Employing huNOG-EXL models as a valuable tool in prostate cancer studies

Developing more effective treatments for prostate cancer is of paramount importance. However, preclinical murine models, historically used to successfully model many other types of cancer, pose unique challenges to researchers. The mouse prostate differs in anatomy compared to the human prostate and will not form tumors on its own.  Although researchers have attempted to use genetically engineered mouse models, they do not capture the complexities of human cancer and prostate cancer will frequently fail to metastasize in these models. Engrafting immunocompromised mice with tumors limits their use in exploring the interactions between the tumor and immune system and in developing effective immunotherapies. 

The paper presents a significant advancement in modeling prostate cancer by using humanized immune system (HIS) mouse models (huNOG and huNOG-EXL) that possess an intact human immune system to increase translatability. The huNOG model allows for human T cells, among other immune cell populations, while the huNOG-EXL model supports human myeloid cell expansion. The combination of a prostate cancer xenograft with a human immune system creates a model that demonstrated clinically relevant metastasis and improved responsiveness to standard-of-care therapies. 

The key findings include:

Validating the humanized immune system (HIS) murine model

The study demonstrated that prostate cancer xenografts in male huNOG and huNOG-EXL mice have improved translatability compared to other approaches for modeling prostate cancer.

The  researchers compared humanized mice engrafted with a highly aggressive cancer cell line and compared them to NOG control mice engrafted with the prostate cancer line. Mice were either surgically castrated or surgically castrated and treated with enzalutamide. In both huNOG and NOG mice, cancer cells migrated to various sites, including bone, lymph nodes, kidneys, and brain. They found that metastasis of the cancer cells was blocked in huNOG mice that were castrated and treated with enzalutamide, which is consistent with clinical data. In NOG mice, the combination of castration and enzalutamide resulted in greater growth and migration of cancer cells. Based on this comparison, the scientists concluded that the prostate cancer cells, “have the capacity to metastasize, with or without the presence of an intact human immune system, but the immune system may be activated to prevent outgrowth at secondary sites. These data also suggest that huNOG mice better recapitulate the patient castration/enzalutamide response and warrant further investigation into the immune populations that may be responsible for this phenotype.”

Immune System Impact: 

The presence of an intact immune system in humanized mice allows for improved evaluation of therapeutic candidates for prostate cancer and highlights the importance of the tumor immune microenvironment in preclinical prostate cancer models.

Using flow cytometry, researchers characterized immune cell profiles in mice engrafted with prostate cancer cells. They found both an increased number and activation of T cells in the tumors of huNOG mice treated with enzalutamide, an androgen inhibitor used to treat prostate cancer, leading the authors to conclude that the immune system interacts with metastasizing cancer cells. The huNOG model, therefore, is a suitable “hot” model for researchers seeking to evaluate enzalutamide therapy. 

In contrast, enzalutamide did not reduce metastasis in huNOG-EXL mice. However, this model supported immune cells of lymphoid and myeloid lineages. The authors note that enzalutamide has been found to be immunosuppressive in myeloid cell populations and that the huNOG-EXL model may be a suitable “cold” model.

Conclusions

In addition to establishing both the huNOG and NOG-EXL models for use in modeling prostate cancer, the researchers also made important strides in assessing interactions between the immune system and cancer cells. They also made several important distinctions between the two models, noting infiltration by T cells into tumors, T cell activation by enzalutamide, and blocked metastasis by enzalutamide in the “hot” huNOG model. The “cold” huNOG-EXL model supported myeloid cell growth, had a reduced number of T cells, supported a regulator T cell population, and enzalutamide did not affect metastasis. These two models can, therefore, capture unique features of different types of prostate cancer.  

“To the best of our knowledge, these results illustrate the first model of human PCa that metastasizes to clinically relevant locations, has an intact human immune system, and responds appropriately to the standard-of-care hormonal therapies .” 

This research provides a valuable tool for future studies on prostate cancer treatment and the role of the immune system in cancer therapy.

Read the entire publication here.