Friday, March 20, 2015

CCL3 and memory CD4 T cells improve tumor antigen RNA loaded dendritic cell vaccine performance

Dendritic cells represent the most potent antigen-presenting cells capable of priming naive T cells against infectious or tumor antigens. However, so far, clinical application of antigen-loaded autologous (patient's own) dendritic cell vaccines produced few encouraging results.

Unlike regular vaccines that contain protein conjugates emulsified in adjuvants, dendritic cell vaccine is a biological vaccine containing live cells pulsed with target antigen. The rules that govern efficacy of live cell vaccines would depend on several conditions such as immunological condition of vaccine injection site, migration and viability of injected live vaccine cells and etc. 

The authors have tested their model both in glioblastoma cancer patients and in mouse model of skin cancer. I would like to point out the this paper was under Nature's review for more than a year, implying that it's data are not as strong as the authors would like to argue.

For one thing, clinical protocol the authors have used is not entirely clear. Initially, the authors showed that immunization of patients with tetanus toxoid (Td vaccine) prior to DC vaccine injection extended glioblastoma patients survival almost two-fold compared to un-pulsed DCs. However, I do not understand why Td was compared to un-pulsed DCs. Even after careful reading of methods section, I still was not able to clearly understand the authors reasoning.

Next, using mouse model, the authors showed that presence of activated memory CD4 T cells contributed to the enhanced migration of antigen-loaded DCs to the local lymph nodes.

Interestingly, Td- or memory CD4 T cell-mediated enhancement of DCs migration was abolished in CCL3-KO host.

In addition, exogenous CCL3 was effective only in presence of activated memory CD4 T cells, implying that both memory CD4 T cells and CCL3 are required for enhancement of DCs migration to local lymph nodes.

In summary, these results revealed that locally Td-activated memory CD4 T cells creates a favorable environment for antigen-loaded DCs migration to local lymph node in a CCL3-dependent manner. Source of Td-driven CCL3 from the injection site is not clear.

If you ask me, only reason this paper ended up in Nature has to do with the fact that somehow the authors' protocol (Td + DC pulsed with pp65 antigen RNA) was able to substantially extend glioblastoma patients' survival. However, it is not clear why would Td-activated skin-resident memory CD4 T cells improve migration of DCs loaded with non-related antigen, CMV pp65? If we consider the fact that glioblastoma patients should already have CMV pp65-specific memory CD4 T cells capable of doing the same function as Td did, then I don't see how Td could have provided any additional benefits over simple CMV pp65 RNA-loaded DCs? This paper raises more questions than provides answers.

David Usharauli

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