Neoadjuvant sipuleucel-T induces both Th1 activation and immune regulation in localized prostate cancer

Abstract

Sipuleucel-T is the only FDA-approved immunotherapy for metastatic castration-resistant prostate cancer. The mechanism by which this treatment improves survival is not fully understood. We have previously shown that this treatment can induce the recruitment of CD4 and CD8 T cells to the tumor microenvironment. In this study, we examined the functional state of these T cells through gene expression profiling. We found that the magnitude of T cell signatures correlated with the frequency of T cells as measured by immunohistochemistry. Sipuleucel-T treatment was associated with increased expression of Th1-associated genes, but not Th2-, Th17 – or Treg-associated genes. Post-treatment tumor tissues with high CD8+T cell infiltration was associated with high levels of CXCL10 expression. On in situ hybridization, CXCL10+ cells colocalized with CD8+T cells in post-treatment prostatectomy tumor tissue. Neoadjuvant sipuleucel-T was also associated with upregulation of immune inhibitory checkpoints, including CTLA4 and TIGIT, and downregulation of the immune activation marker, dipeptidylpeptidase, DPP4. Treatment-associated declines in serum PSA were correlated with induction of Th1 response. In contrast, rises in serum PSA while on treatment were associated with the induction of multiple immune checkpoints, including CTLA4, CEACAM6 and TIGIT. This could represent adaptive immune resistance mechanisms induced by treatment. Taken together, neoadjuvant sipuleucel-T can induce both a Th1 response and negative immune regulation in the prostate cancer microenvironment.

Moving on From Sipuleucel-T: New Dendritic Cell Vaccine Strategies for Prostate Cancer

“…Comparing pre vaccination biopsies to post vaccination resection specimens, T cells had increased TCR sequence diversity in the resected prostate suggesting that Sipuleucel-T recruits T cells to the prostate ( 124 ) rather than reactivating those already in situ . Gene expression profiling showed an increase in Th1 associated genes and upregulation of immune checkpoint inhibitors including CTLA-4 and TIGIT ( 125 ). This raises the question of how long does the immune response last and whether combining with check point inhibitors will improve outcomes.…”

CD4+ T Cells: Multitasking Cells in the Duty of Cancer Immunotherapy

“…Still, some evidence can be collected in different settings. After treatment of prostate carcinoma patients with the FDA-approved Sipuleucel-T (a whole cell vaccine loaded with the fusion protein prostatic acid phosphatase and GM-CSF), decrease in the PSA serum level was positively correlated with an increased expression of Th1 (and CD8+) genes within tumor infiltrating T cells [ 133 ]. More information can be gleaned from vaccines with long peptides, which predominantly activate CD4+ T cells.…”

Novel Combinatorial Approaches to Tackle the Immunosuppressive Microenvironment of Prostate Cancer

“…PAP is an ideal prostate tumor antigen due to its prostate restricted expression and overexpression that correlates with disease progression [ 69 ]. Sipuleucel-T treatment prior to RP has been associated with intratumoral infiltration of CD3+, CD4+, FOXP3- and CD8+ T cells, IFNɣ-detectable responses and Th1-biased activation, which is important for host tumor immunity [ 70 , 71 ]. Additionally, T-cell receptor (TCR) diversity decreases in peripheral blood but increases intratumorally, indicating recruitment of T-specific clones from the peripheral blood to the prostate tumor microenvironment [ 72 ].…”

“…Additionally, T-cell receptor (TCR) diversity decreases in peripheral blood but increases intratumorally, indicating recruitment of T-specific clones from the peripheral blood to the prostate tumor microenvironment [ 72 ]. Sipuleucel-T administration has also been explored in neoadjuvant [ 70 , 71 ] and biochemical recurrent settings [ 73 ]. However, it is not FDA approved for these uses.…”