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Significance of evaluating tumor-infiltrating lymphocytes (TILs) and programmed cell death-ligand 1 (PD-L1) expression in breast cancer

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Abstract

The immune system affects all phases of tumor growth from initiation to progression and dissemination. Tumor-infiltrating lymphocytes (TILs) are mononuclear immune cells that infiltrate tumor tissue. Several retrospective studies have suggested the potential of TILs as a prognostic as well as predictive factor of chemotherapy in some breast cancers. On the other hand, programmed cell death protein-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) eliminate T cell activation in various types of cancers. Prospective trials to evaluate the efficacy of antibody agents to PD-1 and PD-L1 are ongoing in patients with breast cancer. The findings of these studies appear to support the potential of immune checkpoint inhibitors targeting the PD-1/PD-L1 axis in triple negative breast cancer. Further studies are needed in order to confirm previous findings on TILs and promote the development of new immune therapy approaches for breast cancer patients. Furthermore, the search for TILs will soon be introduced into actual clinical practice, for which the standardization of evaluation methods and establishment of a simple evaluation method are expected.

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References

  1. Balkwill F, Mantovani A (2001) Inflammation and cancer: back to Virchow? Lancet 357:539–545

    Article  CAS  PubMed  Google Scholar 

  2. Klein E, Becker S, Svedmyr E, Jondal M, Vanky F (1976) Tumor infiltrating lymphocytes. Ann N Y Acad Sci 276:207–216

    Article  CAS  PubMed  Google Scholar 

  3. Galon J, Angell HK, Bedognetti D, Marincola FM (2013) The continuum of cancer immunosurveillance: prognostic, predictive, and mechanistic signatures. Immunity 39:11–26

    Article  CAS  PubMed  Google Scholar 

  4. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, Tosolini M, Camus M, Berger A, Wind P, Zinzindohoué F, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Pagès F (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313:1960–1964

    Article  CAS  PubMed  Google Scholar 

  5. Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N (2002) Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci 99:12293–12297

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12:252–264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Keir ME, Butte MJ, Freeman GJ, Sharpe AH (2008) PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 26:677–704

    Article  CAS  PubMed  Google Scholar 

  8. Nishimura H, Agata Y, Kawasaki A, Sato M, Imamura S, Minato N, Yagita H, Nakano T, Honjo T (1996) Developmentally regulated expression of the PD-1 protein on the surface of double-negative (CD4−CD8−) thymocytes. Int Immunol 8:773–780

    Article  CAS  PubMed  Google Scholar 

  9. Chen DS, Mellman I (2013) Oncology meets immunology: the cancer-immunity cycle. Immunity 39:1–10

    Article  PubMed  Google Scholar 

  10. Coussens LM, Zitvogel L, Palucka AK (2013) Neutralizing tumor-promoting chronic inflammation: a magic bullet? Science 339:286–291

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Mohammed ZMA, Going JJ, Edwards B, Doughty JC, McMillan DC (2012) The relationship between components of tumor inflammatory cell infiltrate and clinicopathological factors and survival in patients with primary operable invasive ductal breast cancer. Br J Cancer 107:864–873

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Richters A, Kaspersky CL (1975) Surface immunoglobulin positive lymphocytes in human breast cancer tissue and homolateral axillary lymph nodes. Cancer 35:129–133

    Article  CAS  PubMed  Google Scholar 

  13. WHO (2012) Carcinomas with medullary features. In: Lakhani SR, Ellis IO (eds) WHO classification of tumours of the breast. WHO Press, Geneva, pp 46–47

    Google Scholar 

  14. Stanton AE, Adams S, Disis ML (2016) Variation in incidence and magnitude of tumor-infiltrating lymphocytes in breast cancer subtypes: a systematic review. JAMA oncol 2:1354–1360

    Article  PubMed  Google Scholar 

  15. Savas P, Salgado R, Denkert C, Sotiriou C, Darcy PK, Smyth MJ, Loi S (2016) Clinical relevance of host immunity in breast cancer: from TILs to the clinic. Nat Rev Clin Oncol 13:228–241

    Article  CAS  PubMed  Google Scholar 

  16. Salgado R, Denkert C, Demaria S, Sirtaine N, Klauschen F, Pruneri G, Wienert S, Van den Eynden G, Baehner FL, Penault-Llorca F, Perez EA, Thompson EA, Symmans WF, Richardson AL, Brock J, Criscitiello C, Bailey H, Ignatiadis M, Floris G, Sparano J, Kos Z, Nielsen T, Rimm DL, Allison KH, Reis-Filho JS, Loibl S, Sotiriou C, Viale G, Badve S, Adams S, Willard-Gallo K, Loi S, International TILs Working Group 2014 (2015) The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol 26:259–271

    Article  CAS  PubMed  Google Scholar 

  17. Buisseret L, Desmedt C, Garaud S, Fornili M, Wang X, Van den Eyden G, de Wind A, Duquenne S, Boisson A, Naveaux C, Rothé F, Rorive S, Decaestecker C, Larsimont D, Piccart-Gebhart M, Biganzoli E, Sotiriou C, Willard-Gallo K (2017) Reliability of tumor-infiltrating lymphocyte and tertiary lymphoid structure assessment in human breast cancer. Mod Pathol. doi:10.1038/modpathol.2017.43

    PubMed  Google Scholar 

  18. Miyashita M, Sasano H, Tamaki K, Hirakawa H, Takahashi Y, Nakagawa S, Watanabe G, Tada H, Suzuki A, Ohuchi N, Ishida T (2015) Prognostic significance of tumor-infiltrating CD8+ and FOXP3+ lymphocytes in residual tumors and alterations in these parameters after neoadjuvant chemotherapy in triple-negative breast cancer: a retrospective multicenter study. Breast Cancer Res 17:124

    Article  PubMed  PubMed Central  Google Scholar 

  19. Kurozumi S, Inoue K, Matsumoto H, Hayashi Y, Tozuka K, Kubo K, Komatsu K, Takai K, Nagai SE, Oba H, Horiguchi J, Takeyoshi I, Kurosumi M (2015) Prognostic value of tumor-infiltrating lymphocytes in residual tumors after neoadjuvant chemotherapy concomitant with trastuzumab for HER2-positive breast cancer. Cancer Res 76(suppl):abstr: P4-14-17

    Google Scholar 

  20. Nishimura R, Osako T, Okumura Y, Hayashi M, Arima N (2010) Clinical significance of Ki-67 in neoadjuvant chemotherapy for primary breast cancer as a predictor for chemosensitivity and for prognosis. Breast Cancer 17:269–275

    Article  PubMed  Google Scholar 

  21. Honma N, Horii R, Iwase T, Saji S, Younes M, Ito Y, Akiyama F (2015) Ki-67 evaluation at the hottest spot predicts clinical outcome of patients with hormone receptor-positive/HER2-negative breast cancer treated with adjuvant tamoxifen monotherapy. Breast Cancer 22:71–78

    Article  PubMed  Google Scholar 

  22. Loi S, Sirtaine N, Piette F, Salgado R, Viale G, Van Eenoo F, Rouas G, Francis P, Crown JP, Hitre E, de Azambuja E, Quinaux E, Di Leo A, Michiels S, Piccart MJ, Sotiriou C (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 31:860–867

    Article  CAS  PubMed  Google Scholar 

  23. Adams S, Gray RJ, Demaria S, Goldstein L, Perez EA, Shulman LN, Martino S, Wang M, Jones VE, Saphner TJ, Wolff AC, Wood WC, Davidson NE, Sledge GW, Sparano JA, Badve SS (2014) Prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199. J Clin Oncol 32:2959–2966

    Article  PubMed  PubMed Central  Google Scholar 

  24. Loi S, Drubay D, Adams S, Francis PA, Joensuu H, Dieci MV, Badve S, Demaria S, Gray R, Piccart MJ, Lehtinen PLK, Andre F, Denkert C, Salgado R, Michiels S (2016) Pooled individual patient data analysis of stromal tumor infiltrating lymphocytes in primary triple negative breast cancer treated with anthracycline-based chemotherapy. Cancer Res 76(suppl):abstr S1–03

    Article  Google Scholar 

  25. Salgado R, Denkert C, Campbell C, Savas P, Nuciforo P, Aura C, de Azambuja E, Eidtmann H, Ellis CE, Baselga J, Piccart-Gebhart MJ, Michiels S, Bradbury I, Sotiriou C, Loi S (2015) Tumor-infiltrating lymphocytes and associations with pathological complete response and event-free survival in HER2-positive early-stage breast cancer treated with lapatinib and trastuzumab: a secondary analysis of the NeoALTTO Trial. JAMA Oncol 1:448–454

    Article  PubMed  PubMed Central  Google Scholar 

  26. Loi S, Michiels S, Salgado R, Sirtaine N, Jose V, Fumagalli D, Kellokumpu-Lehtinen PL, Bono P, Kataja V, Desmedt C, Piccart MJ, Loibl S, Denkert C, Smyth MJ, Joensuu H, Sotiriou C (2014) Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer: results from the FinHER trial. Ann Oncol 25:1544–1550

    Article  CAS  PubMed  Google Scholar 

  27. Hida AI, Sagara Y, Yotsumoto D, Kanemitsu S, Kawano J, Baba S, Rai Y, Oshiro Y, Aogi K, Sagara Y, Ohi Y (2016) Prognostic and predictive impacts of tumor-infiltrating lymphocytes differ between Triple-negative and HER2-positive breast cancers treated with standard systemic therapies. Breast Cancer Res Treat 158:1–9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ali HR, Provenzano E, Dawson SJ, Blows FM, Liu B, Shah M, Earl HM, Poole CJ, Hiller L, Dunn JA, Bowden SJ, Twelves C, Bartlett JM, Mahmoud SM, Rakha E, Ellis IO, Liu S, Gao D, Nielsen TO, Pharoah PD, Caldas C (2014) Association between CD8+ T-cell infiltration and breast cancer survival in 12,439 patients. Ann Oncol 25:1536–1543

    Article  CAS  PubMed  Google Scholar 

  29. Denkert C, Loibl S, Noske A, Roller M, Müller BM, Komor M, Budczies J, Darb-Esfahani S, Kronenwett R, Hanusch C, von Törne C, Weichert W, Engels K, Solbach C, Schrader I, Dietel M, von Minckwitz G (2010) Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol 28:105–113

    Article  CAS  PubMed  Google Scholar 

  30. Kurozumi S, Inoue K, Kurosumi M, Matsumoto H, Hayashi Y, Tozuka K, Kubo K, Komatsu K, Takai K, Nagai SE, Oba H, Horiguchi J (2016) Values of tumor-infiltrating lymphocytes (TILs), CD8+ TILs, and PDL-1 for predicting pathological complete response and prognosis in HER2-positive breast cancer receiving neoadjuvant chemotherapy with trastuzumab. J Clin Oncol 34(suppl):abstr 589

    Google Scholar 

  31. Dieci MV, Criscitiello C, Goubar A, Viale G, Conte P, Guarneri V, Ficarra G, Mathieu MC, Delaloge S, Curigliano G, Andre F (2015) Prognostic value of tumor-infiltrating lymphocytes on residual disease after primary chemotherapy for triple-negative breast cancer: a retrospective multicenter study. Ann Oncol 26:1518

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Asano Y, Kashiwagi S, Goto W, Kurata K, Noda S, Takashima T, Onoda N, Tanaka S, Ohsawa M, Hirakawa K (2016) Tumour-infiltrating CD8 to FOXP3 lymphocyte ratio in predicting treatment responses to neoadjuvant chemotherapy of aggressive breast cancer. Br J Surg 103:845–854

    Article  CAS  PubMed  Google Scholar 

  33. Topalian SL, Taube JM, Anders RA, Pardoll DM (2016) Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat Rev Cancer 16:275–287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, Wolchok JD (2015) Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 373:23–34

    Article  PubMed  Google Scholar 

  35. Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, Waterhouse D, Ready N, Gainor J, Arén Frontera O, Havel L, Steins M, Garassino MC, Aerts JG, Domine M, Paz-Ares L, Reck M, Baudelet C, Harbison CT, Lestini B, Spigel DR (2015) Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 373:123–135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Motzer RJ, Rini BI, McDermott DF, Redman BG, Kuzel TM, Harrison MR, Vaishampayan UN, Drabkin HA, George S, Logan TF, Margolin KA, Plimack ER, Lambert AM, Waxman IM, Hammers HJ (2015) Nivolumab for metastatic renal cell carcinoma: results of a randomized phase II trial. J Clin Oncol 33:1430–1437

    Article  CAS  PubMed  Google Scholar 

  37. Nanda R, Chow LQ, Dees EC, Berger R, Gupta S, Geva R, Pusztai L, Pathiraja K, Aktan G, Cheng JD, Karantza V, Buisseret L (2016) Pembrolizumab in patients with advanced triple-negative breast cancer: phase Ib KEYNOTE-012 study. J Clin Oncol 34:2460–2467

    Article  CAS  PubMed  Google Scholar 

  38. Gibney GT, Weiner LM, Atkins MB (2016) Predictive biomarkers for checkpoint inhibitor-based immunotherapy. Lancet Oncol 17:e542–e551

    Article  CAS  PubMed  Google Scholar 

  39. Gandini S, Massi D, Mandalà M (2016) PD-L1 expression in cancer patients receiving anti PD-1/PD-L1 antibodies: a systematic review and meta-analysis. Crit Rev Oncol Hematol 100:88–98

    Article  PubMed  Google Scholar 

  40. Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, Patnaik A, Aggarwal C, Gubens M, Horn L, Carcereny E, Ahn MJ, Felip E, Lee JS, Hellmann MD, Hamid O, Goldman JW, Soria JC, Dolled-Filhart M, Rutledge RZ, Zhang J, Lunceford JK, Rangwala R, Lubiniecki GM, Roach C, Emancipator K, Gandhi L, KEYNOTE-001 Investigators (2015) Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 372:2018–2028

    Article  PubMed  Google Scholar 

  41. Mino-Kenudson Mari (2016) Programmed cell death ligand-1 (PD-L1) expression by immunohistochemistry: could it be predictive and/or prognostic in non-small cell lung cancer? Cancer Biol Med 13:157–170

    Article  PubMed  PubMed Central  Google Scholar 

  42. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, Barlesi F, Kohlhäufl M, Arrieta O, Burgio MA, Fayette J, Lena H, Poddubskaya E, Gerber DE, Gettinger SN, Rudin CM, Rizvi N, Crinò L, Blumenschein GR Jr, Antonia SJ, Dorange C, Harbison CT, Graf Finckenstein F, Brahmer JR (2015) Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 373:1627–1639

    Article  CAS  PubMed  Google Scholar 

  43. Sun WY, Lee YK, Koo JS (2016) Expression of PD-L1 in triple-negative breast cancer based on different immunohistochemical antibodies. J Transl Med 14:173

    Article  PubMed  PubMed Central  Google Scholar 

  44. Hurvitz SA, Betting DJ, Stern HM, Quinaux E, Stinson J, Seshagiri S, Zhao Y, Buyse M, Mackey J, Driga A (2012) Analysis of Fcgamma receptor IIIa and IIa polymorphisms: lack of correlation with outcome in trastuzumab-treated breast cancer patients. Clin Cancer Res 18:3478–3486

    Article  CAS  PubMed  Google Scholar 

  45. Sliwkowski MX, Mellman I (2013) Antibody therapeutics in cancer. Science 341:1192–1198

    Article  CAS  PubMed  Google Scholar 

  46. Junttila TT, Li J, Johnston J, Hristopoulos M, Clark R, Ellerman D, Wang BE, Li Y, Mathieu M, Li G, Young J, Luis E, Lewis Phillips G, Stefanich E, Spiess C, Polson A, Irving B, Scheer JM, Junttila MR, Dennis MS, Kelley R, Totpal K, Ebens A (2014) Antitumor efficacy of a bispecific antibody that targets HER2 and activates T cells. Cancer Res 74:5561–5571

    Article  CAS  PubMed  Google Scholar 

  47. Issa-Nummer Y, Darb-Esfahani S, Loibl S, Kunz G, Nekljudova V, Schrader I, Sinn BV, Ulmer HU, Kronenwett R, Just M, Kühn T, Diebold K, Untch M, Holms F, Blohmer JU, Habeck JO, Dietel M, Overkamp F, Krabisch P, von Minckwitz G, Denkert C (2013) Prospective validation of immunological infiltrate for prediction of response to neoadjuvant chemotherapy in HER2-negative breast cancer–a substudy of the neoadjuvant GeparQuinto trial. PLoS One 8:e79775

    Article  PubMed  PubMed Central  Google Scholar 

  48. Denkert C, von Minckwitz G, Brase JC, Sinn BV, Gade S, Kronenwett R, Pfitzner BM, Salat C, Loi S, Schmitt WD, Schem C, Fisch K, Darb-Esfahani S, Mehta K, Sotiriou C, Wienert S, Klare P, André F, Klauschen F, Blohmer JU, Krappmann K, Schmidt M, Tesch H, Kümmel S, Sinn P, Jackisch C, Dietel M, Reimer T, Untch M, Loibl S (2015) Tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy with or without carboplatin in human epidermal growth factor receptor 2-positive and triple-negative primary breast cancers. J Clin Oncol 33:983–991

    Article  CAS  PubMed  Google Scholar 

  49. West NR, Milne K, Truong PT, Macpherson N, Nelson BH, Watson PH (2011) Tumor-infiltrating lymphocytes predict response to anthracycline-based chemotherapy in estrogen receptor-negative breast cancer. Breast Cancer Res 13:R126

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan

    Sasagu Kurozumi, Takaaki Fujii & Hiroyuki Kuwano

  2. Division of Breast Surgery, Saitama Cancer Center, Saitama, Japan

    Sasagu Kurozumi & Hiroshi Matsumoto

  3. Division of Breast Oncology, Saitama Cancer Center, Saitama, Japan

    Kenichi Inoue

  4. Department of Pathology, Saitama Cancer Center, 780 Komuro, Ina-machi, Kitaadachi-gun, Saitama, 362-0806, Japan

    Masafumi Kurosumi

  5. Department of Breast Surgery, International University of Health and Welfare, Chiba, Japan

    Jun Horiguchi

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  1. Sasagu Kurozumi
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  2. Takaaki Fujii
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Correspondence to Masafumi Kurosumi.

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Kurozumi, S., Fujii, T., Matsumoto, H. et al. Significance of evaluating tumor-infiltrating lymphocytes (TILs) and programmed cell death-ligand 1 (PD-L1) expression in breast cancer. Med Mol Morphol 50, 185–194 (2017). https://doi.org/10.1007/s00795-017-0170-y

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