RGD Reference Report - Intratumoral interleukin-2/agonist CD40 antibody drives CD4+ -independent resolution of treated-tumors and CD4+ -dependent systemic and memory responses. - Rat Genome Database

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Intratumoral interleukin-2/agonist CD40 antibody drives CD4+ -independent resolution of treated-tumors and CD4+ -dependent systemic and memory responses.

Authors: Jackaman, C  Nelson, DJ 
Citation: Jackaman C and Nelson DJ, Cancer Immunol Immunother. 2012 Apr;61(4):549-60. doi: 10.1007/s00262-011-1120-5. Epub 2011 Oct 15.
RGD ID: 11522742
Pubmed: PMID:22002241   (View Abstract at PubMed)
DOI: DOI:10.1007/s00262-011-1120-5   (Journal Full-text)

Targeting interleukin-2 (IL-2) and/or agonist anti-CD40 antibody (Ab) into tumors represents an effective vaccination strategy that avoids systemic toxicity and resolves treated-site tumors. Here, we examined IL-2 and/or anti-CD40 Ab-driven local versus systemic T cell function and the installation of T cell memory. Single tumor studies showed that IL-2 induced a potent CD4+ and CD8+ T cell response that was limited to the draining lymph node and treated-site tumor, and lymph node tumor-specific CD8+ T cells did not upregulate CD44. A two-tumor model showed that while IL-2-treated-site tumors resolved, distal tumors continued to grow, implying limited systemic immunity. In contrast, anti-CD40 Ab treatment with or without IL-2 expanded the systemic T cell response to non-draining lymph nodes, and distal tumors resolved. Tumor-specific T cells in lymph nodes of anti-CD40 Ab +/- IL-2-treated mice upregulated CD44, demonstrating activation and transition to effector/memory migratory cells. While CD40-activated CD4+ T cells were not required for eradicating treated-site tumors, they, plus CD8+ T cells, were crucial for removing distal tumors. Rechallenge/depletion experiments showed that the effector/memory phase required the presence of previously CD40/IL-2-activated CD4+ and CD8+ T cells to prevent recurrence. These novel findings show that different T cell effector mechanisms can operate for the eradication of local treated-site tumors versus untreated distal tumors and that signaling through CD40 generates a whole of body, effector/memory CD4+ and CD8+ T cell response that is amplified and prolonged via IL-2. Thus, successful immunotherapy needs to generate collaborating CD4+ and CD8+ T cells for a complete long-term protective cure.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
CD40Humanmalignant mesothelioma treatmentISOCd40 (Mus musculus) RGD 
Cd40Ratmalignant mesothelioma treatmentISOCd40 (Mus musculus) RGD 
Cd40Mousemalignant mesothelioma treatmentIMP  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Cd40  (CD40 molecule)

Genes (Mus musculus)
Cd40  (CD40 antigen)

Genes (Homo sapiens)
CD40  (CD40 molecule)


Additional Information