Prostate cancer exhibits heterogeneity, marked by variations in its biological and clinical progression. The employment of multi-omics to evaluate clinical attributes for risk assessment and to distinguish between localized and metastatically aggressive forms of prostate cancer is crucial for providing improved personalized treatment strategies, prognostic evaluations, and treatment monitoring. As prostate cancer progresses, it inevitably transitions from localized to metastatic disease, gradually reducing its sensitivity to androgens during treatment, leading to the eventual development of CRPC in nearly all patients within 12 to 18 months of treatment initiation. Some patients might progress further, developing NEPC after CRPC, which is identified as a more aggressive subtype. NEPC is generally characterized by a lack of androgen receptor (AR) expression, with a concurrent increase in neuroendocrine markers (Aggarwal et al., 2018; H. Beltran et al., 2016). Given its aggressive nature and resistance, NEPC treatment presents significant challenges, and conventional prostate cancer treatments often fail to halt NEPC progression effectively. Therefore, a tailored and comprehensive treatment strategy, including the targeting of neuroendocrine pathways, immunotherapy, and additional approaches, is crucial for NEPC patients. However, the incomplete understanding of its molecular mechanisms currently hinders the creation of effective targeted therapies.
The intricate interplay between prostate cancer and immune infiltration is noteworthy. The immune system plays a crucial role in combating the development and spread of cancer cells. Nonetheless, cancer cells can evade immune surveillance through various mechanisms, promoting tumor growth and metastasis. Previous studies have found a correlation between chronic inflammation and the progression of prostate cancer (Sfanos & De Marzo, 2012; Sfanos, Yegnasubramanian, Nelson, & De Marzo, 2018), indicating that anti-inflammatory therapy and immune cell-targeted treatments might unveil new treatment strategies for prostate cancer. Currently, the progress of immune therapy in prostate cancer lags behind that of other tumor types, partially due to its lower tumor mutational burden (TMB) and limited immune cell infiltration. The limited infiltration of T cells, despite the identification of immune cells within prostate tumors(such as lymphocytes and macrophages), highlights the lack of understanding regarding the mechanisms regulating tumor infiltration. Apart from the FDA-approved sipuleucel-T vaccine in 2010 (Kantoff et al., 2010), most immune therapies, including checkpoint inhibitors, have shown limited success in prostate cancer, evidenced by the low efficacy rates of these therapeutic drugs (Chalmers et al., 2017; Reimers, Slane, & Pachynski, 2019).
BIRC5 and HMMR are widely expressed in various cancer tissues. BIRC5 is highly expressed in multiple tumors, including lung cancer, pancreatic cancer, breast cancer, ovarian cancer, brain cancer, colorectal cancer, renal cancer, etc. (Andersen, Svane, Becker, & Straten, 2007; Varughese & Torp, 2016; Wheatley & Altieri, 2019; Yuan et al., 2021), whereas HMMR is associated with the progression of gastric cancer, breast cancer, glioblastoma, bladder cancer, and leukemia (Kang, Kim, Kang, Chun, & Kim, 2020; Schwertfeger, Cowman, Telmer, Turley, & McCarthy, 2015; Spranger et al., 2012; Tilghman et al., 2014; D. Yang, Ma, Zhao, Ma, & He, 2021). Limited studies suggest that BIRC5 plays a role in promoting tumor growth and survival in prostate cancer (Frazzi, 2021). Likewise, HMMR expression in prostate cancer is regulated by the AR-mTOR-SRF axis, promoting proliferation and metastasis of prostate cancer (Sun, Li, & Song, 2021). However, the precise roles of these genes in prostate cancer development are still unclear. Therefore, it is crucial to elucidate the roles of BIRC5 and HMMR in prostate cancer. In this study, the pan-cancer expression of these two genes was validated based on the TCGA database. Moreover, BIRC5 and HMMR were found to be significantly upregulated in prostate cancer, particularly in mCRPC and NEPC, compared to localized.PCa, highlighting their involvement in the disease's aggressive and advanced stages. Immunohistochemistry on paraffin-embedded specimens further verified the protein expression of BIRC5 and HMMR.
The expression levels of BIRC5 and HMMR are closely associated with immune cell infiltration and fluctuate across different stages of PCa progression. Within particular microenvironments, initial CD4 + T cells can differentiate into subtypes like Th1, Th2, Th17, and Treg cells. Th1 cells primarily secrete IFN-γ, TNF-α, and lymphotoxin, whereas Th2 cells predominantly release IL-4, IL-13, and IL-5 (Rautajoki, Kylaniemi, Raghav, Rao, & Lahesmaa, 2008). Notably, the principal cytokines from Th1 and Th2 cells exert mutual inhibitory effects on each other's differentiation and function (Morikawa, Zhang, Nonaka, & Morikawa, 2002). Previous studies have shown that Th2 cells and their cytokines impede anti-tumor immune responses, which are closely linked to unfavorable clinical outcomes (De Monte et al., 2011; Kusuda et al., 2005; Ubukata et al., 2010).
Our study revealed a positive correlation between Th2 and HMMR in both localized.PCa and mCRPC, potentially reflecting the tumor's adaptation to immune system pressure through the promotion of a more immune-evasive and tumor-promoting microenvironment. In localized.PCa, a negative correlation was observed between Th2 and BIRC5, indicating that a robust Th1-type response (associated with lower Th2 levels) may aid in controlling tumor growth and dissemination at the early stages of cancer. Conversely, in mCRPC, the relationship between Th2 and BIRC5 shifted to positive, indicating the potential development of more intricate immune evasion mechanisms by tumors in advanced stages.
CD4 + T cells and CD8 + T cells are crucial in modulating tumor immune responses (Apusiga, 2023; Wang, Zhang, & Gao, 2022) In NEPC, negative correlations were observed between both BIRC5 and HMMR with CD4 + T cells, and positive correlations with Th1 cells. This pattern may reflect a combination of immunosuppression, tumor escape mechanisms, and an immune imbalance leading to a relative increase in specific subgroups (such as Th1), possibly due to the complex interplay of immune regulatory pathways involving various cytokines. Additionally, BIRC5 showed a positive correlation with CD8 + T cells in localized PCa and mCRPC, indicating the tumor cells' increased adaptability to immune pressure. In localized PCa, HMMR exhibited a negative correlation with CD8 + T cells, suggesting a link between HMMR expression and immune evasion mechanisms in the early stages of the disease. Conversely, in mCRPC, the correlation between HMMR and CD8 + T cells turned positive, potentially highlighting an increase in the complexity of the immune microenvironment as tumors progress to advanced stages, revealing a potentially aggressive tumor phenotype that may attract but also resist CD8 + T cell attacks.
Different immune-related patterns may result from various factors and interactions within the immune microenvironment, showcasing the dynamic and complex nature of the tumor immune landscape. This complexity likely results from the adaptive evolution of tumor cells, the infiltration and activity changes of immune cells, and the interactions within the tumor microenvironment. Considering the complex etiology of prostate cancer and the presence of various gene mutations at different disease stages, focusing solely on a single type of immune cell may not fully capture the immune system's role in prostate cancer progression and development. Nevertheless, the diagnostic and prognostic significance of multiple immune cells in PCa remains to be fully elucidated. These insights emphasize the necessity of personalized and stage-specific immune therapeutic strategies across different prostate cancer stages.
The regulatory mechanisms of BIRC5 and HMMR in tumors have been previously studied (Liang et al., 2020; C. Yang et al., 2017). As a protein that inhibits cell apoptosis, BIRC5 may affect the composition of immune cells in the TME by preventing the apoptosis of these cells. Additionally, HMMR's expression may impact the migration and localization of immune cells, thereby impacting their anti-tumor effects within the TME. This study explores the expression and potential roles of these two genes in PCa, yet their precise impact on cancer progression across different subgroups requires further clarification. We conducted mRNA-level analysis of BIRC5 and HMMR using mRNA second-generation sequencing data from TCGA database, which may not entirely represent the results of mRNA expression levels. Due to practical constraints, the number of obtained NEPC models was limited. However, this study included a considerable number of validation samples and comprehensive clinical data, rendering it representative and providing clues and a foundation for future research into the functions and mechanisms of BIRC5 and HMMR in PCa progression.
Future studies should use more samples to verify the correlation between the expression of BIRC5 and HMMR in different subgroups of PCa and their association with prognosis. Conducting cell or animal experiments to elucidate how BIRC5 and HMMR regulate Th cell balance and immune responses through which signaling pathways, exploring the specific mechanisms of these molecules in tumor immune regulation, to guide the development of more effective treatment strategies.