A more systematic effort to identify other cytokines that might play a role similar to that of IL-23 in CRPC will help to delineate the cytokine and receptor network and identify additional therapeutic targets.  

“It will be interesting to elucidate the upstream signaling pathways that control the expression of IL-23 in MDSCs upon antiandrogen therapy,” Dr Wang said.

Dr Wang’s team and others have recently shown that MDSCs promote prostate tumor progression and resistance to chemotherapy and immunotherapy.3-6 His laboratory has grant support from the National Institutes of Health (NIH) to do similar research with a different mouse model of prostate cancer.

Clinical testing could also proceed alongside additional preclinical testing.

“At this point in time, it makes sense to structure clinical trials,” Dr Pal commented. “These data provide excellent translational backing for such studies.”

The finding that monoclonal antibody-targeting of IL-23 inhibited CRPC tumor growth in preclinical mouse models suggests a possible path forward for clinical translation of a new immunotherapy modality that targets IL-23 in CRPC, said Jennifer Wu, PhD, a professor of urology and immunology at the Feinberg School of Medicine and Robert Lurie Comprehensive Cancer Center, Northwestern University in Chicago, Illinois.

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“Given that monoclonal antibody-targeting [of] IL-23 has [demonstrated] safety in clinical trials for treating autoimmune disorders, such as psoriasis, this study opens a new avenue of immunotherapy for CRPC,” Dr Wu said.

MDSCs also play a role in breast cancer, another hormone-driven cancer, Dr Wang pointed out.

“It will be interesting to determine whether a similar paracrine mechanism may promote resistance to antiestrogen therapy in breast cancer,” he said.

Nonetheless, the findings “are certainly promising and have the potential to usher [in] an entirely new paradigm of advanced prostate cancer care,” Dr Kutikov said. “Given that prostate cancer is the second-leading cause of death [from cancer] in American men, this is a very big deal.”

References

  1. Calcinotto A, Spataro C, Zagato E, et al. IL-23 secreted by myeloid cells drives castration-resistant prostate cancer. Nature. 2018;559(7714):363-369.
  2. Hossain DM, Pal SK, Moreira D, et al. TLR9-targeted STAT3 silencing abrogates immunosuppressive activity of myeloid-derived suppressor cells from prostate cancer patients. Clin Cancer Res. 2015;21(16):3771-3782.
  3. Di Mitri D, Toso A, Chen JJ, et al. Tumour-infiltrating Gr-1+ myeloid cells antagonize senescence in cancer. Nature. 2014;515:134-137.
  4. Wang G, Lu X, Dey P, et al. Targeting YAP-dependent MDSC infiltration impairs tumor progression. Cancer Discov. 2016;6(1):80-95.
  5. Lu X, Horner JW, Paul E, et al. Effective combinatorial immunotherapy for castration-resistant prostate cancer. Nature. 2017;543(7647):728-732.
  6. Garcia AJ, Ruscetti M, Arenzana TL, et al. Pten null prostate epithelium promotes localized myeloid-derived suppressor cell expansion and immune suppression during tumor initiation and progression. Mol Cell Biol. 2014;34(11):2017-2028.