Deficiencies of GM-CSF and Interferon γ Link Inflammation and Cancer

Enzler, Thomas; Gillessen, Silke; Manis, John P.; Ferguson, David O.; Fleming, James C.; Alt, Frederick W.; Mihm, Martín C.; Dranoff, Glenn

doi:10.1084/jem.20021258

Cited by 167 publications

(146 citation statements)

References 31 publications

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“…Enzler et al suggested a role between GM-CSF and IFNg in the protection against tumor development, since GM-CSF/IFNg double knock-out mice, but not single knock-out mice, developed spontaneous tumors. 24 Whether this mechanism also acts on established tumors is not clear.…”

Section: Discussionmentioning

confidence: 99%

Synergism between GM–CSF and IFNγ: Enhanced immunotherapy in mice with glioma

Smith

Janelidze

Visse

et al. 2006

Intl Journal of Cancer

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Glioblastoma multiforme is the most common malignant primary brain tumor and also one of the most therapy-resistant tumors. Because of the dismal prognosis, various therapies modulating the immune system have been developed in experimental models. Previously, we have shown a 37-70% cure in a rat glioma model where rats were peripherally immunized with tumor cells producing IFNc. On the basis of these results, we wanted to investigate whether a combination of GM-CSF and IFNc could improve the therapeutic effect in a mouse glioma model, GL261 (GL-wt). Three biweekly intraperitoneal (i.p.) immunizations with irradiated GM-CSF-transduced GL261 cells (GL-GM) induced a 44% survival in mice with intracranial glioma. While treatment of GLwt and GL-GM with IFNc in vitro induced upregulation of MHC I and MHC II on the tumor cells, it could not enhance survival after immunization. However, immunizations with GL-GM combined with recombinant IFNc at the immunization site synergistically enhanced survival with a cure rate of 88%. Tumors from mice receiving only 1 immunization on Day 10 after tumor inoculation were sectioned on Day 20 for analysis of leukocyte infiltration. Tumor volume was reduced and the infiltration of macrophages was denser in mice immunized with GL-GM combined with IFNc compared with that of both wildtype and nonimmunized mice. To our knowledge, this is the first study to demonstrate a synergy between GM-CSF and IFNc in experimental immunotherapy of tumors, by substantially increasing survival as well as inducing a potent anti-tumor response after only 1 postponed immunization. ' 2006 Wiley-Liss, Inc.

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Section: Discussionmentioning

confidence: 99%

Synergism between GM–CSF and IFNγ: Enhanced immunotherapy in mice with glioma

Smith

Janelidze

Visse

et al. 2006

Intl Journal of Cancer

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“…This pleiotropic response of T cells in the context of malignancy is reminiscent of the involvement of macrophages which are well known to include those that promote as well as those that antagonize tumor development (31). It is also reminiscent of aspects of normal physiology: thus, whereas NK cells are prototypically cytotoxic, uterine NK cells produce high amounts of cytokines, including IFN␥, but are not cytolytic and are associated with trophoblast growth and invasion of the uterus (25).…”

Section: Phenotypic Analysis Of Cd8 ؉ Til (Putative T-pro) Associatedmentioning

confidence: 99%

Characterizing tumor-promoting T cells in chemically induced cutaneous carcinogenesis

Roberts

Filler

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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There is a longstanding but poorly understood epidemiologic link between inflammation and cancer. Consistent with this, we previously showed that ␣␤ T cell deficiency can increase resistance to chemical carcinogenesis initiated by 7,12-dimethylbenz[a]anthracene and promoted by phorbol 12-myristate 13-acetate. This provoked the hypothesis that ␣␤ T cell deficiency removed T regulatory cells that limit the anti-tumor response or removed a specific tumor-promoting (T-pro) T cell population. Here we provide evidence for the latter, identifying a novel CD8 ؉ subset that is a candidate for T-pro cells. We demonstrate that CD8 cell-deficient mice show substantially less tumor incidence and progression to carcinoma, whereas susceptibility is restored by CD8 ؉ cell reconstitution. To characterize the putative T-pro cells, tumor-infiltrating lymphocytes were isolated from normal and CD4 ؊/؊ mice, revealing an activated population of T cell receptor ␣␤ ؉ CD8 ؉ CD44 ؉ CD62L ؊ cells expressing the inflammatory mediators IFN␥, TNF␣, and cyclooxygenase-2, but deficient in perforin, relative to recirculating cells of equivalent phenotype. This novel population of CD8 ؉ T cells has intriguing similarities with other lymphocytes that have been associated with tissue growth and invasiveness and has implications for inflammation-associated carcinogenesis, models of cancer immunosurveillance, and immunotherapeutic strategies.inflammation ͉ IFN␥ ͉ squamous cell carcinoma ͉ T cell receptor

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“…Recent reports from several groups have re-addressed this issue and provided strong evidence for the existence of an effective cancer immunosurveillance process in mice. [3][4][5][6][7][8][9][10][11] As summarized in Table 1, mice lacking specific cellular populations, such as T cells, natural killer T (NKT) cells, and/or natural killer (NK) cells, as well as specific molecules, such as interferon (IFN)-γ, interleukin (IL)-12, perforin, or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), unequivocally show higher incidences of tumor development. Moreover, administration of IL-12 or α-galactosylceramide (α-GalCer) that can stimulate T, NKT, and/or NK cells, reduces primary tumor incidence.…”

mentioning

confidence: 99%

The critical role of type‐1 innate and acquired immunity in tumor immunotherapy

et al. 2004

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The discovery of a large array of tumor antigens has demonstrated that host lymphocytes can indeed recognize and destroy tumor cells as originally proposed in the cancer immunosurveillance hypothesis. Recent reports that led to the cancer immunoediting concept also strongly support the immunosurveillance hypothesis, and they further indicate that the host immune system plays a critical role not only in promoting host protection against cancer but also in selecting tumors that can better escape from immune attack. Thus, it is now clear that T cells have the ability to recognize and destroy spontaneously arising tumors. However, the generation of antitumor immunity is often difficult in the tumor-bearing host because of various negative regulatory mechanisms. Here, we review our recent work on tumor immunotherapy, which utilizes the activation of type-1 innate and/or acquired immunity as a potent strategy to overcome immunosuppression in the tumor-bearing host. We have established a variety of tumor therapeutic protocols that aim to activate type-1 immunity, such as tumor-vaccine therapy with CpG encapsulated in liposomes, cell therapy using tumor-specific Th1 cells, and gene therapy using gene-engineered Th1 cells. We found that CpG encapsulated in liposomes stimulated IL-12-producing DC and induced IFN-γ γ γ γ-producing NK cells, NKT cells, and tumorspecific CTL. Th1 cell therapy was also shown to be beneficial for acceleration of APC/Th1 cell-cell interaction in the DLN, which was critical for inducing tumor-specific CTL at the tumor site. Therefore, we conclude that the activation of type-1 innate and acquired immunity is crucial for tumor immunotherapy in order to overcome strong immunosuppression in the tumor-bearing host. (Cancer Sci 2004; 95: 697-703) ince the cancer immunosurveillance hypothesis was proposed by Ehrlich, Burnet, and Thomas, 1, 2) tumor immunologists have asked whether the host immune system can prevent tumor growth. Recent reports from several groups have re-addressed this issue and provided strong evidence for the existence of an effective cancer immunosurveillance process in mice.3-11) As summarized in Table 1, mice lacking specific cellular populations, such as T cells, natural killer T (NKT) cells, and/or natural killer (NK) cells, as well as specific molecules, such as interferon (IFN)-γ, interleukin (IL)-12, perforin, or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), unequivocally show higher incidences of tumor development. Moreover, administration of IL-12 or α-galactosylceramide (α-GalCer) that can stimulate T, NKT, and/or NK cells, reduces primary tumor incidence.Although it is much more difficult to address cancer immunosurveillance in humans, three lines of evidence suggest that cancer immunosurveillance indeed occurs in humans: (i) immunosuppressed transplant recipients display higher incidences of non-viral tumors, such as melanomas, colon, lung, pancreas, bladder, kidney, and endocrine system cancers, than agematched immunocompetent control populations, ...

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Deficiencies of GM-CSF and Interferon γ Link Inflammation and Cancer

Cited by 167 publications

References 31 publications

Synergism between GM–CSF and IFNγ: Enhanced immunotherapy in mice with glioma

Synergism between GM–CSF and IFNγ: Enhanced immunotherapy in mice with glioma

Characterizing tumor-promoting T cells in chemically induced cutaneous carcinogenesis

The critical role of type‐1 innate and acquired immunity in tumor immunotherapy

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