Abstract
Background: Despite its widespread use, the use of prostate-specific antigen (PSA) alone as a screening biomarker for prostate cancer (PCa) leads often to unwarranted prostate biopsy, over-diagnosis, and consequently, over-treatment, because of its limited specificity. There are reports that the apoptosis inhibitor of macrophage (AIM), secreted mainly by macrophages and epithelial cells, is upregulated during inflammation and facilitates immune recognition of cancerous cells by blocking human regulator of complement activation. Objective: These controversies around the PSA utility necessitate a reexamination of its use as a screening tool. More so, despite the suggested implication of AIM in anticancer immunosurveillance, there is a dearth of information on its role in therapy response, disease progression, and clinical outcomes of patients with PCa. These inform the present study to probe the nature and role of AIM/PSA signaling in anticancer immunity and prognosis in PCa. Methods: A combination of bioinformatics-aided statistical analyses, gene function annotation, and immune infiltrate analyses, coupled with tissue staining, and function assays, namely migration, invasion, and clonogenicity assays, we employed. Results: We demonstrated that AIM and PSA expression levels are inversely correlated in PCa clinical samples and cell lines, with AIMlowPSAhigh defining PCa, compared to AIMhighPSAlow in normal samples. Concomitant aberrant PSA and significantly suppressed AIM expression levels positively correlated with high-grade disease and characterized by advanced stage prostate cancer, regardless of mutation status. We found that a high PSA/AIM ratio is associated with disease recurrence in patients with prostate cancer but is equivocal for overall survival. In addition, PSA-associated AIM suppression is implicated in the enhanced ‘metastability’ of PCa and a high AIM/PSA ratio is associated with strong castration-induced regression. CRISPR-mediated AIM knockout was associated with higher PSA expression while ectopic expression of AIM significantly attenuated the migration and invasive capability of PC3 and DU145 cells. Interestingly, compared to normal samples, we observed that AIM, biomarkers of T-cell activation and M1 phenotype markers are co-suppressed in PCa samples. Conclusion: Herein, we demonstrate that AIM/CD5L binds to PSA and that a high PSA/AIM ratio defines advanced stage PCa (regardless of mutation status), is implicated in enhanced metastability, and associated with disease recurrence, while a high AIM/PSA ratio is associated with strong castration-induced regression. More so, the ectopic expression of AIM significantly enhances the anticancer effect of Pembrolizumab and elicits an increased CD8+ T-cell count in AIMhiPSAloPDL1+ PCa cases that are respondent to Pembrolizumab treatment.
Highlights
Prostate cancer (PCa) remains one of the most frequently diagnosed male malignancy and cause of cancer-specific mortality, globally, with an incidence of 7.1% and mortality rate of 3.8% in 2018 alone, and projected increase of ~1.8- and 2.1-fold in incidence and mortality, respectively, by the year 2040 [1]
Biomedicines 2021, 9, 1225 we demonstrate that Apoptosis Inhibitor of Macrophage (AIM)/CD5L binds to prostate-specific antigen (PSA) and that a high PSA/AIM ratio defines advanced stage PCa, is implicated in enhanced metastability, and associated with disease recurrence, while a high AIM/PSA ratio is associated with strong castration-induced regression
The ectopic expression of AIM significantly enhances the anticancer effect of Pembrolizumab and elicits an increased CD8+ T-cell count in AIMhiPSAloPDL1+ PCa cases that are respondent to Pembrolizumab treatment
Summary
Prostate cancer (PCa) remains one of the most frequently diagnosed male malignancy and cause of cancer-specific mortality, globally, with an incidence of 7.1% and mortality rate of 3.8% in 2018 alone, and projected increase of ~1.8- and 2.1-fold in incidence and mortality, respectively, by the year 2040 [1]. The acquisition of a metastatic or recurrent phenotype by one in three PCa cases within 48 months from initial diagnosis, and evolution of a fifth of these into castration-resistant PCa (CRPC) by year five of follow up constitutes a clinical quagmire, especially in the context of about 14 months median survival for CRPC cases [2,3]. Coupled with this unabated disease incidence, enhanced risk of disease progression, and comparatively high mortality rate, our understanding of PCa biology and the molecular mechanisms of PCa pathogenesis and progression continue to evolve, remaining largely inconclusive. While immune-checkpoint inhibition (ICI) has triggered a paradigm shift in the treatment of malignancies, including PCa, and that emerging clinical data suggesting that cancer immunotherapy is quickly becoming a key component of contemporary clinical management of cancer, only a subset of patients exhibit durable response/remission, and ICI “has been less successful in treating prostate cancer than other solid tumors” [5,6], necessitating a better understanding of the immune landscape in patients with PCa, identification of immune-related or immune-boosting biomarkers, and discovery of potential actionable therapeutic targets
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