You are apparently trying to support the claim that non-classical MHC can be upregulated on tumors. Yes, it can; that’s widely known, it doesn’t need support. But since not all tumors do that (again, a widely known point), it means nothing at all for CTVT; it’s not relevant. You can’t look at reviews on broad trends in human tumors and expect them to explain everything about one specific and very unique tumor of dogs.

You’re also making points about classical MHC downregulation on tumors. Again, this is widely known, and has been convincingly shown to be down-regulated on CTVT. It’s not my point.

I repeat: There is nothing in the literature that looks at non-classical MHC on CTVT. Siddle et al are making the claim that there is something about non-classical MHC on CTVT, and they are wrong. It’s that simple. It’s not a big deal. They made a throwaway comment in their intro, probably mis-remembering something or conflating two different tumors, and the comment got missed in peer review.

The reason I pointed it out, though, is that it’s very relevant for the point of my blog post here. The point I wanted to make is that for CTVT — unlike Tasmanian Devil tumors — the reason the tumor can spread between individuals is not known. Siddle et al — again, this was a throwaway statement in their intro — claimed that the reason is known, and they’re wrong, it’s not; the mechanism they pointed to, has not been demonstrated.

Many tumors, including CTVT, avoid immunological recognition by down-regulating classical class I (class Ia) expression and up-regulating nonclassical class I (class Ib) expression (10, 21, 22). By expressing class Ib molecules, tumor cells avoid recognition by natural killer cells and escape immune recognition by T cells (22).

Your quote comes from the introduction, the one above comes from the discussion section. Presumably, they thought a summary in the introduction was OK when the detail was in the discussion. The question is why they include CTVT in that class.

From ref 10 discussion:

A recent study (Hsiao et al., 2004) shows that, during progressive growth, secretion of TGF-β1 by CTVT acts as a potent local inhibitor of host immune responses, as does the downmodulation of DLA class I and II expression observed by us and others (Cohen et al., 1984). Thus, the evasion of host immune responses has enabled the tumor to survive and grow until it can be further transmitted.

Backing up to the results section:

Downregulation of MHC Expression in CTVT

The foregoing analysis shows that CTVT has been transmitted as an allograft across many DLA types through innumerable hosts. Although dogs that have recovered from CTVT are immune to tumor development upon reinoculation, naive dogs of many breeds are susceptible to tumor growth (Cohen, 1985). A recent study indicated that secretion of tumor growth factor β (TGF-β1) may play a role in local immune suppression during progressive growth but that interleukin 6 secretion by tumor-infiltrating lymphocytes aids eventual immune destruction during tumor regression (Hsiao et al., 2004). However, the expression of MHC antigens in CTVT has not been analyzed in detail. One study based on immunostaining indicated that β2-microglobulin could not be detected on CTVT cells (Cohen et al., 1984), but MHC mRNA expression has previously not been examined.

We therefore performed RT-PCR with tumor-specific and host-specific primers within the tumor tissue of Sicilian dog C in order to investigate differential expression of tumor and host DLA genes. Figure 6A shows that class I expression was lower in tumor cells than in stromal cells (which serve as a loading control) and that class II expression was absent. This result indicates significant downmodulation of DLA expression in the tumor cells because they were the majority population (not, vert, similar90%) in the microdissected tumor tissue (Figure 6B). If class I genes were wholly unexpressed, NK cells might eliminate the tumor; hence, our finding of low expression appears more plausible than the suggestion of defective β2-microglobulin (Cohen et al., 1984). A systematic and quantitative analysis of several tumors during different phases of growth and regression would be required to elucidate this phenomenon more thoroughly, but that is beyond the scope of this study. Nonetheless, our finding of DLA downregulation at the transcriptional level is consistent with previous suggestions (Cohen, 1985 and Hsiao et al., 2004) that, during progressive growth, CTVT has adapted to evade host immune responses.

Now as I understand the last paragraph, there is a reduction of the amount of Class I expression. Nothing is said whether the remaining Class I is classical or non-classical. Siddle et al are clearly taking it to be non-classical, that is a complete elimination of classical and upregulation of non-classical. But Murgia et al’s results appear to be equally consistent with a reduced amount of classical and no non-classical. Agreed?

So the question is, what is there about ref’s 21 and 22 (see above) that justifies assuming the presence of non-classical.

I can’t even get into ref 21 without buying it for $30, which I don’t intend to do, but ref 22, which is pointed to humans, is describing a set of 7 “major altered HLA class I phenotypes have been defined in different tumor tissues” of which the last is “Phenotype VII: Downregulation of classical HLA A-B-C molecules and appearance of HLA-E molecules” which corresponds to what Siddle et al seem to be assuming. The others phenotypes seem to me (so far) to be human specific, so perhaps Siddle et al are assuming number 7 must be the explanation (which would be a distinct error).

OTOH perhaps the other results in ref 10 imply, or may imply, that option 7 is the correct one. I’m still trying to figure it out, myself.

So they are not arguing that non-classical MHC is DOWN-regulated but rather that it’s UPregulated, and they are very clearly refering to the CTVT, not a generic effect. What’s more, when they make that claim they only cite a single reference, and that reference does not supprot their claim. Nor is there any claim anywhere in the literature that CTVT upregulates non-classical MHC.

I’m not claiming that non-clasical MHC doesn’t block NK, nor that it’s not a tumor immune evasion pathway — those are both trivial observations in that they’re widely known. I’m specifically saying that they’ve made an unsupported claim. And specifically it’s not an obvious conclusion for CTVT; there are lots of tumors that do NOT upregulate non-classical MHC, yet manage to be resistant to NK as well as classical CTL.

blockquote>MHC class I molecules comprise the classical (class Ia) human leukocyte antigens (HLA)-A, -B, and -C antigens in humans and H-2K, D, and L in mice, and the nonclassical (class Ib) E, F, and G, in humans and Qa and Tla antigens in mice (Bjorkman et al., [1987]). They form a trimolecular complex consisting of a 45-kDa heavy chain (HC), peptide antigen, and the nonpolymorphic 12-kDa 2-microglobulin (2-m) light chain. The HLA-A, -B, and -C and the H-2K, D, and L HCs are highly polymorphic (Bjorkman and Parham, [1990]). In humans, the class I HCs are encoded by genes located within the MHC region on chromosome 6, whereas 2-m is encoded by a gene mapped on chromosome 15. In mice, these antigens are encoded in chromosome 17 and chromosome 2, respectively. The classical HLA/H-2 class I molecules are expressed on the surface of most mammalian cells with only a few exceptions (Le Bouteiller, [1994]). It is estimated that there are up to 250,000 of each HLA class I molecule on the surface of a somatic cell (Parham and Ohta, [1996]).

It’s a good guess that if it works for mice and men, it works for dogs. From ref 10:

Allorecognition of nonself from self predates the evolution of the highly polymorphic MHC system and is seen in yeast mating types, sponges, and cellular slime molds. However, natural chimeras (Buss, 1982) do occur in metazoans including colonial urochordates (Rinkevich, 2004), and CTVT can be regarded a special case of somatic cell chimerism. The driving selection for the evolution of the MHC system and cell-mediated adaptive immunity in early jawed vertebrates may have been as much to protect against malignancy as to protect against infectious disease because invasive and metastatic tumors develop only in vertebrates, whereas infections are universal.

It’s pretty clear that Murgia et al are thinking in large clade terms. They are probably assuming that the reduced class I expression was all non-classical, but don’t say so because the research necessary to confirm it was not performed.

Siddle et al seem to be jumping to conclusions here (poor peer review), but it’s a pretty obvious conclusion in view of ref 22.