I will comment after studying this for awhile, but it does open up an additional treatment path(s?) for PCa.
(Excerpts)
Calcinotto's team discovered that prostate tumor cells produce a molecule, ApoE, which can bind to and influence a type of immune cells, neutrophils, resulting in these cells acquiring senescent, or aged features. They also found that these senescent neutrophils could survive for a prolonged period within the tumor environment, contrary to prior beliefs.
. . . we knew already that the prostate tumor microenvironment was highly infiltrated by a population of immune cells to find neutrophils. In 2018, we showed in major paper that these cells, through the production of interleukin-23, were conferring castration-resistant prostate cancer and resistance to therapy. So we aimed to block this population this pathogenic population in prostate cancer microenvironment by blocking their recruitment. Because the dogma regarding this type of cells was that they had short half-life. However, we realized and we demonstrated that these cells could persist in the tumor microenvironment longer and what we discovered here was that these cells acquire features of senescence, of aged and survive for months within the tumor microenvironment. This was completely new and undefined, unexpected from this population. But what we understood better was the mechanism by which these neutrophils, that are pathogenetic in this type of cancer, can become senescent.
Basically, we identified that prostate tumor cells produce a molecule, defined ApoE, and through these molecules, the tumor cells can directly bind TREM2 molecules, specifically expressed by these neutrophils, and through this mechanism, confer long survival, basically, to this population of immunosuppressive, pathogenic neutrophils. The next step was to dissect how we could block and maybe these pathogenic neutrophils. So to have clinical relevance, Nicolo was so smart to identify that there was histone deacetylase inhibitors, so HDAC inhibitors that through the regulation and the inhibition of the machinery of the HDAC, could inhibit the transcription of TREM2. So the inhibition of transcription of TREM2 by the neutrophils were inhibited and we helped these neutrophils to become senescent, to survive, basically.
So we then envision and tested these compounds in vitro and in vivo in a clinical trial and we basically demonstrated that the HDAC inhibitors were inhibiting the process of senescent neutrophils, but even more importantly, were inhibiting and decreasing the tumor progression and the resistance to canonical therapies, such as enzalutamide.
Nicolo Bancaro: What we show is that basically the neutrophils, upon arrival in the tumor microenvironment, they are, like we said, canonical, so the normal neutrophils. Some of them, they undergo apoptosis and they die. But some other, since they can catch these ApoE produced by the tumor, they can survive longer and undergoing senescence. So at the end, it's the tumor that is producing this molecule that inside the tumor environment can induce senescence.
What we found is that there is a correlation between what we call the senescent neutrophil score and the aggressiveness of the disease.
Dr. Calcinotto, you did a triple combination where you looked at the combination of enzalutamide, romidepsin, and a CXCR2 inhibitor. Did you evaluate the impact of this combination on prostate cancer cells alone, and what was the effect when myeloid cells were there or not? Arianna Calcinotto: Yes. Actually, this was one of the questions of the reviewer because they were skeptical at the beginning, and they were right, to see whether HDAC inhibitors were specific against the senescent neutrophils and did not have many other side effect on the tumors, et cetera. So Nicolo performed, actually, this experiment and we clearly showed that the HDAC inhibitors was efficacious in this system, when we had the myeloid, the senescent myeloid. So we had the specific effect on the senescent myeloid.
So the next step is . . . to understand whether we can really run a new clinical trial to decide whether romidepsin can be used in combination with enzalutamide. The second step will be, because there's already trials using romidepsin in other type of cancer, so we'd like to understand whether these senescent neutrophils are also present in other subtypes of cancer, breast cancer, bladder cancer, and others, so that behaves somehow similarly to prostate cancer, and to see whether these findings could be somehow used also for the potential treatment of other type of cancer.
