 + CD25 − FoxP3 − T cells. J Leukoc Biol. 2012;92:987–97. - PubMed
  46. Philippou Y, Sjoberg HT, Murphy E, Alyacoubi S, Jones KI, Gordon-Weeks AN, et al. Impacts of combining anti-PD-L1 immunotherapy and radiotherapy on the tumour immune microenvironment in a murine prostate cancer model. Br J Cancer. 2020;123:1089–1100. - PubMed
  47. Parikh NR, Kishan AU, Kane N, Diaz-Perez S, Ganapathy E, Nazarian R, et al. Phase 1 trial of stereotactic body radiation therapy neoadjuvant to radical prostatectomy for patients with high-risk prostate cancer. Int J Radiat Oncol Biol Phys. 2020;108:930–35. - PubMed
  48. Zhao SG, Lehrer J, Chang SL, Das R, Erho N, Liu Y, et al. The immune landscape of prostate cancer and nomination of PD-L2 as a potential therapeutic target. J Natl Cancer Inst. 2019;111:301–10. - PubMed

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