Exuberated Numbers of Tumor-Specific T Cells Result in Tumor Escape

Goldberger, Ofir; Volovitz, Ilan; Machlenkin, Arthur; Vadai, Ezra; Tzehoval, Esther; Eisenbach, Lea

doi:10.1158/0008-5472.can-07-5006

Cited by 29 publications

(23 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…6). Some tumors that regrew had indeed lost expression of the OVA gene and thus the target Ag, verifying selection pressure against the immune response as a means of tumor escape in this model (32). Surprisingly, however, other tumors that regrew had a higher level of OVA message expression than ex After incubation with ApoB-SIINFEKL, CD11c + BMDCs were gated, and the expression of H-2Kb-SIINFEKL was analyzed by 25D1.16 mAb (bold solid line) without or with LPS or CpG-ODN treatment.…”

Section: Apob-ova Fusion Peptides Elicit Cytotoxic T Cells and Supprementioning

confidence: 65%

Apolipoprotein B Binding Domains: Evidence That They Are Cell-Penetrating Peptides That Efficiently Deliver Antigenic Peptide for Cross-Presentation of Cytotoxic T Cells

Sakamoto

Rosenberg

2011

The Journal of Immunology

View full text Add to dashboard Cite

Low-density lipoproteins (LDLs) are a good source of cholesterol, which is important in cellular homeostasis and production of steroids. Apolipoprotein B-100 (ApoB-100), the sole protein component of LDL, is known to bind to cell surface LDL receptor (LDLR) or cell surface-bound proteoglycans and to be internalized into cells. We found that APCs, consisting of macrophages and dendritic cells, upregulate LDLR on culture in vitro without obvious stimulation. In contrast, T cell populations only upregulate LDLR on activation. Thus, we strategized that tagging immunogens to ApoB-100 might be a useful means to target Ag to APCs. We generated fusion proteins consisting of receptor binding sites in ApoB-100, coupled to OVA peptide (ApoB-OVA), as Ag delivery vehicles and demonstrated that this novel delivery method successfully cross-presented OVA peptides in eliciting CTL responses. Surprisingly, internalization of ApoB-OVA peptide occurred via cell surface proteoglycans rather than LDLRs, consistent with evidence that structural elements of ApoB-100 indicate it to have cell-penetrating peptide properties. Finally, we used this strategy to assess therapeutic vaccination in a tumor setting. OVA-expressing EL-4 tumors grew progressively in mice immunized with ApoB-100 alone but regressed in mice immunized with ApoB-OVA fusion protein, coinciding with development of OVA-specific CTLs. Thus, to our knowledge, this is the first article to describe the cell-penetrating properties of a conserved human origin cell penetrating peptide that may be harnessed as a novel vaccination strategy as well as a therapeutics delivery device.

show abstract

Section: Apob-ova Fusion Peptides Elicit Cytotoxic T Cells and Supprementioning

confidence: 65%

Apolipoprotein B Binding Domains: Evidence That They Are Cell-Penetrating Peptides That Efficiently Deliver Antigenic Peptide for Cross-Presentation of Cytotoxic T Cells

Sakamoto

Rosenberg

2011

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…Since the selective pressure induced by antigen-specific T cells may result in the emergence of tumor escape variants caused by silencing of the antigen expression [21], we also measured, by real-time PCR, the expression of ovalbumin transcript in tumor cells isolated from the different groups of mice at the time of the sacrifice. We found a more marked loss of ovalbumin expression in tumor cells isolated from tumors which expanded in mice vaccinated with fdOVA/sc-aDEC or peptidepulsed DCs, with respect to levels of ovalbumin expression in tumor cells isolated from the other groups of mice (Fig.…”

Section: Induction Of Tumor Protection In Vivomentioning

confidence: 99%

Vaccination with filamentous bacteriophages targeting DEC‐205 induces DC maturation and potent anti‐tumor T‐cell responses in the absence of adjuvants

et al. 2011

View full text Add to dashboard Cite

The efficacy of a new vaccine-delivery vector, based on the filamentous bacteriophage fd displaying a single-chain antibody fragment known to bind the mouse DC surface molecule DEC-205, is reported. We demonstrate both in vitro and in vivo an enhanced receptormediated uptake of phage particles expressing the anti-DEC-205 fragment by DCs. We also report that DCs targeted by fd virions in the absence of other stimuli produce IFN-a and IL-6, and acquire a mature phenotype. Moreover, DC-targeting with fd particles double-displaying the anti-DEC-205 fragment on the pIII protein and the OVA [257][258][259][260][261][262][263][264] antigenic determinant on the pVIII protein induced potent inhibition of the growth of the B16-OVA tumor in vivo. This protection was much stronger than other immunization strategies and similar to that induced by adoptively transferred DCs. Since targeting DEC-205 in the absence of DC activation/maturation agents has previously been described to result in tolerance, the ability of fd bacteriophages to induce a strong tumor-specific immune response by targeting DCs through DEC-205 is unexpected, and further validates the potential employment of this safe, versatile and inexpensive delivery system for vaccine formulation.

show abstract

“…However, they have not been as successful as hoped, in part due to the immune evasion tactics applied by tumor cells to escape immunorecognition (14,15). A prerequisite for the induction of an effective antitumor immune response by MUC1 vaccine is the effective uptake of this molecule by professional antigen-presenting cells (APC).…”

Section: Introductionmentioning

confidence: 99%

Increased Immunogenicity of Tumor-Associated Antigen, Mucin 1, Engineered to Express α-Gal Epitopes: A Novel Approach to Immunotherapy in Pancreatic Cancer

et al. 2010

View full text Add to dashboard Cite

Mucin 1 (MUC1), a bound mucin glycoprotein, is overexpressed and aberrantly glycosylated in >80% of human ductal pancreatic carcinoma. Evidence suggests that MUC1 can be used as a tumor marker and is a potential target for immunotherapy of pancreatic cancer. However, vaccination with MUC1 peptides fails to stimulate the immune response against cancer cells because immunity toward tumor-associated antigens (TAA), including MUC1, in cancer patients is relatively weak, and the presentation of these TAAs to the immune system is poor due to their low immunogenicity. We investigated whether vaccination with immunogenetically enhanced MUC1 (by expressing α-gal epitopes; Galα1-3Galβ1-4GlcNAc-R) can elicit effective antibody production for MUC1 itself as well as certain TAAs derived from pancreatic cancer cells and induced tumor-specific T-cell responses. We also used α1,3galactosyltransferase (α1,3GT) knockout mice that were preimmunized with pig kidney and transplanted with B16F10 melanoma cells transfected with MUC1 expression vector. Vaccination of these mice with α-gal MUC1 resulted in marked inhibition of tumor growth and significant improvement of overall survival time compared with mice vaccinated with MUC1 alone (P = 0.003). Furthermore, vaccination with pancreatic cancer cells expressing α-gal epitopes induced immune responses against not only differentiated cancer cells but also cancer stem cells. The results suggested that vaccination using cells engineered to express α-gal epitopes is a novel strategy for treatment of pancreatic cancer. Cancer Res; 70(13); 5259-69. ©2010 AACR.

show abstract

Exuberated Numbers of Tumor-Specific T Cells Result in Tumor Escape

Cited by 29 publications

References 40 publications

Apolipoprotein B Binding Domains: Evidence That They Are Cell-Penetrating Peptides That Efficiently Deliver Antigenic Peptide for Cross-Presentation of Cytotoxic T Cells

Apolipoprotein B Binding Domains: Evidence That They Are Cell-Penetrating Peptides That Efficiently Deliver Antigenic Peptide for Cross-Presentation of Cytotoxic T Cells

Vaccination with filamentous bacteriophages targeting DEC‐205 induces DC maturation and potent anti‐tumor T‐cell responses in the absence of adjuvants

Increased Immunogenicity of Tumor-Associated Antigen, Mucin 1, Engineered to Express α-Gal Epitopes: A Novel Approach to Immunotherapy in Pancreatic Cancer

Contact Info

Product

Resources

About