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

Blohm, Ulrike; Potthoff, Dan; Kogel, Albert J. van der; Pircher, Hanspeter

doi:10.1002/eji.200526175

Cited by 40 publications

(29 citation statements)

References 47 publications

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“…Blohm et al 54 visualized adoptive CD8 þ T-cell-mediated tumor destruction and found that tumors 'melt' from the inside were derived from destruction of tumor vasculature and accumulation of granulocytes. The enhancement of in vivo therapeutic effect of the engineered T TNF cells observed in this study may not be due to its upregulated expression of perforin, but may be associated with its enhanced secretion of the transgenecoded human TNF-a as well as its elongated survival in vivo.…”

Section: Discussionmentioning

confidence: 99%

Engineered CD8+ cytotoxic T cells with fiber-modified adenovirus-mediated TNF-α gene transfection counteract immunosuppressive interleukin-10-secreting lung metastasis and solid tumors

Shi

Chan

et al. 2007

Cancer Gene Ther

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T-cell suppression derived from tumor-secreted immunosuppressive interleukin (IL)-10 becomes a major barrier to CD8 þ T-cell immunotherapy of tumors. Tumor necrosis factor-alpha (TNF-a) is a multifunctional cytokine capable of activating T and dendritic cells (DCs) and counteracting IL-10-mediated DC inhibition and regulatory T-cell-mediated immune suppression. In this study, we constructed a recombinant adenovirus MF AdVTNF with fiber-gene modified by RGD insertion into the viral knob's H1 loop and a melanoma cell line B16 OVA/ILÀ10 engineered to express ovalbumin (OVA) and to secrete IL-10 (2.2 ng/ml/10 6 cells/24 h). We transfected OVA-specific CD8 þ T cells with MF AdVTNF, and found a fivefold increase in transgene human TNF-a secretion (4.3 ng/ ml/10 6 cells/24 h) by the engineered CD8 þ T TNF cells transfected with MF AdVTNF, compared to that (0.8 ng/ml/10 6 cells/24 h) by CD8 þ T cells transfected with the original AdVTNF without viral fiber modification. The engineered CD8 þ T TNF cells exhibited enhanced cytotoxicity and elongated survival in vivo after adoptive transfer. TNF-a derived from both the donor CD8 þ T cells and the host cells plays an important role in donor CD8 þ T-cell survival in vivo after adoptive transfer. We also demonstrated that the transfected B16 OVA/ILÀ10 tumor cells secreting IL-10 are more resistant to in vivo CD8 þ T-cell therapy than the original B16 OVA tumor cells without IL-10 expression. Interestingly, the engineered CD8 þ T TNF cells secreting transgene-coded TNF-a, but not the control CD8 þ T control cells without any transgene expression eradicated IL-10-secreting 12-day lung micrometastasis in all 10/10 mice and IL-10-secreting solid tumors (B5 mm in diameter) in 6/10 mice. Transfer of the engineered CD8 þ T TNF cells further induced both donor-and host-derived memory CD8 þ T cells, leading to a stronger long-term antitumor immunity against the IL-10-secreting B16 OVA/ILÀ10 tumor cell challenges. Therefore, CD8 þ T cells engineered to secrete TNF-a may be useful when designing strategies for adoptive T-cell therapy of solid tumors.

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Section: Discussionmentioning

confidence: 99%

Engineered CD8+ cytotoxic T cells with fiber-modified adenovirus-mediated TNF-α gene transfection counteract immunosuppressive interleukin-10-secreting lung metastasis and solid tumors

Shi

Chan

et al. 2007

Cancer Gene Ther

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“…In some models, the ability of CTLs to kill (at least some) tumor or stromal cells appeared essential for tumor elimination (5)(6)(7)(8)(9). Other studies have noted a critical role for CD8 + T cell-derived IFN-γ (10)(11)(12)(13)(14)(15) and the recruitment of inflammatory cells. In addition, some CTLs act primarily by promoting the expansion of other anti-tumor T cell clones (16,17).…”

Section: Introductionmentioning

confidence: 99%

Two-photon imaging of intratumoral CD8+ T cell cytotoxic activity during adoptive T cell therapy in mice

Breart¹,

Lemaı̂tre²,

Celli³

et al. 2008

J. Clin. Invest.

262

260

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“…Since then, a multitude of experimental studies has provided strong support in favor of the immune surveillance hypothesis, and it is now generally accepted that the immune system is capable of identifying and eradicating tumor cells (1,2). In addition, comprehensive research in the field has revealed that CTLs play a major role in tumor rejection, and the number of tumorinfiltrating CD8 T cells has often been found to correlate with a good prognosis (3)(4)(5)(6)(7)(8). As a result, many groups have tried to elicit strong antitumor CD8 T cell responses using a variety of vaccination strategies, and many murine model studies have provided promising results.…”

mentioning

confidence: 99%

Comparison of Vaccine-Induced Effector CD8 T Cell Responses Directed against Self- and Non–Self-Tumor Antigens: Implications for Cancer Immunotherapy

Pedersen

Sørensen

Buus

et al. 2013

The Journal of Immunology

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It is generally accepted that CD8 T cells play a major role in tumor control, yet vaccination aimed at eliciting potent CD8 T cell responses are rarely efficient in clinical trials. To try and understand why this is so, we have generated potent adenoviral vectors encoding the endogenous tumor Ags (TA) tyrosinase-related protein-2 (TRP-2) and glycoprotein 100 (GP100) tethered to the invariant chain (Ii). Using these vectors, we sought to characterize the self-TA–specific CD8 T cell response and compare it to that induced against non–self-Ags expressed from a similar vector platform. Prophylactic vaccination with adenoviral vectors expressing either TRP-2 (Ad-Ii-TRP-2) or GP100 (Ad-Ii-GP100) had little or no effect on the growth of s.c. B16 melanomas, and only Ad-Ii-TRP-2 was able to induce a marginal reduction of B16 lung metastasis. In contrast, vaccination with a similar vector construct expressing a foreign (viral) TA induced efficient tumor control. Analyzing the self-TA–specific CD8 T cells, we observed that these could be activated to produce IFN-γ and TNF-α. In addition, surface expression of phenotypic markers and inhibitory receptors, as well as in vivo cytotoxicity and degranulation capacity matched that of non–self-Ag–specific CD8 T cells. However, the CD8 T cells specific for self-TAs had a lower functional avidity, and this impacted on their in vivo performance. On the basis of these results and a low expression of the targeted TA epitopes on the tumor cells, we suggest that low avidity of the self-TA–specific CD8 T cells may represent a major obstacle for efficient immunotherapy of cancer.

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

Cited by 40 publications

References 47 publications

Engineered CD8+ cytotoxic T cells with fiber-modified adenovirus-mediated TNF-α gene transfection counteract immunosuppressive interleukin-10-secreting lung metastasis and solid tumors

Engineered CD8+ cytotoxic T cells with fiber-modified adenovirus-mediated TNF-α gene transfection counteract immunosuppressive interleukin-10-secreting lung metastasis and solid tumors

Two-photon imaging of intratumoral CD8+ T cell cytotoxic activity during adoptive T cell therapy in mice

Comparison of Vaccine-Induced Effector CD8 T Cell Responses Directed against Self- and Non–Self-Tumor Antigens: Implications for Cancer Immunotherapy

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