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A couple weeks ago I was having a chat with a friend about cancer immunity (as one so often does) and he asked if the Holy Grail of cancer immunity would be to identify tumor antigens. Not at all. There are hundreds of tumor antigens known. (The journal Cancer Immunity hosts a database that lists many of the known ones.) The problem is if anything the opposite; there are too many antigens, and many are one-offs, unique to one or a handful of tumors and of no use to most patients. A better Holy Grail would be a single target that many tumors have in common.
Our genomes are littered with the withered corpses of ancient retroviruses. Everyone has them. These human endogenous retroviruses (HERVs) are defective, and their proteins are usually not expressed, or are expressed at low levels. Because they’re not normally expressed much, they don’t necessarily tolerize the immune system. At least hypothetically, if there are pathologic conditions in which HERVs become expressed, they might form targets for immunity.
As it happens, there may be several such conditions. It’s been suggested (though not, to my inexpert eye, all that convincingly) that HERVs might represent targets in autoimmunity. More usefully, Douglas Nixon’s group showed some evidence, last fall, that HIV infection upregulates HERVs, offering a target for CTL that (unlike HIV itself) isn’t constantly mutating.1 And it’s been suggested for quite a while that HERVs might be immunogenic in tumors.
For example, over ten years ago it was shown that patients with certain kinds of tumors, which consistently show high-level HERV activation, often have antibody responses to HERVs.2 However, in general, antibodies are not particularly effective against tumors, and as far as I know, nothing much arose directly from the antibody findings.
On the other hand, T cells are (at least sometimes) more effective against tumors; and T cell immunity was linked to HERVs first (as far as I know) in 2002,3 with the observation that a melanoma tumor antigen was derived from a HERV. Some similar work has followed.4
So: HERVs are potential antigens; they are more or less immutable; they can be upregulated in some tumors; and they can trigger an immune response by antibodies and by T cells. These are interesting observations, but is this at all relevant for tumor treatment?
The next step in answering that question came out recently, in J Clin Invest. 5 Here we see not just reactive T cells (that is, T cells specific for HERV peptides) but a potent immune response that actually cleared a metastatic tumor. The response was due to an allogeneic bone marrow transplant, and when they tracked down the target peptide for the immune response, it was directed against a HERV peptide:
The genes encoding this antigen were found to be derived from human endogenous retrovirus (HERV) type E and were expressed in RCC cell lines and fresh RCC tissue but not in normal kidney or other tissues.
It’s still far from clear how universal a target HERVs might be. This group identified a HERV target in one of their patients, but they treated 74 patients, saw at least partial responses in 29 of those patients, sought to identify targets in four of the responders, and found the HERV target in just one of the four. Some of the other targets were apparently the more standard mutated proteins, specific to the individual tumor.
This peptide target, by the way, is from a group E HERV; most of the previous work has focused on group K HERVs, which tend to be more active and are expressed to some extent in normal tissue. HERV-E generally are pretty quiescent, so if tumors do upregulate HERV-E, it would be a more specific target. The authors did check, and found that most of that particular type of tumor expressed HERV-E. Interestingly, this is the kind of tumor that is most likely to be responsive to immunotherapy:
A histological review of the RCC6 cell lines and fresh RCC tissues used in experiments presented in this article showed all to be clear-cell carcinomas, with more than half expressing HERV-E transcripts. Furthermore, limited preliminary data from an ongoing study of fresh tumors suggest that this HERV-E may have transcriptional activity limited to the clear-cell variant of kidney cancer (unpublished observations), which is intriguing given the track record for this tumor being the immunoresponsive subtype of RCC.
It would be a very useful discovery if this turns out to be a common antigen among these tumors. That said, there are some other known common tumor antigens — such as tyrosinase in melanomas — and immunization hasn’t proven a silver bullet in those yet. But it’s early days, still.
- Garrison, K. E., Jones, R. B., Meiklejohn, D. A., Anwar, N., Ndhlovu, L. C., Chapman, J. M., Erickson, A. L., Agrawal, A., Spotts, G., Hecht, F. M., Rakoff-Nahoum, S., Lenz, J., Ostrowski, M. A., and Nixon, D. F. (2007). T Cell Responses to Human Endogenous Retroviruses in HIV-1 Infection. PLoS Pathog 3, e165. [↩]
- Boller, K., Janssen, O., Schuldes, H., Tonjes, R. R., and Kurth, R. (1997). Characterization of the antibody response specific for the human endogenous retrovirus HTDV/HERV-K. J Virol 71, 4581-4588.[↩]
- Schiavetti, F., Thonnard, J., Colau, D., Boon, T., and Coulie, P. G. (2002). A human endogenous retroviral sequence encoding an antigen recognized on melanoma by cytolytic T lymphocytes. Cancer Res 62, 5510-5516.[↩]
- Rakoff-Nahoum, S., Kuebler, P. J., Heymann, J. J., E Sheehy, M., M Ortiz, G., S Ogg, G., Barbour, J. D., Lenz, J., Steinfeld, A. D., and Nixon, D. F. (2006). Detection of T lymphocytes specific for human endogenous retrovirus K (HERV-K) in patients with seminoma. AIDS Res Hum Retroviruses 22, 52-56.[↩]
- Takahashi, Y., Harashima, N., Kajigaya, S., Yokoyama, H., Cherkasova, E., McCoy, J.P., Hanada, K., Mena, O., Kurlander, R., Abdul, T., Srinivasan, R., Lundqvist, A., Malinzak, E., Geller, N., Lerman, M.I., Childs, R.W. (2008). Regression of human kidney cancer following allogeneic stem cell transplantation is associated with recognition of an HERV-E antigen by T cells. Journal of Clinical Investigation DOI: 10.1172/JCI34409[↩]
- RCC: “Renal cell carcinoma.” IY[↩]