Tumors induced by murine sarcoma virus contain precursor cells capable of generating tumor-specific cytolytic T lymphocytes.

Chapdelaine, Joan M.; Plata, Fernando; Lilly, Frank

doi:10.1084/jem.149.6.1531

Cited by 15 publications

(3 citation statements)

References 13 publications

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“…The observation that solid tumor masses are often infiltrated by T cells (10)(11)(12) suggested the possibility that such tumor-infiltrating lymphocytes (TIL) 1 might be enriched for tumor-reactive T cells that could be expanded in vitro using recombinant cytokines such as IL-2 (13)(14)(15)(16)(17)(18). However, even short-term culture of tumor-reactive T cells in growthpromoting concentrations of IL-2 enhances the generation ofT cells that are dependent upon exogenous IL-2 for growth and survival in vitro and optimal function in vivo.…”

Section: Discussionmentioning

confidence: 99%

Interleukin 7 promotes long-term in vitro growth of antitumor cytotoxic T lymphocytes with immunotherapeutic efficacy in vivo.

Lynch¹,

Miller²

1994

The Journal of Experimental Medicine

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SummaryA major obstacle to the effective use of adoptive immunotherapeutic treatment of cancer is the difficulty of obtaining tumor-reactive lymphocytes in either sufficient numbers or with appropriate in vivo function to make such an approach feasible. Previous studies have shown that antitumor cytotoxic T lymphocytes (CTL) with in vivo efficacy can be generated in vitro from lymphoid cells obtained from lymph nodes that drain the anatomical site of a tumor. Results presented here demonstrate that inclusion of interleukin 7 (IL-7) into the medium in which such CTL are cultured can support their growth in vitro for prolonged periods of time in the absence of repeated stimulation with either tumor stimulator cells or tumor antigen. More importantly, antitumor CTL propagated in medium containing IL-7 have retained both their antigenic specificity and their ability to reject tumors in vivo subsequent to intravenous injection. Parallel cultures of antitumor CTL similarly cultured in medium containing only IL-2 could only be maintained for 5-6 wk, after which the number and proportion of viable cells that were recoverable from such cultures progressively decreased. Phenotypic analysis of CTL maintained after extended culture (i.e., 22 mo) in medium containing IL-7 demonstrated them to be CD3+4-8 § T cells. These cells were also found to express lymphocyte function associated 1, intercellular adhesion molecule 1, and Mel-14 cell interaction molecules. The data also demonstrate that these CTL do not require the presence of antigen-presenting cell populations to mount a proliferative response to tumor stimulator cells. Cells in these cultures were also demonstrated to produce IL-2 after stimulation with irradiated tumor cells, thereby indicating that these CTL have become independent of the requirement for CD4 § helper cells to survive and function either in vitro or in vivo. Collectively, the findings that IL-7 can beneficially augment the generation, and propagate the long-term growth, of antitumor CTL from lymph nodes draining a tumor site may have profound implications for promoting the immunotherapeutic treatment of cancer in humans.

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Section: Discussionmentioning

confidence: 99%

Interleukin 7 promotes long-term in vitro growth of antitumor cytotoxic T lymphocytes with immunotherapeutic efficacy in vivo.

Lynch¹,

Miller²

1994

The Journal of Experimental Medicine

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“…However, the role of such T effector cells in the rejection of established tumors has not been demonstrated. Although regressing sarcomas contain inflammatory cells that could reflect an ongoing DTH response, these regressing tumors also contain directly cytolytic T cells as well as primed tumor-specific CTL precursors that can be expanded to produce increased numbers of CTL (21,27). Moreover, inoculation of immune Lyt-1 +2-T cells into "B" mice, a situation in which potential DTH effectors are present and CTL effectors are absent, did not prevent lethal outgrowth of a subsequent inoculum of MBL tumor (25).…”

Section: Discussionmentioning

confidence: 99%

Eradication of disseminated murine leukemia by chemoimmunotherapy with cyclophosphamide and adoptively transferred immune syngeneic Lyt-1+2- lymphocytes.

Greenberg¹,

Cheever²,

Fefer³

1981

The Journal of Experimental Medicine

286

132

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The phenotype of T cells therapeutically effective in immunotherapy of advanced Friend virus-induced (FBL) leukemia in vivo and cytotoxic to FBL in vitro was determined. Mice bearing disseminated FBL leukemia were successfully treated by a combination of cyclophosphamide and adoptive transfer of syngeneic immune lymphocytes. Therapeutic efficacy was largely dependent on the presence of Lyt-1+2- T cells in the transferred cells, whereas cells cytotoxic to FBL tumor in vitro were derived from the Lyt-1+2+ and Lyt-1-2+ subsets. Thus, the predominate cell required to eradicate tumor in adoptive chemoimmunotherapy was not cytolytic to tumor in vitro. Potentially, the Lyt-1+2- cell may operate in vivo as an amplifier cell rather than by a direct anti-tumor effect. Elimination of the Lyt-1+ population with alpha-Lyt-1 and complement prevented the generation of significant cytotoxic responses during both primary in vitro sensitization to alloantigens and in vitro sensitization of tumour-primed cells. The capacity of Lyt-1+ cell-depleted population to generate cytotoxic responses was partially reconstituted by addition, at the initiation of culture, of interluekin 2, a T cell growth factor derived from Lyt-1+2- cells, which contain the CTL and CTL precursors, were nearly as effective in vitro as unseparated immune cells. If the remaining effector cells (i.e., Lyt-1+2- T cells) function in vivo predominantly as amplifier cells, than the tumour-bearing host must be capable of making a positive contribution to the outcome of therapy.

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“…Several laboratories have tried to relate the systemic studies to the host response within the tumour, in an attempt to identify the important effector mechanisms responsible for regression. Cytotoxic T cells (Plata & Sordat, 1977;Holden et al, 1976;Gillespie et al, 1977;Chapdelaine et al, 1979), cytolytic macrophages and cytostatic macrophages (Puccetti & Holden, 1979;Russell et al, 1977) have been isolated from enzymedispersed tumours induced both by MSV and by the MSC tumour line established from an MSV-induced sarcoma. Studies carried out on both systemic and intratumoral immunity to MSV in A/Sn mice, however, indicated that cytotoxic T cells are not induced in this strain, suggesting that cytotoxic T cells might not be essential for the regression of MSV-induced tumours (Becker & Klein, 1976.…”

Section: Discussionmentioning

confidence: 99%

In vitro demonstration of in situ autologous tumour-cell cytotoxicity in MSV-induced tumours in A/SN mice

Becker¹,

Haskill²

1981

Br J Cancer

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Summary.-Moloney sarcoma-virus (MSV)-induced tumours in A/Sn mice have been dispersed with collagenase and DNase 8-15 days after virus inoculation, and both "sarcoma" and inflammatory cells separated by sedimentation velocity and adherence techniques. The isolated "sarcoma" cells had the morphological characteristics of atypical cells (i.e. cytoplasmic blebbing, vacuolization and prominent nucleoli) and were easily adapted to in vitro growth. As few as 2 x 103 of these cells inoculated i.m. produced new tumours within 8 days of injection in both syngeneic and allogeneic mice. Also, cell-free supernatant from "sarcoma"-cell cultures produced tumours, indicating that the successful transplantation of the "sarcoma" cells was probably due to production of infective virus. Cells cytotoxic in vitro against the ''sarcoma'' cells were present within both spleen and tumour of the tumour donors, but not in the spleens of normal mice. The cytotoxicity was specific against virusinfected cells, since in a mixture of virus-positive (gp 70) and virus-negative cells, positive cells were removed while negative cells were not affected, as measured by a visual cytotoxicity assay using immunostaining. Although T cells could be isolated from the MSV-induced tumours, these cells did not appear to mediate the cytotoxicity detected against the MSV "sarcoma" cells. These results suggest that early MSV infections might be sensitive to cytotoxic mechanisms distinct from those reported with established MLV-or MSV-induced tumour lines.

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Tumors induced by murine sarcoma virus contain precursor cells capable of generating tumor-specific cytolytic T lymphocytes.

Cited by 15 publications

References 13 publications

Interleukin 7 promotes long-term in vitro growth of antitumor cytotoxic T lymphocytes with immunotherapeutic efficacy in vivo.

Interleukin 7 promotes long-term in vitro growth of antitumor cytotoxic T lymphocytes with immunotherapeutic efficacy in vivo.

Eradication of disseminated murine leukemia by chemoimmunotherapy with cyclophosphamide and adoptively transferred immune syngeneic Lyt-1+2- lymphocytes.

In vitro demonstration of in situ autologous tumour-cell cytotoxicity in MSV-induced tumours in A/SN mice

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