Characterization of Tumor-Infiltrating Lymphocytes Derived from Human Tumors for Use as Adoptive Immunotherapy of Cancer

Schiltz, Patric M.; Beutel, Linda D.; Nayak, Shankar K.; Dillman, Robert O.

doi:10.1097/00002371-199709000-00007

Cited by 31 publications

(25 citation statements)

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“…Survival was not addressed in the current study; future investigations will look at melanomas with 10-year follow-up to determine the significance of TIA-1 ϩ TIL as a predictive factor. TIL reinfusion, as well as the use of interleukin-2 to stimulate the antitumor immune response through sensitization of CTLs, has shown promise as a potential adjuvant therapy for melanoma (12)(13)(14)(15)(16)(17). The use of TIA-1 immunohistochemistry to identify CTLs may also help to stratify patients who would benefit from interleukin-2 or TIL infusion therapy.…”

Section: Discussionmentioning

confidence: 99%

TIA-1 Positive Tumor-Infiltrating Lymphocytes in Nevi and Melanomas

2000

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Tumor-infiltrating lymphocytes (TIL) have been shown to be an independent prognostic factor in melanomas. To better characterize the host immune response, we have classified TIL by their immunoreactivity against lymphoid markers in formalin-fixed, paraffin-embedded tissue. Monoclonal antibodies to leukocyte common antigen (LCA) and TIA-1 (a granule-associated protein of cytotoxic T cells and NK cells) were used to immunostain a series of benign nevi, nontumorigenic radial growth phase, and tumorigenic vertical growth phase melanomas and metastases. Among nine nevi, few LCA ؉ TIL were found, among which rare cells were positive for TIA-1 (mean, 2.0). Five nontumorigenic radial growth phase melanomas also had few total TIL and rare TIA-1 ؉ TIL (mean, 3.4); the nontumorigenic radial growth phase component of seven tumorigenic vertical growth phase melanomas had higher numbers of TIA-1 ؉ TIL (mean, 11). Twelve cases of tumorigenic vertical growth phase melanoma showed a variable but significantly greater number of both LCA ؉ TIL and TIA-1 ؉ TIL (mean, 30.6). Nine cases of metastatic melanoma had a wide range of variation in LCA as well as in TIA-1 ؉ TIL (mean, 46). Although the mean total number of TIA-1 ؉ TIL increased from nontumorigenic radial growth phase to tumorigenic vertical growth phase to metastases, TIA-1 ؉ as a percentage of TIL declined across these categories of tumor progression (42%, 31%, and 26%, respectively). Our results show that these attributes of TIA-1 ؉ TIL, both increasing total number but decreasing percentage, appear to be a marker of tumor progression of malignant melanomas. In addition, there was significant variability in the number of TIA-1 ؉ TIL among advanced melanomas, raising the possibility that an assessment of TIA-1 ؉ TIL may prove a useful prognostic tool for the evaluation of primary melanomas.

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Section: Discussionmentioning

confidence: 99%

TIA-1 Positive Tumor-Infiltrating Lymphocytes in Nevi and Melanomas

2000

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“…42 The regulation of CD95 expression by p53 has been analyzed in several cell models. 6,18,43 Recently, a correlation was found between expression of CD95 after girradiation and wild-type p53 activity in different tumor cell lines, including breast cancer cells.…”

Section: Discussionmentioning

confidence: 99%

p53-mediated up-regulation of CD95 is not involved in genotoxic drug-induced apoptosis of human breast tumor cells

Ruiz‐Ruiz

López‐Rivas

1999

Cell Death Differ

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Induction of CD95 (Fas/APO-1) and CD95 ligand during chemotherapeutic treatment may contribute to the death by apoptosis of some tumor cells. In this study, we have analyzed the role of the CD95 system in genotoxic drug-induced death of human breast tumor cells. Incubation of the breast tumor cell lines MCF-7 and EVSA-T with doxorubicin or methotrexate caused apoptosis after 48 h of treatment. These drugs induced a marked increase in the level of CD95 mRNA and protein in wild-type p53-expressing MCF-7 cells. On the contrary, the breast cancer cell line EVSA-T that expresses high levels of an inactive form of p53, did not up-regulate CD95 upon drug treatment. Elevation of CD95 expression by DNAdamaging drugs was notably blocked in MCF-7 cells expressing the human papillomavirus type 16 E6 protein (E6 cells) which prevented p53 accumulation upon DNA damage. However, E6 cells were still killed by the drugs. Furthermore, the genotoxic drugs did not induce the expression of CD95 ligand in MCF-7 cells at doses that caused apoptosis in these breast tumor cells. Moreover, drug-induced apoptosis of breast tumor cells was not prevented in the presence of either a CD95 antagonistic antibody or a CD95 ligand blocking antibody. We also observed a strong synergism between lower doses of DNA-damaging drugs and CD95 agonistic antibody in the induction of apoptosis in MCF-7 cells. In summary, our data indicate that drug-induced apoptosis of breast tumor cells occurs by a CD95/CD95L-independent mechanism although by elevating the tumor suppressor proteins p53 and CD95, genotoxic drugs may sensitize breast tumor cells to CD95-mediated apoptosis.

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“…The transfer of cytolytic effector cells into tumorbearing hosts with the intent to eradicate disease has been the focus of basic and clinical research for over two decades [30][31][32][33][34][35][36][37][38][39][40][41][42]. While historically a great deal of emphasis has been placed upon the role of either natural killer (NK) cells or classical cytotoxic CD8+ ab-T cells (CTL) as the primary mediators of anti-tumor cytotoxicity [43][44][45][46][47][48][49][50][51][52], until now little attention has been paid to the role of cd-T cells in this capacity.…”

Section: Discussonmentioning

confidence: 99%

Innate Anti-breast Cancer Immunity of Apoptosis-resistant Human γδ-T cells

Guo

Aldrich

et al. 2005

Breast Cancer Res Treat

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We previously identified a CD2-initiated signaling pathway which inhibits activation-induced cell death in mitogen-stimulated human gammadelta-T cells permitting the large-scale expansion of these cells. Here we report the innate anti-tumor activity of expanded human gammadelta-T cells against human breast cancer cells. Apoptosis-resistant human gammadelta-T cells which were expanded in vitro from cultured human peripheral blood mononuclear cells displayed lytic activity against breast cancer cell lines MDA-MB-231, MCF-7 and T-47D, but failed to kill normal human skin fibroblasts and normal human liver cells. Monoclonal antibodies (mAb) directed against the gammadelta-T cell receptor (TCR) or mAb directed against either the Vgamma9 or the Vdelta2 TCR chains were able to block gammadelta-T cell-mediated lysis of MDA-MB-231 cells. In addition, mAb against intercellular adhesion molecules-1 (ICAM-1/CD54) or CD18 (beta subunit of ICAM-1 counter-receptor) also blocked gammadelta-T cell-mediated killing of MDA-MB-231 cells. Ex vivo expanded human gammadelta-T cells are thus able to innately recognize and kill human breast cancer cells in a gammadelta-TCR-dependent manner; ICAM-1 and CD18 also appear to be involved in the interactions between sensitive breast cancer cells and cytolytic gammadelta-T cells. As apoptosis-resistant human gammadelta-T cells can now readily be expanded to large numbers (clinical scale), these findings must be considered in the context of developing adoptive immunotherapy strategies to exploit gammadelta-T cell innate immune responses for the primary or adjuvant treatment of breast cancer.

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Characterization of Tumor-Infiltrating Lymphocytes Derived from Human Tumors for Use as Adoptive Immunotherapy of Cancer

Cited by 31 publications

References 0 publications

TIA-1 Positive Tumor-Infiltrating Lymphocytes in Nevi and Melanomas

TIA-1 Positive Tumor-Infiltrating Lymphocytes in Nevi and Melanomas

p53-mediated up-regulation of CD95 is not involved in genotoxic drug-induced apoptosis of human breast tumor cells

Innate Anti-breast Cancer Immunity of Apoptosis-resistant Human γδ-T cells

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