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Cancer Immunology, Immunotherapy : CII logoLink to Cancer Immunology, Immunotherapy : CII
. 1994 Jan;39(1):15–21. doi: 10.1007/BF01517175

Tumor-infiltrating lymphocytes: their phenotype, functions and clinical use

Theresa L Whiteside 1,, Giorgio Parmiani 2
PMCID: PMC11037962  PMID: 8044822

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References

  • 1.Aebersold P, Hyatt C, Johnson S, Hines K, Korcak L, Sanders M, Lotze M, Topalian S, Yang J, Rosenberg SA. Lysis of autologous melanoma cells by tumor-infiltrating lymphocytes: association with clinical response. J Natl Cancer Inst. 1991;83:932. doi: 10.1093/jnci/83.13.932. [DOI] [PubMed] [Google Scholar]
  • 2.Albertini MR, Nicklas JA, Chasternay BF, Hunter TC, Albertini RJ, Clark SS, Hank JA, Sondel PM. Analysis of the T cell receptor beta and gamma genes from peripheral blood, regional lympho nodes and tumor-infiltrating lymphocyte clones from melanoma patients. Cancer Immunol Immunother. 1991;32:325. doi: 10.1007/BF01789051. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Alexander J, Connelly R, Edinger M, Tubbs R, Boyett J, Pontes E, Murthy S, Bukowski R, Finke J. Tumor infiltrating lymphocytes from renal cell carcinoma: state of activation, phenotypes and functional analysis. Proc Am Assoc Cancer Res. 1990;31:254. [Google Scholar]
  • 4.Alexander JP, Kudoh S, Melsop KA, Hamilton TA, Edinger MG, Tubbs RR, Sica D, Tuason L, Klein E, Bukowski RM, Finke JH. T-cells infiltrating renal cell carcinoma display a poor proliferative response even though they can produce interleukin 2 and express interleukin 2 receptors. Cancer Res. 1993;53:1380. [PubMed] [Google Scholar]
  • 5.Allen C, Hogg N. Elevation of infiltrating mononuclear phagocytes in human colorectal tumors. J Natl Cancer Inst. 1987;78:465. [PubMed] [Google Scholar]
  • 6.Anichini A, Fossati G, Parminani G. Clonal analysis of cytotoxic T-lymphocyte response to autologous human metastatic melanoma. Int J Cancer. 1985;35:683. doi: 10.1002/ijc.2910350518. [DOI] [PubMed] [Google Scholar]
  • 7.Anichini A, Mazzocchi A, Fossati G, Parmiani G. Cytotoxic T lymphocyte clones from peripheral blood and from tumor site detect intratumor heterogeneity of melanoma cells. Analysis of specificity and mechanisms of interaction. J Immunol. 1989;142:3692. [PubMed] [Google Scholar]
  • 8.Applegate KG, Balch CM, Pellis NR. In vitro migration of lymphocytes through collagen matrix: arrested locomotion in tumor-infiltrating lymphocytes. Cancer Res. 1990;50:7153. [PubMed] [Google Scholar]
  • 9.Arienti F, Belli F, Rivoltini L, Gambacorti-Passerini C, Furlan L, Mascheroni L, Prada A, Rizzi M, Marchesi E, Vaglini M, Parmiani G, Cascinelli N. Adoptive immunotherapy of advanced melanoma patients with interleukin 2 (IL2) and tumor-infiltrating lymphocytes selected in vitro with low doses of IL2. Cancer Immunol Immunother. 1993;36:315. doi: 10.1007/BF01741170. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Bilik R, Mor C, Hazaz B, Moroz C. Characterization of T-lymphocyte subpopulations infiltrating primary breast cancer. Cancer Immunol Immunother. 1989;28:143. doi: 10.1007/BF00199115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Boon T. Tumor antigens recognized by cytolytic T lymphocytes: present perspective for specific immunotherapy. Int J Cancer. 1993;54:177. doi: 10.1002/ijc.2910540202. [DOI] [PubMed] [Google Scholar]
  • 12.Broker BM, Tsygankov AY, Muller-Fleckenstein I, Guse AH, Chitaev NA, Biesinger B, Fleckenstein B, Emmrich F. Immortalization of human T cell clones by Herpes virus saimiri. J Immunol. 1993;151:1184. [PubMed] [Google Scholar]
  • 13.Cardi G, Mastrangelo MJ, Berd D. Depletion of T-cells with the CD4+CD45R+ phenotype in lymphocytes that infiltrate subcutaneous metastases of human melanoma. Cancer Res. 1989;49:6562. [PubMed] [Google Scholar]
  • 14.Colombo P, Modesti A, Parmiani G, Forni G. Local cytokine availability elicits tumor rejection and systemic immunity through granulocyte-T lymphocyte cross talk. Cancer Res. 1992;52:4853. [PubMed] [Google Scholar]
  • 15.Coulie PG, Somville M, Lehmann F, Hainaut P, Brasseur RD, Devos R, Boon T. Precursor frequency analysis of human cytolytic T lymphocytes directed against autologous melanoma cells. Int J Cancer. 1992;50:289. doi: 10.1002/ijc.2910500220. [DOI] [PubMed] [Google Scholar]
  • 16.Der simonian H, band H, Brenner MB. Increased frequency of T-cell receptor V alpha 12.1 expression on CD8+ T cells: evidence that V alpha participates in shaping the peripheral T cell repertoire. j Exp Med. 1991;174:639–648. doi: 10.1084/jem.174.3.639. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Dillman RO, Oldham RK, Barth NM, Cohen RJ, Minor DR, Birch R, Yannelli JR, Maleckar JR, Sferruzza A, Arnold J, West WH. Continuous interleukin-2 and tumor-infiltrating lymphocytes as treatment of advanced melanoma. A National Biotherapy Study Group Trial. Cancer. 1991;68:1. doi: 10.1002/1097-0142(19910701)68:1<1::aid-cncr2820680102>3.0.co;2-k. [DOI] [PubMed] [Google Scholar]
  • 18.Ferradini L, Mackensen A, Genevee C, Bosq J, Duvillard P, Avril MF, Hercend T. Analysis of T cell receptor variability in tumor-infiltrating lymphocytes from a human regressive melanoma. J Clin Invest. 1993;91:1183. doi: 10.1172/JCI116278. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Finke JH, Rayman P, Alexander J, Edinger M, Tubbs RR, Connelly R, Pontes E, Bukowski R. Characterization of the cytolytic activity of CD4+ and CD8− tumor-infiltrating lymphocytes in human renal cell carcinoma. Cancer Res. 1990;50:2363. [PubMed] [Google Scholar]
  • 20.Finke JH, Zea AH, Stanley J, Longo DL, Mizoguchi H, Tubbs RR, Wiltrout RH, O'Shea JJ, Kudoh S, Klein E, Bukowski RM, Ochoa AC. Loss of T-cell receptor zeta chain and p56lck in T-cells infiltrating human renal cell carcinoma. Cancer Res. 1993;53:5613. [PubMed] [Google Scholar]
  • 21.Ioachim HL. The stromal reaction of tumors: an expression of immune surveillance. J Natl Cancer Inst. 1976;57:465. doi: 10.1093/jnci/57.3.465. [DOI] [PubMed] [Google Scholar]
  • 22.Ioannides CG, Friedman RS. Selective usage of TCR V beta in tumor-specific CTL lines isolated from ovarian tumor-associated lymphocytes. Anticancer Res. 1991;11:1921. [PubMed] [Google Scholar]
  • 23.Ioannides CG, Whiteside TL. T cell recognition of human tumors: implications for molecular immunotherapy of cancer. Clin Immunol Immunopathol. 1993;66:91. doi: 10.1006/clin.1993.1012. [DOI] [PubMed] [Google Scholar]
  • 24.Itoh K, Platsoucas CD, Balch CM. Autologous tumorspecific cytotoxic T lymphocytes in the infiltrate of human metastatic melanomas. Activation by interleukin 2 and autologous tumor cells, and involvement of the T cell receptor. J Exp Med. 1988;168:1419. doi: 10.1084/jem.168.4.1419. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Jack AS, Boylston AW, Carrel S, Grigor I. Cutaneous T-cell lymphoma cells employ a restricted range of T-cell antigen receptor variable region genes. Am J Pathol. 1990;136:17. [PMC free article] [PubMed] [Google Scholar]
  • 26.Jaffee EM, Dranoff G, Cohen LK, Hauda KM, Clift S, Marshall FF, Mulligan RC, Pardoll DM. High efficiency gene transfer into primary human tumor explants without cell selection. Cancer Res. 1993;53:2221. [PubMed] [Google Scholar]
  • 27.Kradin RL, Kurnick JT, Lazarus DS, Preffer FI, Dubinett SM, Pinto CE, Gifford J, Davidson E, Grove B, Callahan RJ, Strauss HW. Tumor-infiltrating lymphocytes and interleukin-2 in treatment of advanced cancer. Lancet. 1989;1:577. doi: 10.1016/s0140-6736(89)91609-7. [DOI] [PubMed] [Google Scholar]
  • 28.Letessier EM, Sacchi M, Johnson JT, Herberman RB, Whiteside TL. The absence of lymphoid suppressor cells in tumor-involved lympho nodes of patients with head and neck cancer. Cell Immunol. 1990;130:446. doi: 10.1016/0008-8749(90)90286-z. [DOI] [PubMed] [Google Scholar]
  • 29.Loeffler CM, Smyth MJ, Longo DL, Kopp WC, Harvey LK, Tribble HR, Tase JE, Urba WJ, Leonard AS, Young HA, Ochoa AC. Immunoregulation in cancer-bearing hosts. Downregulation of gene expression and cytotoxic function in CD8+ T cells. J Immunol. 1992;149:949. [PubMed] [Google Scholar]
  • 30.Mackensen A, Ferradini L, Carcelain G, Triebel F, Faure F, Viel S, Hercend T. Evidence for in situ amplification of cytotoxic T-lymphocytes with antitumor activity in a human regressive melanoma. Cancer Res. 1993;53:3569. [PubMed] [Google Scholar]
  • 31.Mantovani A. Tumor-associated macrophages. Curr Opin Immunol. 1990;2:689. doi: 10.1016/0952-7915(90)90031-b. [DOI] [PubMed] [Google Scholar]
  • 32.Mazzocchi A, Belli F, Mascheroni L, Vegetti C, Parmiani G, Anichini A (1994) Frequency of cytotoxic T lymphocyte precursors interacting with the autologous tumor by the T-cell receptor: limiting dilution analysis of specific CTLp in peripheral blood and tumor-invaded lympho nodes of melanoma patients. Int J Cancer (in press) [DOI] [PubMed]
  • 33.Miescher S, Whiteside TL, Carrel S, Von Fliedner V. Functional properties of tumor-infiltrating and blood lymphocytes in patients with solid tumors: effects of tumor cells and their supernatants on proliferative responses of lymphocytes. J Immunol. 1986;136:1899. [PubMed] [Google Scholar]
  • 34.Miescher S, Whiteside TL, Moretta L, Von Fliedner V. Clonal and frequency analyses of tumor-infiltrating T lymphocytes from human solid tumors. J Immunol. 1987;138:4004. [PubMed] [Google Scholar]
  • 35.Miescher S, Stoeck M, Qiao L, Barras C, Barrelet L, Von Fliedner V. Proliferative and cytolytic potentials of purified human tumor-infiltrating T lymphocytes. Impaired response to mitogen-driven stimulation despite T-cell receptor expression. Int J Cancer. 1988;42:659. doi: 10.1002/ijc.2910420504. [DOI] [PubMed] [Google Scholar]
  • 36.Mizoguchi H, O'Shea JJ, Longo DL, Loeffler CM, McVicar DW, Ochoa AC. Alterations in signal transduction molecules in T lymphocytes from tumor-bearing mice. Science. 1992;258:1795. doi: 10.1126/science.1465616. [DOI] [PubMed] [Google Scholar]
  • 37.Morita T, Salmeron MA, Moser RP, Ross MI, Itoh K. Oligoclonal expansion of V beta 8+ cells in interleukin-2-activated T cells residing in subcutaneous metastatic melanoma. Clin Exp Metastasis. 1992;10:69. doi: 10.1007/BF00163578. [DOI] [PubMed] [Google Scholar]
  • 38.Nakagomi H, Petersson M, Magnusson I, Juhlin C, Matsuda M, Mellstedt H, Taupin J-L, Vivier E, Anderson P, Kiessling R. Decreased expression of the signal-transducing zeta chains in tumor-infiltrating T-cells and NK cells of patients with colorectal carcinoma. Cancer Res. 1993;53:5610. [PubMed] [Google Scholar]
  • 39.Nitta T, Oksenberg JR, Rao NA, Steinman L. Predominant expression of T cell receptor V alpha 7 in tumor-infiltrating lymphocytes of uveal melanoma. Science. 1990;249:672. doi: 10.1126/science.2382141. [DOI] [PubMed] [Google Scholar]
  • 40.Ogasawara M, Rosenberg SA. Enhanced expression of HLA molecules and stimulation of autologous human tumorinfiltrating lymphocytes following transduction of melanoma cells with gamma interferon genes. Cancer Res. 1993;53:3561. [PubMed] [Google Scholar]
  • 41.Parmiani G, Anichini A, Fossati G. Cellular immune response against autologous human malignant melanoma: are in vitro studies providing a framework for a more effective immunotherapy? J Natl Cancer Inst. 1990;82:361. doi: 10.1093/jnci/82.5.361. [DOI] [PubMed] [Google Scholar]
  • 42.Parmiani G, Arienti F, Rivoltini L, Belli F, Cascinelli N. Human tumor-infiltrating lymphocytes in the treatment of cancer. Forum. 1992;2:412. [Google Scholar]
  • 43.Pitzalis C, Kingsley G, Haskard D, Panayi G. The preferential accumulation of helper-inducer T lymphocytes in inflammatory lesions: evidence for regulation by selective endothelial and homotypic adhesion. Eur J Immunol. 1988;18:1397. doi: 10.1002/eji.1830180915. [DOI] [PubMed] [Google Scholar]
  • 44.Pretlow TP, Keith EF, Cryar AK, Bartolucci AA, Pitts AM, Pretlow TG, Kimball PM, Bookmaker EA. Eosinophil infiltration of human colon carcinoma as a prognostic indicator. Cancer Res. 1987;43:2997. [PubMed] [Google Scholar]
  • 45.Rabinowich H, Cohen R, Bruderman I, Steiner Z, Klajman A. Functional analysis of mononuclear cells infiltrating into tumors: lysis of autologous human tumor cells by cultured infiltrating lymphocytes. Cancer Res. 1987;47:173. [PubMed] [Google Scholar]
  • 46.Rivoltini L, Arienti F, Orazi A, Cefalo G, Gasparini M, Gambacorti-Passerini C, Fossati-Bellani F, Parmiani G. Phenotypic and functional analysis of lymphocytes infiltrating pediatric tumors, with a characterization of the tumor phenotype. Cancer Immunol Immunother. 1992;34:241. doi: 10.1007/BF01741792. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Rosenberg SA, Packard BS, Aebersold PM, Solomon D, Topalian SL, Toy ST, Simon P, Lotze MT, Yang JC, Seipp CA, Simpson C, Carter C, Bock S, Schwartzentruber D, Wei JP, White DE. Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report. N Engl J Med. 1988;319:1676. doi: 10.1056/NEJM198812223192527. [DOI] [PubMed] [Google Scholar]
  • 48.Sanders ME, Makgoba MW, Shaw S. Human naive and memory T cells reinterpretation of helper-inducer and suppressor-inducer subsets. Immunol Today. 1988;9:195. doi: 10.1016/0167-5699(88)91212-1. [DOI] [PubMed] [Google Scholar]
  • 49.Schendel DJ, Gansbacher B. Tumor-specific lysis of human renal cell carcinomas by tumor-infiltrating lymphocytes: modulation of recognition through retroviral transduction of tumor cells with interleukin 2 complementary DNA and exogenous alpha interferon treatment. Cancer Res. 1993;53:4020. [PubMed] [Google Scholar]
  • 50.Sensi ML, Castelli C, Anichini A, Grossberger D, Mazzocchi A, Mortarini R, Parmiani G. Two autologous melanoma-specific and MHC-restricted human T cell clones with identical intra-tumor reactivity do not share the same V alpha and V beta gene families. Melanoma Res. 1991;1:261. doi: 10.1097/00008390-199111000-00006. [DOI] [PubMed] [Google Scholar]
  • 51.Sensi M, Salvi S, Castelli C, Maccalli C, Mazzocchi A, Mortarini R, Nicolini G, Herlyn M, Parmiani G, Anichini A. T cell receptor (TCR) structure of autologous melanoma-reactive cytotoxic T lymphocyte (CTL) clones: tumor-infiltrating lymphocytes overexpress in vivo the TCR beta chain sequence used by an HLA-A2-restricted and melanocyte-lineage-specific CTL clones. J Exp Med. 1993;178:1231. doi: 10.1084/jem.178.4.1231. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Shimizu Y, Iwatsuki S, Herberman RB, Whiteside TL. Clonal analysis of tumor-infiltrating lymphocytes from human primary and metastatic liver tumors. Int J Cancer. 1990;46:878. doi: 10.1002/ijc.2910460521. [DOI] [PubMed] [Google Scholar]
  • 53.Shimizu Y, Iwatsuki S, Herberman RB, Whiteside TL. Effects of cytokines on in vitro growth of tumor-infiltrating lymphocytes obtained from human primary and metastatic liver tumors. Cancer Immunol Immunother. 1991;32:280. doi: 10.1007/BF01789045. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54.Shimokawara I, Imamura M, Yamanaka N, Ishii Y, Kikuchi K. Identification of lymphocyte subpopulations in human breast cancer tissue and its significance: an immunoperoxidase study with anti-human T and B cell sera. Cancer. 1982;49:1456. doi: 10.1002/1097-0142(19820401)49:7<1456::aid-cncr2820490724>3.0.co;2-#. [DOI] [PubMed] [Google Scholar]
  • 55.Stewart THM, Tsai S-CJ. The possible role of stromal cell stimulation in worsening the prognosis of a subset of patients with breast cancer. Clin Exp Metastasis. 1993;11:295. doi: 10.1007/BF00058049. [DOI] [PubMed] [Google Scholar]
  • 56.Takagi S, Chen K, Schwarz R, Iwatsuki S, Herberman RB, Whiteside TL. Functional and phenotypic analysis of tumor-infiltrating lymphocytes isolated from human primary and metastatic liver tumors and cultured in recombinant interleukin 2. Cancer. 1989;63:102. doi: 10.1002/1097-0142(19890101)63:1<102::aid-cncr2820630117>3.0.co;2-t. [DOI] [PubMed] [Google Scholar]
  • 57.Thor Straten P, Scholler J, Hon-Jansen K, Zenthen J (1994) Preferential usage of T-cell receptor alpha beta variable regions among tumor-infiltrating lymphocytes in primary human malignant melanomas. Int J Cancer (in press) [DOI] [PubMed]
  • 58.Ullman KS, Northrop JP, Verweij CL, Crabtree GR. Transmission of signals from the T lymphocyte antigen receptor to the genes responsible for cell proliferation and immune function: the missing link. Cancer Res. 1993;53:1. doi: 10.1146/annurev.iy.08.040190.002225. [DOI] [PubMed] [Google Scholar]
  • 59.Underwood JCE. Lymphoreticular infiltration in human tumors: prognostic and biological implications. A review. Br J Cancer. 1974;30:538. doi: 10.1038/bjc.1974.233. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60.Vaccarello L, Kanbour A, Kanbour-Shakir A, Whiteside TL. Tumor-infiltrating lymphocytes from ovarian tumors of low malignant potential. Int J Gynecol Pathol. 1993;12:41. doi: 10.1097/00004347-199301000-00006. [DOI] [PubMed] [Google Scholar]
  • 61.Vitolo D, Letessier EM, Johnson JT, Whiteside TL. Immunologic effector cells in head and neck cancer. J Natl Cancer Inst Mono. 1992;13:203. [PubMed] [Google Scholar]
  • 62.Vitolo D, Zerbe T, Kanbour A, Dahl C, Herberman RB, Whiteside TL. Expression of mRNA for cytokines in tumor-infiltrating mononuclear cells in ovarian adenocarcinoma and invasive breast cancer. Int J Cancer. 1992;51:573. doi: 10.1002/ijc.2910510412. [DOI] [PubMed] [Google Scholar]
  • 63.Vose BM, Moore M. Human tumor-infiltrating lymphocytes: a marker of host response. Semin Hematol. 1985;22:27. [PubMed] [Google Scholar]
  • 64.Weidmann E, Whiteside TL, Giorda T, Herberman RB, Trucco M. The T cell receptor V beta gene usage in tumor-infiltrating lymphocytes and blood of patients with hepatocellular carcinoma. Cancer Res. 1992;52:5913. [PubMed] [Google Scholar]
  • 65.Weidmann E, Elder EM, Trucco M, Lotze MT, Whiteside TL. Usage of T-cell receptor V beta chain genes in fresh and cultured tumor-infiltrating lymphocytes from human melanoma. Int J Cancer. 1993;54:383. doi: 10.1002/ijc.2910540306. [DOI] [PubMed] [Google Scholar]
  • 66.Weidmann E, Logan TF, Yasumura S, Kirkwood JM, Trucco M, Whiteside TL. Evidence for oligoclonal T-cell response in a metastasis of renal cell carcinoma responding to vaccination with autologous tumor cells and transfer of in vitro-sensitized vaccine-draining lymph node lymphocytes. Cancer Res. 1993;53:4745. [PubMed] [Google Scholar]
  • 67.Whiteside TL. Human tumor-infiltrating lymphocytes and their characterization. In: Lotzova E, Herberman RB, editors. Role of interleukin 2 activated killer cells in cancer. Boca Raton, Fla: CRC Press; 1990. p. 133. [Google Scholar]
  • 68.Whiteside TL. Tumor-infiltrating lymphocytes as antitumor effector cells. Biotherapy. 1992;5:47. doi: 10.1007/BF02194785. [DOI] [PubMed] [Google Scholar]
  • 69.Whiteside TL. Tumor infiltrating lymphocytes in human malignancies. Austin, Tex: R. G. Landes Company; 1993. [Google Scholar]
  • 70.Whiteside TL, Miescher S, Hurlimann J, Von Fliedner V. Separation, phenotyping and limiting-dilution analysis of T-lymphocytes infiltrating human solid tumors. Int J Cancer. 1986;37:803. doi: 10.1002/ijc.2910370602. [DOI] [PubMed] [Google Scholar]
  • 71.Zocchi MR, Poggi A. Lymphocyte-endothelial cell adhesion molecules at the primary tumor site in human lung and renal cell carcinomas. J Natl Cancer Inst. 1993;85:246. doi: 10.1093/jnci/85.3.246. [DOI] [PubMed] [Google Scholar]
  • 72.Zocchi MR, Ferrarini M, Rugarli C. Selective lysis of the autologous tumor by delta TCS1+gamma/delta+tumor-infiltrating lymphocytes from human lung carcinomas. Eur J Immunol. 1990;20:2685. doi: 10.1002/eji.1830201224. [DOI] [PubMed] [Google Scholar]
  • 73.Zocchi MR, Poggi A, Crosti F, Tongiani S, Rugarli C. Signalling in human tumor infiltrating lymphocytes: the CD28 molecule is functional and is physically associated with CD45RO molecule. Eur J Cancer. 1992;28A:749. doi: 10.1016/0959-8049(92)90108-e. [DOI] [PubMed] [Google Scholar]

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