Adoptive cell transfer (ACT) therapy using tumor-inflitrating lymphocytes (TIL) is at the cutting edge of immuno-oncology treatments involving metastatic melanoma and other indications (1). The idea is that at some point during the growth of a tumor, some T cells attempted to mount an immune response, extravasated and got into the tumor, but they became overwhelmed and exhausted. The therapy itself involves taking these cells out from some excised tumor, reversing their condition and since they're already neo-antigen specific from having attempted an attack on that cancer: Expand them, put them back in the patient, let them hit the tumor much harder than before.

Not only do you need to reverse exhaustion in the TIL, but you also need to have the right population of T cells to get the best response. The factors involved are beyond this question, and so I'll get to the point.

In the tumor environment, the T cells become exhausted and their expression profile changes (2). It makes them more prone to apoptosis and they lose effector functions like GranzymeB production. You can tell how this is problematic. My suspicion is that in the tumor the T cells may become hypoxic, and what we know is that in the oxygen-sensing pathway, hypoxia inducible factors exert their effect. Normally, these should be kept in check by inhibiting proteins if they get produced under normoxia:

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And so to my question:

After prolonged exposure to hypoxia, are there any regulatory or transcriptional changes that after prolonged return to normoxia render either of HIF1α or HIF2α active where they would normally be repressed?

Whether I just need a fresh set of eyes or the data just doesn't exist, I haven't necessarily found it obviously. I'd like to know if there's a remnant hypoxia-like regulation framework that remains after O2 gets back to normal that affect pathways like mTORC1/2. Thanks if advance for any insights!

  • $\begingroup$ It seems like you've made up a hypothesis with no evidence, and rather than actually look for evidence for the hypothesis you're charging down the pathway and asking about hypothetical recovery from hypothetical effects of hypothetical problems. Why not actually try to validate your model before asking about far-downstream effects? $\endgroup$
    – iayork
    Jun 13, 2016 at 17:33
  • $\begingroup$ @iayork It seems that way when I type things up (I miss a lot), but it's established that the T cells we're getting out of these tumors are in bad shape due to many factors including hypoxia, and that HIF very much modulates T cell responses (1) (2). If there's even a mundane tidbit I'm missing while I trudge through tons of papers, however, it will be great to find out. $\endgroup$
    – CKM
    Jun 13, 2016 at 19:43
  • $\begingroup$ Have you actually looked at HIF1α/HIF1α-Pro-OH levels in your TILs compared to circulating T cells with the same or similar surface markers, then made the same comparison after culturing TILs under normoxia for some period of time? $\endgroup$
    – MattDMo
    Jun 13, 2016 at 21:23
  • $\begingroup$ Alternatively, you could label the cells, then do an adoptive transfer of extracted TILs into non-tumor-bearing mice and follow them that way, if you're afraid that ex vivo culture might muddle the picture too much. $\endgroup$
    – MattDMo
    Jun 13, 2016 at 21:26
  • $\begingroup$ @MattDMo Just because it's not on our project list, I haven't run any such tests. We also don't work with mice (that's a collaborators' job). I'd like to do something similar, however, at some point in the future. I'm just looking for data that exists so i can come at the issue from the correct angles. $\endgroup$
    – CKM
    Jun 15, 2016 at 20:33


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