Skip to main content
NCBI home page
Cancer Immunology, Immunotherapy : CII logoLink to Cancer Immunology, Immunotherapy : CII
. 1990 Nov;31(6):325–334. doi: 10.1007/BF01741403

Immunosuppression in murine renal cell carcinoma

I. Characterization of extent, severity and sources

Shahik K Gregorian 1, Jack R Battisto 2,✉
PMCID: PMC11038414  PMID: 2386978

Abstract

Four cell-mediated immunological responses related to tumor elimination have been examined in mice injected with a transplantable renal cell carcinoma (Renca). Lymphokine-activated killer (LAK) cells generatedin vitro from spleen cells of normal mice were capable of attacking Renca, EL-4, P815 and YAC-1 targets, but those from mice bearing Renca for 3 weeks could not. Natural killer activity, stimulatedin vivo by administering poly(I) poly(C), was less than 50% of normal in Rencabearing hosts. In addition, development of cytotoxic T lymphocytes to allogeneic targets was markedly inhibited in mice possessing the renal tumor. Finally, the delayed hypersensitivity response to a dermally applied hapten was approximately 70% less than normal in tumor-bearing mice, no matter whether the tumor existed subcutaneously or intrarenally. A kinetic study of the development of nonresponsiveness using the LAK assay showed onset of poor response at 1 week, which became maximal within 3 weeks following receipt of tumor subcutaneously. The immunological depression was seen to be attributable in part to suppressor cells present among spleen cells but not bone marrow cells of tumor-bearing hosts. The suppressor cells preventedin vitro LAK generation by normal spleen cells and, when adoptively transferred to normal mice, they inhibited natural killer stimulation and delayed hypersensitivity generation. Another source of immunological downregulation was provided by Renca cells themselves. Incorporation of Renca cells that had been X-irradiated with 30000 rad into cultures of normal and Renca-derived splenic cells suppressed replication of both almost completely. Furthermore, the presence of X-irradiated Renca cells in cultures of normal spleen cells prevented development of LAK cells. Thus, the suppression seen in Renca-bearing mice derives from multiple sources and whether each is in any way related to the other has been discussed. Identification of the phenotypes of cells responsible for the lymphoid cell-mediated suppression and examination of its elimination are communicated in the companion paper.

Keywords: Natural Killer, Renal Cell Carcinoma, Spleen Cell, Suppressor Cell, Natural Killer Activity

Footnotes

Offered in partial fulfillment of the requirements for the Ph. D. degree at Cleveland State University by SKG.

References

  • 1.Asherson GL, Zembala M. The role of T acceptor cell in suppressor systems: antigen specific T suppressor factor acts via a T acceptor cell; this releases a non-specific inhibitor of the transfer of contact sensitivity when exposed to antigen in the context of I-J. Ann NY Acad Sci. 1982;392:71–71. doi: 10.1111/j.1749-6632.1982.tb36099.x. [DOI] [PubMed] [Google Scholar]
  • 2.Bassil B, Dosoretz DE, Prout GR., Jr Validation of the tumor, nodes and metastasis classification of renal cell carcinoma. J Urol. 1985;134:450–450. doi: 10.1016/s0022-5347(17)47235-1. [DOI] [PubMed] [Google Scholar]
  • 3.Bear HD. Tumor-specific T-cells which inhibit thein vitro generation of cytolytic T-cells from immune and early tumor bearing host spleens. Cancer Res. 1986;46:1805–1805. [PubMed] [Google Scholar]
  • 4.Bear HD, Susskind BM, Close KA, Barrett SK. Phenotype of syngeneic tumor-specific cytotoxic T-lymphocytes and requirements for theirin vitro generation from tumor-bearing host and immune spleens. Cancer Res. 1988;48:1422–1422. [PubMed] [Google Scholar]
  • 5.Berendt MJ, North RJ. T-cell-mediated suppression of antitumor immunity. J Exp Med. 1980;151:69–69. doi: 10.1084/jem.151.1.69. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Bluestone JA, Lopez C. Suppression of the immune response in tumor-bearing mice. II. Characterization of adherent suppressor cells. J Natl Cancer Inst. 1979;63:1221–1221. [PubMed] [Google Scholar]
  • 7.Bukowski RM. Suppressor cells and their factors. Boca Raton, Fla: CRC Press; 1981. Suppressor cells in oncology; pp. 103–103. [Google Scholar]
  • 8.Chow KN, Battisto JR. Down-regulation of cytotoxic T-lymphocytes development by a minor stimulating locus-induced suppressor cascade that involved Lyt1+T-cells, Ia−macrophages, and their factors. J Immunol. 1988;140:1–1. [PubMed] [Google Scholar]
  • 9.DiGiacoma A, North RJ. T cell suppressors of antitumor immunity. J Exp Med. 1986;164:1179–1179. doi: 10.1084/jem.164.4.1179. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Dye ES, North RJ. T-cell mediated immunosuppression: an obstacle to adoptive immunotherapy of the p815 mastocytoma and its metastasis. J Exp Med. 1981;154:1033–1033. doi: 10.1084/jem.154.4.1033. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Ebihara T, Koyama S, Fukao K, Osuga T. Lymphokine-activated suppressor (LAS) cells in patients with gastric carcinoma. Cancer Immunol Immunother. 1989;28:218–218. doi: 10.1007/BF00204992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Elgert KD, Farrar WL. Suppressor cell activity in tumor-bearing mice. I. Dualistic inhibition by suppressor T-lymphocytes and macrophages. J Immunol. 1978;120:1345–1345. [PubMed] [Google Scholar]
  • 13.Eura M, Maehara T, Ikawa T, Ishikawa T. Suppressor cells in the effector phase of autologous cytotoxic reactions in cancer patients. Cancer Immunol Immunother. 1988;27:147–147. doi: 10.1007/BF00200020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Fujii T, Igaraski T, Kishimoto S. Significance of suppressor macrophages for immunosurveillance of tumor-bearing mice. J Natl Cancer Inst. 1987;78:509–509. [PubMed] [Google Scholar]
  • 15.Garner RE, Elgert KD. Changes in splenic macrophage Mac antigen expression during tumor growth: a kinetic study of accessory cell function and antigen-defined phenotypes. J Leukocyte Biol. 1986;40:709–709. doi: 10.1002/jlb.40.6.709. [DOI] [PubMed] [Google Scholar]
  • 16.Garner RE, Malick AD, Yurochko AD, Elgert KD. Shifts in macrophage surface phenotypes during tumor growth: association of Mac-2+ and Mac-3+ macrophage with immunosuppressive activity. Cell Immunol. 1987;108:255–255. doi: 10.1016/0008-8749(87)90211-5. [DOI] [PubMed] [Google Scholar]
  • 17.Gautam SC, Battisto JR. Suppression of contact sensitivity and cell-mediated lympholysis by oral administration of hapten is caused by different mechanisms. Cell Immunol. 1983;78:295–295. doi: 10.1016/0008-8749(83)90284-8. [DOI] [PubMed] [Google Scholar]
  • 18.Gautam SC, Battisto JR. Orally induced tolerance generates an efferently acting suppressor T cell and an acceptor T cell that together down-regulate contact sensitivity. J Immunol. 1985;135:2975–2975. [PubMed] [Google Scholar]
  • 19.Gautam SC, Battisto JR. Feeding trinitrochlorobenzene inhibits development of hapten T-cell function. Regional Immunol. 1989;2:33–33. [PubMed] [Google Scholar]
  • 20.Gorelik E, Wiltrout R, Okumura K, Habu S, Herberman RB. NK cells and other natural effector cells. New York: Academic Press; 1982. Excelleration of the metastatic growth in anti-asialo-GM1-treated mice; pp. 1331–1331. [Google Scholar]
  • 21.Gregorian SK, Battisto JR. Immunosuppression in renal cell carcinoma: II. Identification of responsible lymphoid cell phenotypes and examination of elimination of suppression. Cancer Immunol Immunother. 1990;31:335–341. doi: 10.1007/BF01741404. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Grimm EA. Human lymphokine activated killer cells as a potential immunotherapeutic modality. Biochim Biophys Acta. 1986;865:867–867. doi: 10.1016/0304-419x(86)90017-x. [DOI] [PubMed] [Google Scholar]
  • 23.Grimm EA, Mazumder A, Zhang HZ, Rosenberg SA. Lymphokine-activated killer cell phenomenon. Lysis of natural killer-resistant fresh solid tumor cells by interleukin-2 activated autologous human peripheral blood lymphocytes. J Exp Med. 1982;155:1823–1823. doi: 10.1084/jem.155.6.1823. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Guillou PJ, Sedman PC, Ramsden CW. Inhibition of lymphokine-activated killer cell generation by cultured tumor cell linesin vitro . Cancer Immunol Immunother. 1989;28:4–4. doi: 10.1007/BF00205800. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Herberman RB, Nunn ME, Holden HT, Stale S, Djeu JY. Augmentation of natural cytotoxic reactivity of mouse lymphoid cells against syngeneic and allogenic target cells. Int J Cancer. 1977;19:555–555. doi: 10.1002/ijc.2910190417. [DOI] [PubMed] [Google Scholar]
  • 26.Hrushesky WJ, Murphy GP. Investigation of a new renal tumor model. J Surg Res. 1973;15:327–327. doi: 10.1016/0022-4804(73)90096-6. [DOI] [PubMed] [Google Scholar]
  • 27.Huben RP, Connely R, Goldrosen MH, Murphy GP, Pontes EJ. Immunotherapy of a murine renal cancer. J Urol. 1983;129:1075–1075. doi: 10.1016/s0022-5347(17)52545-8. [DOI] [PubMed] [Google Scholar]
  • 28.Kamo I, Friedman H. Immunosuppression and the role of suppressive factors in cancer. Adv Cancer Res. 1977;25:271–271. doi: 10.1016/s0065-230x(08)60636-3. [DOI] [PubMed] [Google Scholar]
  • 29.Lala PK, Santer V, Libenson H, Parhar RS. Changes in the host natural killer cell population in mice during tumor development. I. Kinetics andin vitro significance. Cell Immunol. 1985;93:250–250. doi: 10.1016/0008-8749(85)90132-7. [DOI] [PubMed] [Google Scholar]
  • 30.Loutit JF, Townsand KMS, Knowles JR. Tumor surveillance in beige mice. Nature. 1980;285:66–66. [Google Scholar]
  • 31.Maccubbin DL, Mace KF, Ehrke MJ, Mihich E. Modification of host antitumor defense mechanisms in mice by progressively growing tumor. Cancer Res. 1989;49:4216–4216. [PubMed] [Google Scholar]
  • 32.Mazumder A, Rosenberg SA. Successful immunotherapy of natural killer-resistant established pulmonary melanoma metastases by the intravenous adoptive transfer of syngeneic lymphocytes activated by interleukin-2. J Exp Med. 1984;159:495–495. doi: 10.1084/jem.159.2.495. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Mills CD, North RJ, Dye ES. Mechanism of anti-tumor action ofCorynebacterium parvum. Potentiated cytolytic T cell response and its tumor-induced suppression. J Exp Med. 1981;54:621–621. doi: 10.1084/jem.154.3.621. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Murphy GP, Hrushesky WJ. A murine renal cell carcinoma. J Natl Cancer Inst. 1973;50:1013–1013. doi: 10.1093/jnci/50.4.1013. [DOI] [PubMed] [Google Scholar]
  • 35.Nepom GT, Hellstrom I, Hellstrom KE. Suppressor mechanisms in tumor immunity. Experientia. 1983;39:235–235. doi: 10.1007/BF01955286. [DOI] [PubMed] [Google Scholar]
  • 36.North RJ, Bursuker I. Generation and decay of immune response to a progressive fibrosarcoma: I. Lyt1+2− suppressor T cells down regulate the generation of Lyt1−2+ effector T cells. J Exp Med. 1984;159:1295–1295. doi: 10.1084/jem.159.5.1295. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.North RJ, Dye ES. Lyt1+2− suppressor T cells down regulate the generation of Lyt1−2+ effector T cells during progressive growth of mastocytoma. Immunology. 1985;54:47–47. [PMC free article] [PubMed] [Google Scholar]
  • 38.North RJ, Dye ES, Mills CT. The potential role of T-cells in cancer therapy. NY: Raven Press; 1982. T-cell mediated negative regulation of concomitant anti-tumor immunity as an obstacle to adoptive immunotherapy of established tumors; pp. 65–65. [Google Scholar]
  • 39.Parhar RS, Lala PK. Changes in the host natural killer cell population in mice during tumor development. 2. The mechanism of suppression of NK activity. Cell Immunol. 1985;93:265–265. doi: 10.1016/0008-8749(85)90133-9. [DOI] [PubMed] [Google Scholar]
  • 40.Remacle-Bonnet MM, Pommier GJ, Kaplauski S, Rance AJ, Depiech RC. Inhibition of normal allogeneic lymphocyte mitogenesis by a soluble inhibitor extracted from human colonic carcinoma. J Immunol. 1976;117:1145–1145. [PubMed] [Google Scholar]
  • 41.Rosenberg SA. Lymphokine activated killer cells: a new approach to immunotherapy of cancer. J Natl Cancer Inst. 1985;75:595–595. [PubMed] [Google Scholar]
  • 42.Roth JA, Grimm EA, Gupta RK, Ames RS. Immuno regulatory factors derived from human tumors I. Immunologic and biochemical characterization of factors that suppress lymphocyte proliferation and cytotoxic responsesin vitro . J Immunol. 1982;128:1922–1922. [PubMed] [Google Scholar]
  • 43.Salup RR, Wiltrout RH. Adjuvant immunotherapy of established murine renal cancer by interleukin-2 stimulated cytotoxic lymphocytes. Cancer Res. 1985;46:335–335. [PubMed] [Google Scholar]
  • 44.Salup RR, Herberman RB, Wiltrout RH. Role of natural killer activity in development of spontaneous metastases in murine renal cancer. J Urol. 1985;134:1236–1236. doi: 10.1016/s0022-5347(17)47702-0. [DOI] [PubMed] [Google Scholar]
  • 45.Salup RR, Back TC, Wiltrout RH. Successful treatment of advanced murine renal cell cancer by bicompartmental adoptive chemoimmunotherapy. J Immunol. 1987;138:641–641. [PubMed] [Google Scholar]
  • 46.Taramelli D, Fossati G, Balbsari A, Marolda R, Parmiani G. The inhibition of lymphocyte stimulation by autologus human metastatic melanoma cells correlated with the expression of HLA-DT antigens on the tumor cells. Int J Cancer. 1984;34:797–797. doi: 10.1002/ijc.2910340610. [DOI] [PubMed] [Google Scholar]
  • 47.Ting CC, Hargrove ME. Tumor cell-triggered macrophagemediated suppression of the T-cell cytotoxic response to tumor-associated antigens. II. Mechanisms for induction of suppression. J Natl Cancer Inst. 1982;69:873–873. [PubMed] [Google Scholar]
  • 48.Ting CC, Rodrigues D. Switching on the macrophage-mediated suppressor mechanism by tumor cells to evade host immune surveillance. Proc Natl Acad Sci USA. 1980;77:4265–4265. doi: 10.1073/pnas.77.7.4265. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Ting CC, Rodrigues D. Tumor cell-triggered macrophage-mediated suppression of the T-cell cytotoxic response to tumor-associated antigens. I. Characterization of the cell components for induction of suppression. J Natl Cancer Inst. 1982;69:867–867. [PubMed] [Google Scholar]
  • 50.Ting CC, Wunderlich JR, Hargrove ME, Winkler D. In vitro andin vivo antitumor activity of lymphokine-induced cytotoxic cells. Int J Cancer. 1985;36:117–117. doi: 10.1002/ijc.2910360118. [DOI] [PubMed] [Google Scholar]
  • 51.Ting CC, Hargrove ME, Stephany D. Generation of activated killer cells in tumor-bearing hosts. Int J Cancer. 1987;34:797–797. doi: 10.1002/ijc.2910390218. [DOI] [PubMed] [Google Scholar]
  • 52.Whitehead JS, Kim YS. An inhibitor of lymphocyte proliferation produced by a human colonic adenocarcinoma cell line in culture. Cancer Res. 1980;40:29–29. [PubMed] [Google Scholar]
  • 53.Wiltrout RH, Boyd MR, Back TC, Salup RR, Arthur JA, Hornung RL. Flavone-8-acetic acid augments systemic natural killer cell activity and synergizes with IL-2 for treatment of murine renal cancer. J Immunol. 1988;140:3261–3261. [PubMed] [Google Scholar]
  • 54.Yurochko AD, Pyle RH, Elgert KD. Changes in macrophage populations: Phenotypic differences between the normal and tumorbearing host macrophages. Immunobiology. 1989;178:416–416. doi: 10.1016/s0171-2985(89)80063-4. [DOI] [PubMed] [Google Scholar]
  • 55.Yurochko AD, Nagarkatti PS, Nagarkatti M, Elgert KD. Tumor-induced alteration in macrophage accessory cell activity on autoreactive T cells. Cancer Immunol Immunother. 1989;30:170–170. doi: 10.1007/BF01669426. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Cancer Immunology, Immunotherapy : CII are provided here courtesy of Springer

RESOURCES