I was reading an interview with Jacques Miller [1] who discovered the immunological function of the thymus in the early 1960s, & this reminded me of something I had read a dozen years ago.
T cells develop in the thymus [2] & are central to the immune response. At puberty, the thymus "begins to decrease in size and activity in a process called thymic involution."
"The atrophy is due to the increased circulating level of sex hormones, and chemical or physical castration of an adult results in the thymus increasing in size and activity."
When I became aware of this, I wondered what the implications were for men on ADT.
In the years that have passed, I have seen no reference to the thymus in the PCa literature.
Elimination of CD4lowHLA-G+ T cells overcomes castration- resistance in prostate cancer therapy
Chao Wang1,2, Jiahuan Chen3, Qianfei Zhang1,2, Wang Li1, Shengbo Zhang1,2, Yanjie Xu1,2, Fang Wang1, Bing Zhang3, Yan Zhang1,2 and Wei-Qiang Gao1,2
Androgen deprivation therapy (ADT) is a main treatment for prostate cancer (PCa) but the disease often recurs and becomes castration-resistant in nearly all patients. Recent data implicate the involvement of immune cells in the development of this castration-resistant prostate cancer (CRPC). In particular, T cells have been found to be expanded in both PCa patients and mouse models shortly after androgen deprivation. However, whether or which of the T cell subtypes play an important role during the development of CRPC is unknown. Here we identified a novel population of CD4lowHLA-G+ T cells that undergo significant expansion in PCa patients after ADT. In mouse PCa models, a similar CD4low T cell population expands during the early stages of CRPC onset. These cells are identified as IL-4-expressing TH17 cells, and are shown to be associated with CRPC onset in patients and essential for the development of CRPC in mouse models. Mechanistically, CD4lowHLA-G+ T cells drive androgen-independent growth of prostate cancer cells by modulating the activity and migration of CD11blowF4/80hi macrophages. Furthermore, following androgen deprivation, elevated PGE2-EP2 signaling inhibited the expression of CD4 in thymocytes, and subsequently induced the polarization of CD4low naïve T cells towards the IL-4-expressing TH17 phenotype via up-regulation of IL23R. Therapeutically, inactivating PGE2 signaling with celecoxib at a time when CD4lowHLA-G+ T cells appeared, but not immediately following androgen deprivation, dramatically suppressed the onset of CRPC. Collectively, our results indicate that an unusual population of CD4lowHLA- G+ T cells is essential for the development of CRPC and point to a new therapeutic avenue of combining ADT with PGE2 inhibition
I know that some here are Celebrex [Celecoxib] users, & they might be disturbed to read the following (from your link):
"Our findings indicate that application of celecoxib starting at different time points after ADT may produce distinct therapeutic outcomes. On the one hand, celecoxib treatment starting at eight weeks after castration, when CD4lowHLA-G+ T cells are detected, dramatically inhibits the occurrence of CRPC, and more importantly prolongs survival times in PCa mouse models.On the other hand, administration of celecoxib immediately following ADT leads to the failure of prostate cancer therapy, with enhanced tumor cell infiltration and proliferation as well as failure to abrogate the production of CD4lowHLA-G+ T cells in mouse models. A similar phenomenon has been reported in a recent clinical trial for prostate cancer: namely, application of celecoxib and ADT simultaneously does not produce better clinical outcomes than ADT alone.44 A possible explanation for the difference may be that the long-term use of celecoxib activates a compensatory mechanism to enhance PGE2 synthesis and/or up-regulate the expression of proteins in downstream signaling of PGE2. Support for this notion comes from the current study in which long-term use of celecoxib in the PCa mouse models led to compensatory elevation of EP2 expression in T cells, which reactivates PGE2-EP2 signaling to promote the generation of CD4lowHLA-G+ T cells. Similar observations are also reported in intestinal tumors, where long-term use of celecoxib has been shown to produce significantly higher levels of PGE2 and reactivation of PGE2-associated signaling pathways in tumors and normal tissues.49 Taken together, these results highlight the importance of timing in implementing celecoxib treatment and further, demonstrate that CD4lowHLA-G+ T cells can be used as an indicative marker of therapeutic efficacy in celecoxib treatment on prostate cancer after ADT."
Thanks as always for your knowledge posts. However, This is all very hard for us layman to follow. We can not change when we started Celebrex but many of us use it (including me) and added zometa based upon the studies showing the two combined reduced deaths by some 22%. Bottom line, if we’ve been on Celebrex (with or without zometa) do you think it best to stop it continue or still unknown?
I think that you should continue because it inhibits COX2 & thereby inhibits the conversion of arachidonic acid to PGE2. In the context of cancer, PGE2 is bad news.
From a recent paper:
"Cyclooxygenase (COX)-derived prostaglandin E2 (PGE2 ) affects many mechanisms that have been shown to play roles in carcinogenesis. Recently, we found that, in androgen-independent prostate cancer PC3 cells, PGE2 acts through an intracrine mechanism by which its uptake by the prostaglandin transporter (PGT) results in increased intracellular PGE2 (iPGE2 ), leading to enhanced cell proliferation, migration, invasion, angiogenesis, and loss of cell adhesion to collagen I. ..."
Would radiation to the lymph nodes reduce the cd4lowHLG cells?
Just putting this together. SBRT to lymph nodes due to its limited duration theoretically conserves more of the cd4 cells. So would Long duration IMRT potentially produce a protective benefit against crpc?
"Just putting this together. SBRT to lymph nodes due to its limited duration theoretically conserves more of the cd4 cells. So would Long duration IMRT potentially produce a protective benefit against crpc?"
Logically, you would sort of think so.
There are a cohort of perhaps over a thousand Dr. Myers prostate cancer patients who have lymph node Imrt and low cd4 t-cell levels.
Cesces. Hmmm. We are in the process of deciding where to do radiation. My Hangup with Dattoli has been that he is still doing IMRT to lymph nodes, BUT, maybe that is not such a bad thing?
But I now have aids levels of cd4 t-Cells. Seems like a lot of his patients have this.
I think maybe I would tell him to stay away from the lymph nodes.
Sbrt looks a lot more interesting these days. I don't know if you can use it in lymph nodes.
You might consider investigating surgery for the lymph nodes.
If you want aggressive treatment, certainly Dattoli is the guy to see. Still you can elect to do the rest of the treatment and defer the lymph node treatment until you get additional opinions and options on that.
If you do get any additional opinions and options on it, please come back and post a new thread on that subject.
While you are talking to Dattoli, you should probably arrange with him to get a long term relationship so you can get long term access to trental prescription.
For what it's worth...I was diagnosed with Thyroid cancer when I was 30. Thye removed half of my thyroid and I have been on levothyroxine (.125g) since and no adjustment when I went onto Lupron et al.
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