The Rate of the CD8-Dependent Initial Reduction in Tumor Volume Is Not Limited by Contact-Dependent Perforin, Fas Ligand, or TNF-Mediated Cytolysis

Hollenbaugh, Joseph A.; Reome, Joyce B.; Dobrzanski, Mark J.; Dutton, Richard

doi:10.4049/jimmunol.173.3.1738

Cited by 41 publications

(42 citation statements)

References 23 publications

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“…This result would correlate with previous data on CD8 cells obtained from Bcl-x L transgenic mice in which Bcl-x L antagonized apoptosis of effector cells, but only delayed the contraction phase of an Ag-induced CD8 T cell response rather than preventing it (32). Recent results have suggested that recruitment of host cells is essential to the therapeutic action of adoptively transferred CD8 cells, rather than these cells directly targeting the tumor (27,33). If so, long-term protection will then be mediated by host cells and will not require adoptive CD8 cells.…”

Section: Discussionsupporting

confidence: 80%

OX40 and Bcl-xL Promote the Persistence of CD8 T Cells to Recall Tumor-Associated Antigen

Song

Tang

Harms

et al. 2005

The Journal of Immunology

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The molecular signals that allow primed CD8 T cells to persist and be effective are particularly important during cancer growth. With response to tumor-expressed Ag following adoptive T cell transfer, we show that CD8 effector cells deficient in OX40, a TNFR family member, could not mediate short-term tumor suppression. OX40 was required at two critical stages. The first was during CD8 priming in vitro, in which APC-transmitted OX40 signals endowed the ability to survive when adoptively transferred in vivo before tumor Ag encounter. The second was during the in vivo recall response of primed CD8 T cells, the stage in which OX40 contributed to the further survival and accumulation of T cells at the tumor site. The lack of OX40 costimulation was associated with reduced levels of Bcl-xL, and retroviral expression of Bcl-xL in tumor-reactive CD8 T cells conferred greatly enhanced tumor protection following adoptive transfer. These data demonstrate that OX40 and Bcl-xL can control survival of primed CD8 T cells and provide new insights into both regulation of CD8 immunity and control of tumors.

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Section: Discussionsupporting

confidence: 80%

OX40 and Bcl-xL Promote the Persistence of CD8 T Cells to Recall Tumor-Associated Antigen

Song

Tang

Harms

et al. 2005

The Journal of Immunology

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“…Perforin-deficient mice were reported to be more susceptible to tumor development in some models [5][6][7][8], while other studies found that perforin-deficient CTL were fully capable of exerting anti-tumor activity in vivo [9][10][11][12][13]. Similarly, CD95L-dependent effector mechanisms have been shown to be important in some models [14][15][16] but not in others [9,13,17]. The release of soluble factors represents an additional mechanism by which CD8 T cells could exert anti-tumor activity.…”

Section: Introductionmentioning

confidence: 99%

“…An early study in mice revealed that rejection of pulmonary metastases by cultured tumorspecific CD8 T cells correlates better with their capacity to produce IFN-c than with their cytotoxicity in vitro [18]. More recent studies using IFN-c-deficient mice have provided compelling evidence for the important role of IFN-c in T cell-mediated tumor cell rejection [7,9,10,13,14,[19][20][21][22][23][24][25][26]. Various possibilities can be envisaged to explain the anti-tumor activity of IFN-c: first, IFN-c is known to increase MHC expression and antigen presentation, thereby rendering tumor target cells more susceptible to CTL attack [27][28][29].…”

Section: Introductionmentioning

confidence: 99%

Solid tumors “melt” from the inside after successful CD8 T cell attack

Blohm¹,

Potthoff²,

Kogel³

et al. 2006

Eur J Immunol

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Adoptive transfer of tumor-specific T cells represents a promising approach for cancer immunotherapy. Here, we visualized the anti-tumor response of CD8 T cells from P14 TCR-transgenic mice specific for the model antigen GP33 by immunohistology. P14 T cells, adoptively transferred into tumor-bearing hosts, induced regression of established 3LL-A9 GP33 and MCA102 GP33 tumors that express GP33 as a tumor-associated model antigen. Strikingly, the visible effects of P14 T cell attack, such as the destruction of the tumor vasculature and accumulation of granulocytes, were predominantly detected inside the tumor mass. In regressing tumors, P14 T cells were found in the intact rim zone but not in central areas that were infiltrated with granulocytes and lacked CD31 + endothelial cells. The rim of P14 T cell-treated tumors showed an increase in vascular density and decrease in hypoxia compared to untreated tumors. Hypoxic areas of tumors are known to exhibit decreased sensitivity to radiation therapy or chemotherapy. Thus, our data also imply that adoptive transfer of tumor-specific CD8 T cells might synergize with radiation therapy or chemotherapy in the elimination of solid tumors in vivo.

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“…IFN-␥ can activate macrophages, enhance Ag processing, and increase MHC expression, including up-regulation of class I expression on tumor cells, making them more susceptible to CTL lysis. IFN-␥ produced by CD8 T cells responding to tumor Ag has been shown to be critical for E.G7 tumor rejection in an adoptive immunotherapy model (30). To determine whether the OT-I cells that were responding to tumor-derived Ag were capable of producing IFN-␥, cells isolated from the tumor and DLN were restimulated with OVA-peptide Ag in vitro and then stained with Abs to IFN-␥.…”

Section: Responding Cd8 T Cells Have An Effector Phenotypementioning

confidence: 99%

Signal 3 Availability Limits the CD8 T Cell Response to a Solid Tumor

Curtsinger

Gerner

Lins

et al. 2007

The Journal of Immunology

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CD8 T cells need a third signal, along with Ag and costimulation, for effective survival and development of effector functions, and this can be provided by IL-12 or type I IFN. Adoptively transferred OT-I T cells, specific for H-2Kb and OVA, encounter Ag in the draining lymph nodes of mice with the OVA-expressing E.G7 tumor growing at a s.c. site. The OT-I cells respond by undergoing limited clonal expansion and development of effector functions (granzyme B expression and IFN-γ production), and they migrate to the tumor where they persist but fail to control tumor growth. In contrast, OT-I T cells deficient for both the IL-12 and type I IFN receptors expand only transiently and rapidly disappear. These results suggested that some signal 3 cytokine is available, but that it is insufficient to support a CTL response that can control tumor growth. Consistent with this, administration of IL-12 at day 10 of tumor growth resulted in a large and sustained expansion of wild-type OT-I cells with enhanced effector functions, and tumor growth was controlled. This did not occur when the OT-I cells lacked the IL-12 and type I IFN receptors, demonstrating that the therapeutic effect of IL-12 results from direct delivery of signal 3 to the CD8 T cells responding to tumor Ag in the signal 3-deficient environment of the tumor.

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The Rate of the CD8-Dependent Initial Reduction in Tumor Volume Is Not Limited by Contact-Dependent Perforin, Fas Ligand, or TNF-Mediated Cytolysis

Cited by 41 publications

References 23 publications

OX40 and Bcl-xL Promote the Persistence of CD8 T Cells to Recall Tumor-Associated Antigen

OX40 and Bcl-xL Promote the Persistence of CD8 T Cells to Recall Tumor-Associated Antigen

Solid tumors “melt” from the inside after successful CD8 T cell attack

Signal 3 Availability Limits the CD8 T Cell Response to a Solid Tumor

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