CD4+ T Cells Contribute to the Remodeling of the Microenvironment Required for Sustained Tumor Regression upon Oncogene Inactivation

Rakhra, Kavya; Bachireddy, Pavan; Zabuawala, Tahera; Zeiser, Robert; Xu, Liwen; Kopelman, Andrew M.; Fan, Alice C.; Yang, Qiwei; Braunstein, Lior Z.; Crosby, Erika J.; Ryeom, Sandra; Felsher, Dean W.

doi:10.1016/j.ccr.2010.10.002

Cited by 314 publications

(232 citation statements)

References 78 publications

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“…The murine T-ALL cell line 4188, which is induced by a doxycycline-repressible MYC transgene, was obtained from Dean Felsher, 23 and grown in RPMI 1640 (Invitrogen) with 10% fetal bovine serum (Sigma-Aldrich), 1% penicillin/streptomycin (Invitrogen), and 50 μM 2-mercaptoethanol (Invitrogen). Doxycycline (20 ng/ml) was added to the media to downregulate MYC transgene expression in 4188 cells.…”

Section: Methodsmentioning

confidence: 99%

Repression of BIM mediates survival signaling by MYC and AKT in high-risk T-cell acute lymphoblastic leukemia

et al. 2014

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Treatment resistance in T-cell acute lymphoblastic leukemia (T-ALL) is associated with PTEN deletions and resultant PI3K-AKT pathway activation, as well as MYC overexpression, and these pathways repress mitochondrial apoptosis in established T-lymphoblasts through poorly defined mechanisms. Normal T-cell progenitors are hypersensitive to mitochondrial apoptosis, a phenotype that is dependent on expression of proapoptotic BIM. In a conditional zebrafish model, MYC downregulation induced BIM expression in T-lymphoblasts, an effect that was blunted by expression of constitutively active AKT. In human T-ALL cell lines and treatment- resistant patient samples, treatment with MYC or PI3K-AKT pathway inhibitors each induced BIM upregulation and apoptosis, indicating that BIM is repressed downstream of MYC and PI3K-AKT in high-risk T-ALL. Restoring BIM function in human T-ALL cells using a stapled peptide mimetic of the BIM BH3 domain had therapeutic activity, indicating that BIM repression is required for T-ALL viability. In the zebrafish model, where MYC downregulation induces T- ALL regression via mitochondrial apoptosis, T-ALL persisted despite MYC downregulation in 10% of bim wild-type zebrafish, 18% of bim heterozygotes, and in 33% of bim homozygous mutants (P = 0.017). We conclude that downregulation of BIM represents a key survival signal downstream of oncogenic MYC and PI3K-AKT signaling in treatment-resistant T-ALL.

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Section: Methodsmentioning

confidence: 99%

Repression of BIM mediates survival signaling by MYC and AKT in high-risk T-cell acute lymphoblastic leukemia

et al. 2014

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“…71 In mouse models of T-cell acute lymphoblastic lymphoma and pro-B-cell leukemia, the anti-angiogenic effects of thrombospondins secreted by CD4 + T cells were sufficient to elicit spontaneous oncogene inactivation leading to tumor regression. 72 Overall, the evidence demonstrates that anti-angiogenic therapy (typically blockade of VEGF signaling) has remarkable therapeutic effects in various types of human cancers. However, the molecular bases of cancer type-dependent resistance mechanisms against VEGF blockade, especially VEGF-independent pro-angiogenic mechanisms, now need to be clarified.…”

Section: Future Directions and Perspectivesmentioning

confidence: 99%

Tumor Angiogenesis and Anti-angiogenic Therapy

2012

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“…In conditional transgenic mouse models of MYC or BCR-ABL tumorigenesis [95], oncogene inactivation only results in sustained tumor regression in immune intact hosts [58]. Notably, the kinetics of tumor regression, the extent of tumor regression, and the ability to maintain sustained tumor regression were all perturbed by up to 1000-fold in an immune compromised host [58] (Fig. 2).…”

Section: Oncogene Addiction and The Immune Responsementioning

confidence: 99%

“…In CD4 −/− hosts, oncogene inactivation continued to result in proliferative arrest and apoptosis, but cellular senescence and shut down of angiogenesis was impeded [58]. Reconstitution of RAG1 −/− hosts with CD4 + T cells alone was sufficient to enable oncogene inactivation to induce sustained tumor regression.…”

Section: Oncogene Addiction and The Immune Responsementioning

confidence: 99%

“…Oncogenes can regulate angiogenesis; MYC inactivation can result in the shut down of angiogenesis, contributing to tumor regression [54–57]. Inactivation of an oncogene recruits a marked change in the tumor microenvironment associated with the recruitment of immune effector cells, and this plays a direct role in the mechanism of oncogene addiction [12,58–61]. The innate and the adaptive immune systems are known to play a critical role in tumor initiation and progression [62–65] as well as immunosurveillance [66–69].…”

Section: Introduction: Oncogene Addictionmentioning

confidence: 99%

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An essential role for the immune system in the mechanism of tumor regression following targeted oncogene inactivation

Casey

Felsher

2014

Immunol Res

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Tumors are genetically complex and can have a multitude of mutations. Consequently, it is surprising that the suppression of a single oncogene can result in rapid and sustained tumor regression, illustrating the concept that cancers are often “oncogene addicted.” The mechanism of oncogene addiction has been presumed to be largely cell autonomous as a consequence of the restoration of normal physiological programs that induce proliferative arrest, apoptosis, differentiation, and/or cellular senescence. Interestingly, it has recently become apparent that upon oncogene inactivation, the immune response is critical in mediating the phenotypic consequences of oncogene addiction. In particular, CD4+ T cells have been suggested to be essential to the remodeling of the tumor microenvironment, including the shut down of host angiogenesis and the induction of cellular senescence in the tumor. However, adaptive and innate immune cells are likely involved. Thus, the effectors of the immune system are not only involved in tumor initiation, tumor progression, and immunosurveillance, but are also involved in the mechanism of tumor regression upon targeted oncogene inactivation. Hence, oncogene inactivation may be an effective therapeutic approach because it both reverses the neoplastic state within a cancer cell and reactivates the host immune response that remodels the tumor microenvironment.

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CD4+ T Cells Contribute to the Remodeling of the Microenvironment Required for Sustained Tumor Regression upon Oncogene Inactivation

Cited by 314 publications

References 78 publications

Repression of BIM mediates survival signaling by MYC and AKT in high-risk T-cell acute lymphoblastic leukemia

Repression of BIM mediates survival signaling by MYC and AKT in high-risk T-cell acute lymphoblastic leukemia

Tumor Angiogenesis and Anti-angiogenic Therapy

An essential role for the immune system in the mechanism of tumor regression following targeted oncogene inactivation

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