U-118 glioma cells (Nikon Microscopy Gallery)
U-118 Glioma cells 

In one of the earliest posts I made to Mystery Rays,  I commented on an exciting anti-tumor finding. 1  Basically, the suggestion was that when chemotherapy of tumors works, it doesn’t actually work by killing all the tumor cells; or at least not directly.  Instead, the authors said, chemo works because the dying tumor cells release adjuvants (immune stimulants),2 and what actually eliminates the tumor is the specific immune response to the tumor, driven and enhanced by the immune stimulants.   In other words, the chemotherapy is actually acting like the adjuvant in an anti-cancer vaccine. 

Presumably the reason this form of adjuvant is effective, whereas just giving an adjuvant to a cancer patient is not, is that it’s so tightly linked to the tumor you want the immune system to target.   

In the subsequent year and a half there have been a handful of papers looking more at this phenomenon (not counting the review papers, which have churned out at a great rate). For example, it’s been shown that dying tumor cells are cross-presented efficiently due to HMGB1 and similar immune stimulators.3    Now, there’s a more specific support of the concept. 4 

I don’t know if the Apetoh et al paper was the initial impetus for the latest one, or (more likely) if it was already in progress, but a any rate, unless I’ve missed one, this is the second study that directly looks at HMGB1 effects on tumor regression following tumor cell death, and it reaches basically the same conclusion as the first paper.  This was strictly a mouse study, but they used a highly aggressive brain tumor (glioblastoma multiforme).  As well as chemotherapy they used a gene therapy approach, thus managing to hit four of my Mystery Rays buzzwords (tumor immunity, immunity to viruses, innate adjuvants, and if you’re generous oncolytic viruses as well) all at once.  (What would a Mystery Rays Bingo Card look like?)

Glioblastoma
Glioblastoma

If the model is correct, then what you really want to do when treating tumors is a double whammy — kill tumor cells, and simultaneously attract in immune cells.  Curtin et al did this by injecting two recombinant adenoviruses directly into the tumor; one rendered the infected cells sensitive to chemotherapy, and the other attracted dendritic cells (DC are important cells for initiating immune responses). Following chemo, the tumors regressed dramatically (about half the mice survived, compared to 100% death without treatment).  And both of the viruses were necessary; without the immune system, killing the cells wasn’t enough, and without tumor cell death, the immune system couldn’t do enough. 

The same treatment in mice without TLR2 did nothing.  TLR2 is an innate immune recognition molecule that triggers inflammation in the presence of (among other things) HMGB1, which is released from dying cells.  This is similar to the Apetoh et al paper, and Curtin et al took the studies a little further by showing that TLR2 had to be on dendritic cells (as opposed to the tumor itself). What’s more, when all the parts were in place (tumor cell death, DC  present, DC expressing TLR2) there was a strong specific anti-tumor cytotoxic T lymphocyte response, while without the TLR2 stimulation there was little such response.

In other words, they’ve firmed up the probable pathway by which chemotherapy eliminated these tumors. The chemotherapy killed cells directly, and the dying cells released HMGB1; the HMGB1 activated dendritic cells in the tumor, by triggering their TLR2 receptor; the activated DC then in turn activated CTL specific for the tumor; and the CTL then completely eliminated the tumor and prevented the remains from regrowing.  (Some of the steps in this pathway remain formally unproven, but the data are consistent with this model.) 

It’s not clear, yet, if this is the universal explanation for successful chemotherapy, or whether chemo sometimes or often works by killing the tumor directly with no requirement for immunity. The authors here looked at several different tumors, expanding on the more correlative data from Apetoh et al., and so far all the cancers that have been checked fall into the immune clearance category.  So, while it’s a long, long way from the bedside, it’s certainly encouraging. 

In conclusion, the results reported provide compelling evidence for the role played by HMGB1 in mediating the efficacy of antiglioma therapeutic regimes that are based on tumor cell killing strategies … [C]ancer immunotherapies coupled with effective cell killing modalities may be necessary to achieve therapeutically relevant antitumor efficacy. 4


  1. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Apetoh et al. Nature Medicine 13, 1050 – 1059 (2007)  doi:10.1038/nm1622

    Also this review:

    Apetoh, L., F. Ghiringhelli, A. Tesniere, A. Criollo, C. Ortiz, R. Lidereau, C. Mariette, N. Chaput, J. P. Mira, S. Delaloge, F. Andre, T. Tursz, G. Kroemer, and L. Zitvogel. 2007. The interaction between HMGB1 and TLR4 dictates the outcome of anticancer chemotherapy and radiotherapy. Immunol. Rev. 220:47-59.

    and this one:

    Apetoh, L., A. Tesniere, F. Ghiringhelli, G. Kroemer, and L. Zitvogel. 2008. Molecular interactions between dying tumor cells and the innate immune system determine the efficacy of conventional anticancer therapies. Cancer Res. 68:4026-4030.

    and this review from a different group:

    Campana, L., L. Bosurgi, and P. Rovere-Querini. 2008. HMGB1: a two-headed signal regulating tumor progression and immunity. Curr. Opin. Immunol. 20:518-523.[]

  2. Specifically, the dying cells release a protein called HMGB1, which has been shown to be an endogenous adjuvant[]
  3. Brusa, D., S. Garetto, G. Chiorino, M. Scatolini, E. Migliore, G. Camussi, and L. Matera. 2008. Post-apoptotic tumors are more palatable to dendritic cells and enhance their antigen cross-presentation activity. Vaccine 26:6422-6432.[]
  4. James F. Curtin, Naiyou Liu, Marianela Candolfi, Weidong Xiong, Hikmat Assi, Kader Yagiz, Matthew R. Edwards, Kathrin S. Michelsen, Kurt M. Kroeger, Chunyan Liu, A. K. M. Ghulam Muhammad, Mary C. Clark, Moshe Arditi, Begonya Comin-Anduix, Antoni Ribas, Pedro R. Lowenstein, Maria G. Castro (2009). HMGB1 Mediates Endogenous TLR2 Activation and Brain Tumor Regression PLoS Medicine, 6 (1) DOI: 10.1371/journal.pmed.1000010[][]