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

General

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.

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Term	Qualifier	Evidence	With	Reference	Notes	Source	Original Reference(s)
malignant mesothelioma	treatment	ISO	Cd40 (Mus musculus)	11522742; 11522742		RGD
malignant mesothelioma	treatment	IMP		11522742		RGD

Objects Annotated

Genes (Rattus norvegicus)

Cd40 (CD40 molecule)

Genes (Mus musculus)

Cd40 (CD40 antigen)

Genes (Homo sapiens)

CD40 (CD40 molecule)

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