Immunoprofiling as a predictor of patient's response to cancer therapy—promises and challenges

Current Opinion in Immunology

Volumn 45, Issue , 2017, Pages 60-72

  Bethmann, Daniel ^a,b   Feng, Zipei ^b,c   Fox, Bernard A ^b,d  

^a MARTIN LUTHER UNIVERSITY HALLE WITTENBERG   (Germany)

^b EARLE A CHILES RESEARCH INSTITUTE   (United States)

^c OREGON HEALTH AND SCIENCE UNIVERSITY   (United States)

^d OREGON HEALTH AND SCIENCE UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

IPILIMUMAB; NIVOLUMAB; PACLITAXEL; PEMBROLIZUMAB; PROGRAMMED DEATH 1 LIGAND 1; CD274 PROTEIN, HUMAN; TUMOR PROTEIN;

AUTOIMMUNE DISEASE; AUTOMATION; BREAST CANCER; CANCER IMMUNOTHERAPY; CANCER PROGNOSIS; CANCER STAGING; CANCER THERAPY; CHEMILUMINESCENCE IMMUNOASSAY; DIGITAL IMAGING; HEAD AND NECK SQUAMOUS CELL CARCINOMA; HUMAN; IMAGE ANALYSIS; IMMUNOHISTOCHEMISTRY; LYMPHOCYTIC INFILTRATION; MACHINE LEARNING; NON SMALL CELL LUNG CANCER; NONHUMAN; OVERALL SURVIVAL; PERSONALIZED MEDICINE; REVIEW; SKIN DEFECT; SMALL CELL LUNG CANCER; STAINING; TREATMENT RESPONSE; TUMOR ASSOCIATED LEUKOCYTE; TUMOR ESCAPE; ANIMAL; COLON TUMOR; GENE EXPRESSION PROFILING; GENE EXPRESSION REGULATION; IMMUNOLOGY; LUNG TUMOR; PATHOLOGY;

ANIMALS; B7-H1 ANTIGEN; CARCINOMA, NON-SMALL-CELL LUNG; COLONIC NEOPLASMS; GENE EXPRESSION PROFILING; GENE EXPRESSION REGULATION, NEOPLASTIC; HUMANS; LUNG NEOPLASMS; NEOPLASM PROTEINS;

EID: 85013150687     PISSN: 09527915     EISSN: 18790372     Source Type: Journal    
DOI: 10.1016/j.coi.2017.01.005     Document Type: Review

References (129)

1. 1• Virchow, R., Die Krankhaften Geschwülste. 1863 Interest in the stromal response to neoplasia began in the latter half of the 19th century, when Virchow in this manuscript stated that the frequent presence of lymphatic cells in human tumors reflects the origin of cancer at sites of previous chronic inflammation.
2. 2 Waldeyer, H.G.W., Die Entwicklung der Karzinome. Virchows Arch Path Anat, 55, 1872, 67.
3. 3 Handley, W.S., The Bunterian lectures on the pathology of melanotic growths in relation to their operative treatment. Lancet 169 (1907), 927–933.
4. 4 Wade, H., An experimental investigation of infective sarcoma in the dog, with a consideration of its relationship to cancer. J Path Bact, 12, 1908, 384.
5. 5 De Fano, C., A cytological analysis of the reaction in animals resistant to implanted carcinomata. Fifth Sci Rep Imrp Cancer Res Fund, 1912 [no volume].
6. 6 MacCarty, W.C., Mahle, A.E., Relation of differentiation and lymphocytic infiltration to postoperative longevity in gastric carcinoma. J Lab Clin Med, 6, 1921, 473.
7. 7 Underwood, J.C., Lymphoreticular infiltration in human tumours: prognostic and biological implications: a review. Br J Cancer 30 (1974), 538–548.
8. 8 Fridman, W.H., Pagès, F., Sautès-Fridman, C., Galon, J., The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer 12 (2012), 298–306.
9. 9 Holman, C.D., James, I.R., Heenan, P.J., Matz, L.R., Blackwell, J.B., Kelsall, G.R., Singh, A., ten Seldam, R.E., An improved method of analysis of observer variation between pathologists. Histopathology 6 (1982), 581–589.
10. 10•• Mella, M., Kauppila, J.H., Karihtala, P., Lehenkari, P., Jukkola-Vuorinen, A., Soini, Y., Auvinen, P., Vaarala, M.H., Ronkainen, H., Kauppila, S., et al. Tumor infiltrating CD8+ T lymphocyte count is independent of tumor TLR9 status in treatment naïve triple negative breast cancer and renal cell carcinoma. OncoImmunology, 4, 2015, e1002726.
11. 11 Jensen, H.K., Donskov, F., Nordsmark, M., Marcussen, N., von der Maase, H., Increased intratumoral FOXP3-positive regulatory immune cells during interleukin-2 treatment in metastatic renal cell carcinoma. Clin Cancer Res 15 (2009), 1052–1058.
12. 12 Siddiqui, S.A., Frigola, X., Bonne-Annee, S., Mercader, M., Kuntz, S.M., Krambeck, A.E., Sengupta, S., Dong, H., Cheville, J.C., Lohse, C.M., et al. Tumor-infiltrating Foxp3-CD4+ CD25+ T cells predict poor survival in renal cell carcinoma. Clin Cancer Res 13 (2007), 2075–2081.
13. 13•• Ness, N., Andersen, S., Valkov, A., Nordby, Y., Donnem, T., Al-Saad, S., Busund, L.-T., Bremnes, R.M., Richardsen, E., Infiltration of CD8+ lymphocytes is an independent prognostic factor of biochemical failure-free survival in prostate cancer. Prostate 74 (2014), 1452–1461.
14. 14 Kärjä, V., Aaltomaa, S., Lipponen, P., Isotalo, T., Talja, M., Mokka, R., Tumour-infiltrating lymphocytes: a prognostic factor of PSA-free survival in patients with local prostate carcinoma treated by radical prostatectomy. Anticancer Res 25 (2005), 4435–4438.
15. 15 Stewart, T.J., Abrams, S.I., How tumours escape mass destruction. Oncogene 27 (2008), 5894–5903.
16. 16 Kursunel, M.A., Esendagli, G., The untold story of IFN-γ in cancer biology. Cytokine Growth Factor Rev 31 (2016), 73–81.
17. 17•• Zaretsky, J.M., Garcia-Diaz, A., Shin, D.S., Escuin-Ordinas, H., Hugo, W., Hu-Lieskovan, S., Torrejon, D.Y., Abril-Rodriguez, G., Sandoval, S., Barthly, L., et al. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N Engl J Med 375 (2016), 819–829 Using whole exome sequencing, Zaretsky et al. demonstrated that acquired resistance to PD-1 blockade immunotherapy in patients with melanoma was associated with the functional inactivation of CD8+ T-cells by loss-of function mutations in Janus kinases 1 and 2 genes as well as the loss of MHC class I expression on the tumor surface as presented by a truncating mutation in the gene encoding β2-microglobulin.
18. 18 Barth, R.J., Camp, B.J., Martuscello, T.A., Dain, B.J., Memoli, V.A., The cytokine microenvironment of human colon carcinoma: lymphocyte expression of tumor necrosis factor-α and interleukin-4 predicts improved survival. Cancer 78 (1996), 1168–1178.
19. 19 Galon, J., Mlecnik, B., Bindea, G., Angell, H.K., Berger, A., Lagorce, C., Lugli, A., Zlobec, I., Hartmann, A., Bifulco, C., et al. Towards the introduction of the Immunoscore in the classification of malignant tumours. J Pathol 232 (2014), 199–209.
20. 20 Ma, W., Gilligan, B.M., Yuan, J., Li, T., Current status and perspectives in translational biomarker research for PD-1/PD-L1 immune checkpoint blockade therapy. J Hematol Oncol J Hematol Oncol, 9, 2016, 47.
21. 21 Gandini, S., Massi, D., Mandalà, M., PD-L1 expression in cancer patients receiving anti PD-1/PD-L1 antibodies: a systematic review and meta-analysis. Crit Rev Oncol Hematol 100 (2016), 88–98.
22. 22•• Daud, A.I., Wolchok, J.D., Robert, C., Hwu, W.-J., Weber, J.S., Ribas, A., Hodi, F.S., Joshua, A.M., Kefford, R., Hersey, P., et al. Programmed death-ligand 1 expression and response to the anti–programmed death 1 antibody pembrolizumab in melanoma. J Clin Oncol 34 (2016), 4102–4109 In this clinical study, Daud et al. showed that in melanoma patients, the assessment of PD-L1 expression in pretreatment biopsy samples positively correlates with response rate, progression free- (PFS) and overall survival (OS) following the administration of anti-PD-1 antibody Pembrolizumab. However, some patients with PD-L1–negative tumors also achieved durable responses.
23. 23•• Garon, E.B., Rizvi, N.A., Hui, R., Leighl, N., Balmanoukian, A.S., Eder, J.P., Patnaik, A., Aggarwal, C., Gubens, M., Horn, L., et al. Pembrolizumab for the treatment of non–small-cell lung cancer. N Engl J Med 372 (2015), 2018–2028 In this clinical study (Keynote-001), the authors showed that in non-small-cell lung cancer (NSCLC), first-line anti-PD-1 therapy with Pembrolizumab in patients with ≥50% of the tumor expressing PD-L1 was significantly more efficacious compared to standard 1st line chemotherapy.
24. 24 Socinski, M., Creelan, B., Horn, L., Reck, M., Paz-Ares, L., Steins, M., Felip, E., Heuvel van den, M., Ciuleanu, T.E., Badin, F., et al. NSCLC, metastaticCheckMate 026: a phase 3 trial of nivolumab vs investigator's choice (IC) of platinum-based doublet chemotherapy (PT-DC) as first-line therapy for stage iv/recurrent programmed death ligand 1 (PD-L1)-positive NSCLC. Ann Oncol, 2016, 27 LBA7_PR.
25. 25 Nghiem, P.T., Bhatia, S., Lipson, E.J., Kudchadkar, R.R., Miller, N.J., Annamalai, L., Berry, S., Chartash, E.K., Daud, A., Fling, S.P., et al. PD-1 blockade with pembrolizumab in advanced Merkel-cell carcinoma. N Engl J Med 374 (2016), 2542–2552.
26. 26 Motzer, R.J., Rini, B.I., McDermott, D.F., Redman, B.G., Kuzel, T.M., Harrison, M.R., Vaishampayan, U.N., Drabkin, H.A., George, S., Logan, T.F., et al. Nivolumab for metastatic renal cell carcinoma: results of a randomized phase II trial. J Clin Oncol 33 (2015), 1430–1437.
27. 27 Sharma, P., Callahan, M.K., Bono, P., Kim, J., Spiliopoulou, P., Calvo, E., Pillai, R.N., Ott, P.A., de Braud, F., Morse, M., et al. Nivolumab monotherapy in recurrent metastatic urothelial carcinoma (CheckMate 032): a multicentre, open-label, two-stage, multi-arm, phase 1/2 trial. Lancet Oncol 17 (2016), 1590–1598.
28. 28 Inman, B.A., Longo, T.A., Ramalingam, S., Harrison, M.R., Atezolizumab: a PD-L1 blocking antibody for bladder cancer. Clin Cancer Res, 2016, 10.1158/1078-0432.ccr-16-1417 (epub ahead of print).
29. 29 Armand, P., Nagler, A., Weller, E.A., Devine, S.M., Avigan, D.E., Chen, Y.-B., Kaminski, M.S., Holland, H.K., Winter, J.N., Mason, J.R., et al. Disabling immune tolerance by programmed death-1 blockade with pidilizumab after autologous hematopoietic stem-cell transplantation for diffuse large B-cell lymphoma: results of an international phase II trial. J Clin Oncol 31 (2013), 4199–4206.
30. 30 Westin, J.R., Chu, F., Zhang, M., Fayad, L.E., Kwak, L.W., Fowler, N., Romaguera, J., Hagemeister, F., Fanale, M., Samaniego, F., et al. Safety and activity of PD1 blockade by pidilizumab in combination with rituximab in patients with relapsed follicular lymphoma: a single group, open-label, phase 2 trial. Lancet Oncol 15 (2014), 69–77.
31. 31•• Larkin, J., Chiarion-Sileni, V., Gonzalez, R., Grob, J.J., Cowey, C.L., Lao, C.D., Schadendorf, D., Dummer, R., Smylie, M., Rutkowski, P., et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 373 (2015), 23–34 In this randomized, phase 3 clinical trial (Checkmate 067) of previously untreated patients with unresectable, metastatic melanoma, the authors showed that a therapy with nivolumab alone and the combination immunotherapy of nivolumab plus ipilimumab results in a significantly longer PFS in comparison with ipilimumab alone. Furthermore, IHC analysis suggests that it is the patients with <5% tumor PD-L1 expression who benefit from the combination immunotherapy while patients with ≥than 5% PD-L1 expressing tumors do not see added benefit to the combination over anti-PD-1 alone.
32. 32•• Tumeh, P.C., Harview, C.L., Yearley, J.H., Shintaku, I.P., Taylor, E.J.M., Robert, L., Chmielowski, B., Spasic, M., Henry, G., Ciobanu, V., et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515 (2014), 568–571 In 2014, Ribas et al. discovered that tumor regression after PD-1-blockade in melanoma patients appeared to require an increased density of CD8+ T cells in close proximity to PD-1 / PD-L1 expressing cells at the invasive tumor margin and inside the tumors.
33. 33• Hirsch, F.R., McElhinny, A., Stanforth, D., Ranger-Moore, J., Jansson, M., Kulangara, K., Richardson, W., Towne, P., Hanks, D., Vennapusa, B., et al. PD-L1 immunohistochemistry assays for lung cancer: results from phase 1 of the blueprint PD-L1 IHC Assay Comparison Project [Internet]. J Thorac Oncol, 2016, 10.1016/j.jtho.2016.11.2228 (epub ahead of print) In this article, the “Blueprint PD-L1 IHC Assay Comparison Project”, an industrial-academic collaborative partnership, tested four PD-L1 IHC assays used in clinical trials and found that, despite showing a similar analytical performance on tumor cell staining of PD-L1 expression by three of the four assays, there was a significant problem in the variability in immune cell staining. Remarkably, in as many as 37% of the cases, different PD-L1 classification would have been made depending on which assay / scoring system was used.
34. 34• McLaughlin, J., Han, G., Schalper, K.A., Carvajal-Hausdorf, D., Pelekanou, V., Rehman, J., Velcheti, V., Herbst, R., LoRusso, P., Rimm, D.L., Quantitative Assessment of the Heterogeneity of PD-L1 Expression in Non–Small-Cell Lung Cancer. JAMA Oncol, 2, 2016, 46 Using both conventional IHC, quantitative IF and an automated image analysis on NSCLC specimen to compare PD-L1 expression in two different monoclonal antibodies, the authors showed a significant interassay heterogeneity with discordant expression rates at a frequency as high as 25%.
35. 35• Rehman, J.A., Han, G., Carvajal-Hausdorf, D.E., Wasserman, B.E., Pelekanou, V., Mani, N.L., McLaughlin, J., Schalper, K.A., Rimm, D.L., Quantitative and pathologist-read comparison of the heterogeneity of programmed death-ligand 1 (PD-L1) expression in non-small cell lung cancer [Internet]. Mod Pathol, 2016, 10.1038/modpathol.2016.186 (epub ahead of print) Evaluating PD-L1 assay heterogeneity between different pathologists and different tissue blocks on NSCLC samples, Rehmann et al. found a high tumoral but only a low stromal/immune cell PD-L1 expression correlation factor. Furthermore, they demonstrated that scoring was similar among different blocks from each tumor, indicating that the spatial distribution of heterogeneity of expression of PD-L1 is within the area represented in a single tissue block.
36. 36 Obeid, J.M., Wages, N.A., Hu, Y., Deacon, D.H., Slingluff, C.L., Heterogeneity of CD8+ tumor-infiltrating lymphocytes in non-small-cell lung cancer: impact on patient prognostic assessments and comparison of quantification by different sampling strategies. Cancer Immunol Immunother, 2016, 10.1007/s00262-016-1908-4 (epub ahead of print).
37. 37•• Hodi, F.S., Chesney, J., Pavlick, A.C., Robert, C., Grossmann, K.F., McDermott, D.F., Linette, G.P., Meyer, N., Giguere, J.K., Agarwala, S.S., et al. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol 17 (2016), 1558–1568 In this multicentre, randomised clinical trial (CheckMate 069) of patients with previously untreated, unresectable stage III or IV melanoma, the authors showed that the first-line combination immunotherapy of nivolumab plus ipilimumab might lead to improved outcomes compared with first-line ipilimumab alone, though with the cost of significantly higher treatment-related side effects.
38. 38•• Hellmann, M.D., Rizvi, N.A., Goldman, J.W., Gettinger, S.N., Borghaei, H., Brahmer, J.R., Ready, N.E., Gerber, D.E., Chow, L.Q., Juergens, R.A., et al. Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study [Internet]. Lancet Oncol, 2016 In this phase 1, multicohort study (CheckMate 012) of patients with recurrent stage IIIb or stage IV, chemotherapy-naive NSCLC, the authors showed for the first time that the first-line combination immunotherapy of nivolumab plus ipilimumab had a tolerable safety profile, a high response rate and durable response rates. It is furthermore the first suggestion of an improved survival compared with anti-PD-1 monotherapy in this cancer entity.
39. 39 Antonia, S.J., López-Martin, J.A., Bendell, J., Ott, P.A., Taylor, M., Eder, J.P., Jäger, D., Pietanza, M.C., Le, D.T., de Braud, F., et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol 17 (2016), 883–895.
40. 40 Friedman, C.F., Proverbs-Singh, T.A., Postow, M.A., Treatment of the immune-related adverse effects of immune checkpoint inhibitors: a review. JAMA Oncol 2 (2016), 1346–1353.
41. 41 Bertrand, A., Kostine, M., Barnetche, T., Truchetet, M.-E., Schaeverbeke, T., Immune related adverse events associated with anti-CTLA-4 antibodies: systematic review and meta-analysis [Internet]. BMC Med, 2015, 13.
42. 42 Broussard, E.K., Disis, M.L., TNM staging in colorectal cancer: T Is for T cell and M is for memory. J Clin Oncol 29 (2011), 601–603.
43. 43•• Mlecnik, B., Tosolini, M., Kirilovsky, A., Berger, A., Bindea, G., Meatchi, T., Bruneval, P., Trajanoski, Z., Fridman, W.-H., Pagès, F., et al. Histopathologic-based prognostic factors of colorectal cancers are associated with the state of the local immune reaction. J Clin Oncol 29 (2011), 610–618 In this report, Bernard Mlecnik and colleagues demonstrated that the quantitative assessment of CD3+, CD8+ and CD45RO+ T cells at the invasive margin and tumor center of colorectal cancer specimen, termed “Immunoscore”, was a highly prognostic biomarker, and remarkably superior to conventional AJCC TNM staging.
44. 44• Anitei, M.-G., Zeitoun, G., Mlecnik, B., Marliot, F., Haicheur, N., Todosi, A.-M., Kirilovsky, A., Lagorce, C., Bindea, G., Ferariu, D., et al. Prognostic and predictive values of the immunoscore in patients with rectal cancer. Clin Cancer Res 20 (2014), 1891–1899 Adding to the discussion about the “Immunoscore” being a vital prognostic tool, Anitei et al. demonstrated in this study on 111 rectal cancer patients that the densities of CD3+ and CD8+ lymphocytes and the associated Immunoscore were significantly correlated with differences in disease free- (DFS) and OS. In consensus to the results by Galon et al., Cox multivariate analysis here supports the advantage of the Immunoscore compared with current AJCC TNM-G staging in predicting recurrence and survival.
45. 45 Galon, J., Pagès, F., Marincola, F.M., Angell, H.K., Thurin, M., Lugli, A., Zlobec, I., Berger, A., Bifulco, C., Botti, G., et al. Cancer classification using the Immunoscore: a worldwide task force. J Transl Med, 10, 2012, 205.
46. ® colon. J Immunother Cancer, 4, 2016, 57.
47. 47•• Stack, E.C., Wang, C., Roman, K.A., Hoyt, C.C., Multiplexed immunohistochemistry, imaging, and quantitation: a review, with an assessment of Tyramide signal amplification, multispectral imaging and multiplex analysis. Methods 70 (2014), 46–58 In this article, Stack et al. summarizes different approaches towards multiplexed immunohistochemistry, imaging, and quantitation with an emphasis on Tyramide signal amplification, multispectral imaging and multiplex analysis.
48. 48•• Feng, Z., Puri, S., Moudgil, T., Wood, W., Hoyt, C.C., Wang, C., Urba, W.J., Curti, B.D., Bifulco, C.B., Fox, B.A., Multispectral imaging of formalin-fixed tissue predicts ability to generate tumor-infiltrating lymphocytes from melanoma. J Immunother Cancer, 3, 2015, 47 Using 7-color multispectral fluorescent immunohistochemistry to analyze the tumor microenvironment in melanoma patients, Feng et al. demonstrated that, while the presence of CD8+ T cells alone was insufficient, the assessment of the CD8+ to FoxP3+ in combination with the CD8+ to PD-L1+ ratio lead to high positive-predictive- and negative-predictive values towards successful tumor-reactive tumor-infiltrating lymphocytes (TIL) generation.
49. 49•• Remark, R., Merghoub, T., Grabe, N., Litjens, G., Damotte, D., Wolchok, J.D., Merad, M., Gnjatic, S., In-depth tissue profiling using multiplexed immunohistochemical consecutive staining on single slide. Sci Immunol, 1, 2016 aaf6925–aaf6925 In this research article, Remark et al. propose a multiplexed chromogen-based IHC staining assay named “multiplexed immunohistochemical consecutive staining on single slide” (MICSSS), enabling the consecutive staining of up to 10 epitopes on the same FFPE tissue slide.
50. 50 Feng, Z., Jensen, S.M., Messenheimer, D.J., Farhad, M., Neuberger, M., Bifulco, C.B., Fox, B.A., Multispectral imaging of T and B cells in murine spleen and tumor. J Immunol 196 (2016), 3943–3950.
51. 51•• Zhang, W., Hubbard, A., Jones, T., Bhaumik, S., Racolta, A., Lefever, M., Garsha, K., Cummins, N., Ventura, F., Tang, L., Automated 5-plex fluorescent immunohistochemistry with tyramide signal amplification using antibodies from the same species. J Immunother Cancer, 3, 2015, P111 By using a fully automated heat deactivation process on the BenchMark ULTRA automated slide stainer, Zhang et al. demonstrated a fully automated 5-plex fluorescent IHC assay that achieved comparable staining results to the respective single-plex chromogenic IHC assays.
52. 52 Kakavand, H., Vilain, R.E., Wilmott, J.S., Burke, H., Yearley, J.H., Thompson, J.F., Hersey, P., Long, G.V., Scolyer, R.A., Tumor PD-L1 expression, immune cell correlates and PD-1+ lymphocytes in sentinel lymph node melanoma metastases. Mod Pathol 28 (2015), 1535–1544.
53. 53 Erdag, G., Schaefer, J.T., Smolkin, M.E., Deacon, D.H., Shea, S.M., Dengel, L.T., Patterson, J.W., Slingluff, C.L., Immunotype and immunohistologic characteristics of tumor-infiltrating immune cells are associated with clinical outcome in metastatic melanoma. Cancer Res 72 (2012), 1070–1080.
54. 54 Piras, F., Colombari, R., Minerba, L., Murtas, D., Floris, C., Maxia, C., Corbu, A., Perra, M.T., Sirigu, P., The predictive value of CD8, CD4, CD68, and human leukocyte antigen-D-related cells in the prognosis of cutaneous malignant melanoma with vertical growth phase. Cancer 104 (2005), 1246–1254.
55. 55 Al-Batran, S.-E., Rafiyan, M.-R., Atmaca, A., Neumann, A., Karbach, J., Bender, A., Weidmann, E., Altmannsberger, H.-M., Knuth, A., Jäger, E., Intratumoral T-cell infiltrates and MHC class I expression in patients with stage IV melanoma. Cancer Res 65 (2005), 3937–3941.
56. 56 Rozek, L.S., Schmit, S.L., Greenson, J.K., Tomsho, L.P., Rennert, H.S., Rennert, G., Gruber, S.B., Tumor-infiltrating lymphocytes, Crohn's-like lymphoid reaction, and survival from colorectal cancer. J Natl Cancer Inst, 108, 2016 djw027.
57. 57 Nosho, K., Baba, Y., Tanaka, N., Shima, K., Hayashi, M., Meyerhardt, J.A., Giovannucci, E., Dranoff, G., Fuchs, C.S., Ogino, S., Tumour-infiltrating T-cell subsets, molecular changes in colorectal cancer, and prognosis: cohort study and literature review. J Pathol 222 (2010), 350–366.
58. 58 Galon, J., Costes, A., Sanchez-Cabo, F., Kirilovsky, A., Mlecnik, B., Lagorce-Pagès, C., Tosolini, M., Camus, M., Berger, A., Wind, P., et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313 (2006), 1960–1964.
59. 59 Pagès, F., Berger, A., Camus, M., Sanchez-Cabo, F., Costes, A., Molidor, R., Mlecnik, B., Kirilovsky, A., Nilsson, M., Damotte, D., et al. Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med 353 (2005), 2654–2666.
60. 60 Nguyen, N., Bellile, E., Thomas, D., McHugh, J., Rozek, L., Virani, S., Peterson, L., Carey, T.E., Walline, H., Moyer, J., et al. Tumor infiltrating lymphocytes and survival in patients with head and neck squamous cell carcinoma. Head Neck 38 (2016), 1074–1084.
61. 61•• Ferris, R.L., Blumenschein, G.J., Fayette, J., Guigay, J., Colevas, A.D., Licitra, L., Harrington, K., Kasper, S., Vokes, E.E., Vokes, E.E., et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med 375 (2016), 1856–1867 In this clinical study, Ferris et al. depict that among patients with platinum-refractory, recurrent squamous-cell carcinoma of the head and neck, treatment with PD-1 monoclonal antibody nivolumab resulted in longer overall survival than treatment with standard, single-agent therapy.
62. 62 Balermpas, P., Michel, Y., Wagenblast, J., Seitz, O., Weiss, C., Rödel, F., Rödel, C., Fokas, E., Tumour-infiltrating lymphocytes predict response to definitive chemoradiotherapy in head and neck cancer. Br J Cancer 110 (2014), 501–509.
63. 63 Watanabe, Y., Katou, F., Ohtani, H., Nakayama, T., Yoshie, O., Hashimoto, K., Tumor-infiltrating lymphocytes, particularly the balance between CD8+ T cells and CCR4+ regulatory T cells, affect the survival of patients with oral squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endodontol 109 (2010), 744–752.
64. 64 Distel, L.V., Fickenscher, R., Dietel, K., Hung, A., Iro, H., Zenk, J., Nkenke, E., Büttner, M., Niedobitek, G., Grabenbauer, G.G., Tumour infiltrating lymphocytes in squamous cell carcinoma of the oro- and hypopharynx: prognostic impact may depend on type of treatment and stage of disease. Oral Oncol 45 (2009), e167–e174.
65. 65 Badoual, C., Hans, S., Rodriguez, J., Peyrard, S., Klein, C., Agueznay, N.E.H., Mosseri, V., Laccourreye, O., Bruneval, P., Fridman, W.H., et al. Prognostic value of tumor-infiltrating CD4+ T-cell subpopulations in head and neck cancers. Clin Cancer Res 12 (2006), 465–472.
66. 66 Shiao, S.L., Ruffell, B., DeNardo, D.G., Faddegon, B.A., Park, C.C., Coussens, L.M., TH2-polarized CD4+ T cells and macrophages limit efficacy of radiotherapy. Cancer Immunol Res 3 (2015), 518–525.
67. 67 Ali, H.R., Provenzano, E., Dawson, S.-J., Blows, F.M., Liu, B., Shah, M., Earl, H.M., Poole, C.J., Hiller, L., Dunn, J.A., et al. Association between CD8+ T-cell infiltration and breast cancer survival in 12 439 patients. Ann Oncol 25 (2014), 1536–1543.
68. 68 Miyashita, M., Sasano, H., Tamaki, K., Chan, M., Hirakawa, H., Suzuki, A., Tada, H., Watanabe, G., Nemoto, N., Nakagawa, S., et al. Tumor-infiltrating CD8+ and FOXP3+ lymphocytes in triple-negative breast cancer: its correlation with pathological complete response to neoadjuvant chemotherapy. Breast Cancer Res Treat 148 (2014), 525–534.
69. 69 Liu, S., Lachapelle, J., Leung, S., Gao, D., Foulkes, W.D., Nielsen, T.O., CD8+ lymphocyte infiltration is an independent favorable prognostic indicator in basal-like breast cancer. Breast Cancer Res, 14, 2012, R48.
70. 70• DeNardo, D.G., Brennan, D.J., Rexhepaj, E., Ruffell, B., Shiao, S.L., Madden, S.F., Gallagher, W.M., Wadhwani, N., Keil, S.D., Junaid, S.A., et al. Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov 1 (2011), 54–67 In this article DeNardo et al. highlighted the importance of macrophages for tumor progression in demonstrating that blockade of macrophage-recruitment by inhibition of CSF-1 in combination with Paclitaxel improves survival of mammary tumor bearing mice via slowing primary tumor development and reducing pulmonary metastasis.
71. 71 Mahmoud, S.M.A., Paish, E.C., Powe, D.G., Macmillan, R.D., Grainge, M.J., Lee, A.H.S., Ellis, I.O., Green, A.R., Tumor-infiltrating CD8+ lymphocytes predict clinical outcome in breast cancer. J Clin Oncol 29 (2011), 1949–1955.
72. 72 Zhang, Y., Ma, C., Wang, M., Hou, H., Cui, L., Jiang, C., Sun, J., Qu, X., Prognostic significance of immune cells in the tumor microenvironment and peripheral blood of gallbladder carcinoma patients. Clin Transl Oncol, 2016, 10.1007/s12094-016-1553-6 (epub ahead of print).
73. 73 Oguro, S., Ino, Y., Shimada, K., Hatanaka, Y., Matsuno, Y., Esaki, M., Nara, S., Kishi, Y., Kosuge, T., Hiraoka, N., Clinical significance of tumor-infiltrating immune cells focusing on BTLA and Cbl-b in patients with gallbladder cancer. Cancer Sci 106 (2015), 1750–1760.
74. 74 Zhang, Y., Huang, Y., Qin, M., Tumour-infiltrating FoxP3+ and IL-17-producing T cells affect the progression and prognosis of gallbladder carcinoma after surgery. Scand J Immunol 78 (2013), 516–522.
75. 75 Nakakubo, Y., Miyamoto, M., Cho, Y., Hida, Y., Oshikiri, T., Suzuoki, M., Hiraoka, K., Itoh, T., Kondo, S., Katoh, H., Clinical significance of immune cell infiltration within gallbladder cancer. Br J Cancer 89 (2003), 1736–1742.
76. 76 Al-Attar, A., Shehata, M., Durrant, L., Moseley, P., Deen, S., Chan, S., T cell density and location can influence the prognosis of ovarian cancer. Pathol Oncol Res 16 (2010), 361–370.
77. 77 Leffers, N., Gooden, M.J.M., de Jong, R.A., Hoogeboom, B.-N., ten Hoor, K.A., Hollema, H., Boezen, H.M., van der Zee, A.G.J., Daemen, T., Nijman, H.W., Prognostic significance of tumor-infiltrating T-lymphocytes in primary and metastatic lesions of advanced stage ovarian cancer. Cancer Immunol Immunother, 58, 2009, 449.
78. 78 Adams, S.F., Levine, D.A., Cadungog, M.G., Hammond, R., Facciabene, A., Olvera, N., Rubin, S.C., Boyd, J., Gimotty, P.A., Coukos, G., Intraepithelial T cells and tumor proliferation. Cancer 115 (2009), 2891–2902.
79. 79 Callahan, M.J., Nagymanyoki, Z., Bonome, T., Johnson, M.E., Litkouhi, B., Sullivan, E.H., Hirsch, M.S., Matulonis, U.A., Liu, J., Birrer, M.J., et al. Increased HLA-DMB expression in the tumor epithelium is associated with increased CTL infiltration and improved prognosis in advanced-stage serous ovarian cancer. Clin Cancer Res 14 (2008), 7667–7673.
80. 80 Clarke, B., Tinker, A.V., Lee, C.-H., Subramanian, S., van de Rijn, M., Turbin, D., Kalloger, S., Han, G., Ceballos, K., Cadungog, M.G., et al. Intraepithelial T cells and prognosis in ovarian carcinoma: novel associations with stage, tumor type, and BRCA1 loss. Mod. Pathol 22 (2008), 393–402.
81. 81 Han, L.Y., Fletcher, M.S., Urbauer, D.L., Mueller, P., Landen, C.N., Kamat, A.A., Lin, Y.G., Merritt, W.M., Spannuth, W.A., Deavers, M.T., et al. HLA class I antigen processing machinery component expression and intratumoral T-cell infiltrate as independent prognostic markers in ovarian carcinoma. Clin Cancer Res 14 (2008), 3372–3379.
82. 82 Sato, E., Olson, S.H., Ahn, J., Bundy, B., Nishikawa, H., Qian, F., Jungbluth, A.A., Frosina, D., Gnjatic, S., Ambrosone, C., et al. Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci U S A 102 (2005), 18538–18543.
83. 83 Brambilla, E., Le Teuff, G., Marguet, S., Lantuejoul, S., Dunant, A., Graziano, S., Pirker, R., Douillard, J.-Y., Le Chevalier, T., Filipits, M., et al. Prognostic effect of tumor lymphocytic infiltration in resectable non–small-cell lung cancer. J Clin Oncol 34 (2016), 1223–1230.
84. 84 Suzuki, K., Kadota, K., Sima, C.S., Nitadori, J., Rusch, V.W., Travis, W.D., Sadelain, M., Adusumilli, P.S., Clinical impact of immune microenvironment in stage I lung adenocarcinoma: tumor interleukin-12 receptor β2 (IL-12Rβ2), IL-7R, and stromal FoxP3/CD3 ratio are independent predictors of recurrence. J Clin Oncol 31 (2013), 490–498.
85. 85 Donnem, T., Al-Shibli, K., Andersen, S., Al-Saad, S., Busund, L.-T., Bremnes, R.M., Combination of low vascular endothelial growth factor A (VEGF-A)/VEGF receptor 2 expression and high lymphocyte infiltration is a strong and independent favorable prognostic factor in patients with nonsmall cell lung cancer. Cancer 116 (2010), 4318–4325.
86. 86 Ruffini, E., Asioli, S., Filosso, P.L., Lyberis, P., Bruna, M.C., Macrì, L., Daniele, L., Oliaro, A., Clinical significance of tumor-infiltrating lymphocytes in lung neoplasms. Ann Thorac Surg 87 (2009), 365–372.
87. 87 Kawai, O., Ishii, G., Kubota, K., Murata, Y., Naito, Y., Mizuno, T., Aokage, K., Saijo, N., Nishiwaki, Y., Gemma, A., et al. Predominant infiltration of macrophages and CD8+ T Cells in cancer nests is a significant predictor of survival in stage IV nonsmall cell lung cancer. Cancer 113 (2008), 1387–1395.
88. 88 Wakabayashi, O., Yamazaki, K., Oizumi, S., Hommura, F., Kinoshita, I., Ogura, S., Dosaka-Akita, H., Nishimura, M., CD4+ T cells in cancer stroma, not CD8+ T cells in cancer cell nests, are associated with favorable prognosis in human non-small cell lung cancers. Cancer Sci 94 (2003), 1003–1009.
89. 89 Wang, B., Wu, S., Zeng, H., Liu, Z., Dong, W., He, W., Chen, X., Dong, X., Zheng, L., Lin, T., et al. CD103+ tumor infiltrating lymphocytes predict a favorable prognosis in urothelial cell carcinoma of the bladder. J Urol 194 (2015), 556–562.
90. 90 Sharma, P., Shen, Y., Wen, S., Yamada, S., Jungbluth, A.A., Gnjatic, S., Bajorin, D.F., Reuter, V.E., Herr, H., Old, L.J., et al. CD8 tumor-infiltrating lymphocytes are predictive of survival in muscle-invasive urothelial carcinoma. Proc Natl Acad Sci 104 (2007), 3967–3972.
91. 91 Yamagami, W., Susumu, N., Tanaka, H., Hirasawa, A., Banno, K., Suzuki, N., Tsuda, H., Tsukazaki, K., Aoki, D., Immunofluorescence-detected infiltration of CD4+ FOXP3+ Regulatory T cells is relevant to the prognosis of patients with endometrial cancer. Int J Gynecol Cancer 21 (2011), 1628–1634.
92. 92 de Jong, R.A., Leffers, N., Boezen, H.M., ten Hoor, K.A., van der Zee, A.G.J., Hollema, H., Nijman, H.W., Presence of tumor-infiltrating lymphocytes is an independent prognostic factor in type I and II endometrial cancer. Gynecol Oncol 114 (2009), 105–110.
93. 93 Kondratiev, S., Sabo, E., Yakirevich, E., Lavie, O., Resnick, M.B., Intratumoral CD8+ T lymphocytes as a prognostic factor of survival in endometrial carcinoma. Clin Cancer Res 10 (2004), 4450–4456.
94. 94 Sugimura, K., Miyata, H., Tanaka, K., Takahashi, T., Kurokawa, Y., Yamasaki, M., Nakajima, K., Takiguchi, S., Mori, M., Doki, Y., High infiltration of tumor-associated macrophages is associated with a poor response to chemotherapy and poor prognosis of patients undergoing neoadjuvant chemotherapy for esophageal cancer. J Surg Oncol 111 (2015), 752–759.
95. 95 Lv, L., Pan, K., Li, X., She, K., Zhao, J., Wang, W., Chen, J., Chen, Y., Yun, J., Xia, J., The accumulation and prognosis value of tumor infiltrating IL-17 producing cells in esophageal squamous cell carcinoma. PLoS One, 6, 2011, e18219.
96. 96 Yoshioka, T., Miyamoto, M., Cho, Y., Ishikawa, K., Tsuchikawa, T., Kadoya, M., Li, L., Mishra, R., Ichinokawa, K., Shoji, Y., et al. Infiltrating regulatory T cell numbers is not a factor to predict patient's survival in oesophageal squamous cell carcinoma. Br J Cancer 98 (2008), 1258–1263.
97. 97 Cho, Y., Miyamoto, M., Kato, K., Fukunaga, A., Shichinohe, T., Kawarada, Y., Hida, Y., Oshikiri, T., Kurokawa, T., Suzuoki, M., et al. CD4+ and CD8+ T cells cooperate to improve prognosis of patients with esophageal squamous cell carcinoma. Cancer Res 63 (2003), 1555–1559.
98. 98 Gabrielson, A., Wu, Y., Wang, H., Jiang, J., Kallakury, B., Gatalica, Z., Reddy, S., Kleiner, D., Fishbein, T., Johnson, L., et al. Intratumoral CD3 and CD8 T-cell densities associated with relapse-free survival in HCC. Cancer Immunol Res 4 (2016), 419–430.
99. 99 Wang, F., Jing, X., Li, G., Wang, T., Yang, B., Zhu, Z., Gao, Y., Zhang, Q., Yang, Y., Wang, Y., et al. Foxp3+ regulatory T cells are associated with the natural history of chronic hepatitis B and poor prognosis of hepatocellular carcinoma. Liver Int 32 (2012), 644–655.
100. 100 Gao, Q., Zhou, J., Wang, X.-Y., Qiu, S.-J., Song, K., Huang, X.-W., Sun, J., Shi, Y.-H., Li, B.-Z., Xiao, Y.-S., et al. Infiltrating memory/senescent T cell ratio predicts extrahepatic metastasis of hepatocellular carcinoma. Ann Surg Oncol 19 (2012), 455–466.
101. 101 Li, Y.-W., Qiu, S.-J., Fan, J., Zhou, J., Gao, Q., Xiao, Y.-S., Xu, Y.-F., Intratumoral neutrophils: a poor prognostic factor for hepatocellular carcinoma following resection. J Hepatol 54 (2011), 497–505.
102. 102 Gao, Q., Qiu, S.-J., Fan, J., Zhou, J., Wang, X.-Y., Xiao, Y.-S., Xu, Y., Li, Y.-W., Tang, Z.-Y., Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol 25 (2007), 2586–2593.
103. 103 Cornelissen, R., Lievense, L.A., Maat, A.P., Hendriks, R.W., Hoogsteden, H.C., Bogers, A.J., Hegmans, J.P., Aerts, J.G., Ratio of intratumoral macrophage phenotypes is a prognostic factor in epithelioid malignant pleural mesothelioma. PLoS One, 9, 2014, e106742.
104. 104 Yamada, N., Oizumi, S., Kikuchi, E., Shinagawa, N., Konishi-Sakakibara, J., Ishimine, A., Aoe, K., Gemba, K., Kishimoto, T., Torigoe, T., et al. CD8+ tumor-infiltrating lymphocytes predict favorable prognosis in malignant pleural mesothelioma after resection. Cancer Immunol Immunother 59 (2010), 1543–1549.
105. 105 Anraku, M., Cunningham, K.S., Yun, Z., Tsao, M.-S., Zhang, L., Keshavjee, S., Johnston, M.R., de Perrot, M., Impact of tumor-infiltrating T cells on survival in patients with malignant pleural mesothelioma. J Thorac Cardiovasc Surg 135 (2008), 823–829.
106. 106 Hu, W.-H., Miyai, K., Cajas-Monson, L.C., Luo, L., Liu, L., Ramamoorthy, S.L., Tumor-infiltrating CD8+ T lymphocytes associated with clinical outcome in anal squamous cell carcinoma. J Surg Oncol 112 (2015), 421–426.
107. 107 Grabenbauer, G.G., Lahmer, G., Distel, L., Niedobitek, G., Tumor-infiltrating cytotoxic T cells but not regulatory T cells predict outcome in anal squamous cell carcinoma. Clin Cancer Res 12 (2006), 3355–3360.
108. 108 Wang, W.-Q., Liu, L., Xu, H.-X., Wu, C.-T., Xiang, J.-F., Xu, J., Liu, C., Long, J., Ni, Q.-X., Yu, X.-J., Infiltrating immune cells and gene mutations in pancreatic ductal adenocarcinoma. Br J Surg 103 (2016), 1189–1199.
109. 109 Wartenberg, M., Zlobec, I., Perren, A., Koelzer, V.H., Gloor, B., Lugli, A., Karamitopoulou, E., Wartenberg, M., Zlobec, I., Perren, A., et al. Accumulation of FOXP3+T-cells in the tumor microenvironment is associated with an epithelial-mesenchymal-transition-type tumor budding phenotype and is an independent prognostic factor in surgically resected pancreatic ductal adenocarcinoma. Oncotarget 6 (2015), 4190–4201.
110. 110 Ino, Y., Yamazaki-Itoh, R., Shimada, K., Iwasaki, M., Kosuge, T., Kanai, Y., Hiraoka, N., Immune cell infiltration as an indicator of the immune microenvironment of pancreatic cancer. Br J Cancer 108 (2013), 914–923.
111. 111 Hiraoka, N., Onozato, K., Kosuge, T., Hirohashi, S., Prevalence of FOXP3+ regulatory T cells increases during the progression of pancreatic ductal adenocarcinoma and its premalignant lesions. Clin Cancer Res 12 (2006), 5423–5434.
112. 112 Heeren, A.M., de, Boer E., Bleeker, M.C.G., Musters, R.J.P., Buist, M.R., Kenter, G.G., de, Gruijl T.D, Jordanova, E.S., Heeren, A.M., de Boer, E., et al. Nodal metastasis in cervical cancer occurs in clearly delineated fields of immune suppression in the pelvic lymph catchment area. Oncotarget 6 (2015), 32484–32493.
113. 113 Carus, A., Ladekarl, M., Hager, H., Nedergaard, B.S., Donskov, F., Tumour-associated CD66b+ neutrophil count is an independent prognostic factor for recurrence in localised cervical cancer. Br J Cancer 108 (2013), 2116–2122.
114. 114 Jordanova, E.S., Gorter, A., Ayachi, O., Prins, F., Durrant, L.G., Kenter, G.G., van der, Burg S.H, Fleuren, G.J., Human leukocyte antigen class I, MHC class I chain-related molecule A, and CD8+/regulatory T-cell ratio: which variable determines survival of cervical cancer patients?. Clin Cancer Res 14 (2008), 2028–2035.
115. 115 Sayour, E.J., McLendon, P., McLendon, R., Leon, G.D., Reynolds, R., Kresak, J., Sampson, J.H., Mitchell, D.A., Increased proportion of FoxP3+ regulatory T cells in tumor infiltrating lymphocytes is associated with tumor recurrence and reduced survival in patients with glioblastoma. Cancer Immunol Immunother 64 (2015), 419–427.
116. 116 Yue, Q., Zhang, X., Ye, H., Wang, Y., Du, Z., Yao, Y., Mao, Y., The prognostic value of Foxp3+ tumor-infiltrating lymphocytes in patients with glioblastoma. J Neurooncol 116 (2014), 251–259.
117. 117 Thomas, A.A., Fisher, J.L., Rahme, G.J., Hampton, T.H., Baron, U., Olek, S., Schwachula, T., Rhodes, C.H., Gui, J., Tafe, L.J., et al. Regulatory T cells are not a strong predictor of survival for patients with glioblastoma. Neuro-Oncol 17 (2015), 801–809.
118. 118 Keane, C., Vari, F., Hertzberg, M., Cao, K.-A.L., Green, M.R., Han, E., Seymour, J.F., Hicks, R.J., Gill, D., Crooks, P., et al. Ratios of T-cell immune effectors and checkpoint molecules as prognostic biomarkers in diffuse large B-cell lymphoma: a population-based study. Lancet Haematol 2 (2015), e445–e455.
119. 119 Coutinho, R., Clear, A.J., Mazzola, E., Owen, A., Greaves, P., Wilson, A., Matthews, J., Lee, A., Alvarez, R., da Silva, M.G., et al. Revisiting the immune microenvironment of diffuse large B-cell lymphoma using a tissue microarray and immunohistochemistry: robust semi-automated analysis reveals CD3 and FoxP3 as potential predictors of response to R-CHOP. Haematologica 100 (2015), 363–369.
120. 120 Lee, N.-R., Song, E.-K., Jang, K.Y., Choi, H.N., Moon, W.S., Kwon, K., Lee, J.-H., Yim, C.-Y., Kwak, J.-Y., Prognostic impact of tumor infiltrating FOXP3 positive regulatory T cells in diffuse large B-cell lymphoma at diagnosis. Leuk Lymphoma 49 (2008), 247–256.
121. 121 Hasselblom, S., Sigurdadottir, M., Hansson, U., Nilsson-Ehle, H., Ridell, B., Andersson, P.-O., The number of tumour-infiltrating TIA-1+ cytotoxic T cells but not FOXP3+ regulatory T cells predicts outcome in diffuse large B-cell lymphoma. Br J Haematol 137 (2007), 364–373.
122. 122 Farinha, P., Al-Tourah, A., Gill, K., Klasa, R., Connors, J.M., Gascoyne, R.D., The architectural pattern of FOXP3-positive T cells in follicular lymphoma is an independent predictor of survival and histologic transformation. Blood 115 (2010), 289–295.
123. 123 Carreras, J., Lopez-Guillermo, A., Roncador, G., Villamor, N., Colomo, L., Martinez, A., Hamoudi, R., Howat, W.J., Montserrat, E., Campo, E., High numbers of tumor-infiltrating programmed cell death 1–positive regulatory lymphocytes are associated with improved overall survival in follicular lymphoma. J Clin Oncol 27 (2009), 1470–1476.
124. 124 de, Jong D, Koster, A., Hagenbeek, A., Raemaekers, J., Veldhuizen, D., Heisterkamp, S., de Boer, J.P., van Glabbeke, M., Impact of the tumor microenvironment on prognosis in follicular lymphoma is dependent on specific treatment protocols. Haematologica 94 (2009), 70–77.
125. 125 Assis, M.C.G., Campos, A.H.F.M., Oliveira, J.S.R., Soares, F.A., Silva, J.M.K., Silva, P.B., Penna, A.D., Souza, E.M., Baiocchi, O.C.G., Increased expression of CD4 + CD25 + FOXP3+ regulatory T cells correlates with Epstein–Barr virus and has no impact on survival in patients with classical Hodgkin lymphoma in Brazil. Med Oncol 29 (2012), 3614–3619.
126. 126 Schreck, S., Friebel, D., Buettner, M., Distel, L., Grabenbauer, G., Young, L.S., Niedobitek, G., Prognostic impact of tumour-infiltrating Th2 and regulatory T cells in classical Hodgkin lymphoma. Hematol Oncol 27 (2009), 31–39.
127. 127 Álvaro-Naranjo, T., Lejeune, M., Salvadó-Usach, M.T., Bosch-Príncep, R., Reverter-Branchat, G., Jaén-Martínez, J., Pons-Ferré, L.E., Tumor-infiltrating cells as a prognostic factor in Hodgkin's lymphoma: a quantitative tissue microarray study in a large retrospective cohort of 267 patients. Leuk Lymphoma 46 (2005), 1581–1591.
128. 128 Tzankov, A., Meier, C., Hirschmann, P., Went, P., Pileri, S.A., Dirnhofer, S., Correlation of high numbers of intratumoral FOXP3+ regulatory T cells with improved survival in germinal center-like diffuse large B-cell lymphoma, follicular lymphoma and classical Hodgkin's lymphoma. Haematologica 93 (2008), 193–200.
129. 129 Richardsen, E., Uglehus, R.D., Due, J., Busch, C., Busund, L.-T.R., The prognostic impact of M-CSF, CSF-1 receptor, CD68 and CD3 in prostatic carcinoma. Histopathology 53 (2008), 30–38.