The tumor microenvironment and immune responses in prostate cancer patients

Abstract

The landscape of cancer treatment has been transformed over the past decade by the success of immune-targeting therapies. However, despite sipuleucel-T being the first-ever approved vaccine for cancer and the first immunotherapy licensed for prostate cancer in 2010, immunotherapy has since seen limited success in the treatment of prostate cancer. The tumour microenvironment of prostate cancer presents particular barriers for immunotherapy. Moreover, prostate cancer is distinguished by being one of only two solid tumours where increased T cell-infiltration correlates with a poorer, rather than improved, outlook. Here, we discuss the specific aspects of the prostate cancer microenvironment that converge to create a challenging microenvironment, including myeloid-derived immune cells and cancer-associated fibroblasts. By exploring the immune microenvironment of defined molecular subgroups of prostate cancer, we propose an immunogenomic subtyping approach to single-agent and combination immune-targeting strategies that could lead to improved outcomes in prostate cancer treatment.

Keywords: immunotherapy; molecular subgroup; personalised medicine; prostate; tumour microenvironment.

Figure 1

Immunosuppression and tumour-promoting circuitry within the prostate TME. Tumours are able to co-opt immune populations through various chemokine axes and initiate a complex interplay that facilitates tumour development. In addition to driving proliferation and survival of cancer cells through several soluble mediators, MDSCs upregulate suppressive factors that curb CTL activity while also being able to impede tumour killing through the recruitment of T_reg cells. Moreover, immature MDSCs can differentiate into either neutrophils or monocytes and subsequently M2 macrophages, all of which can further suppress CTL effector function. CAFs can additionally influence tumour immune contexture by recruiting B cells which not only support tumour growth and progression but also differentiate into immunosuppressive plasma cells. Alternatively, CAFs can instigate the differentiation of monocytes into M2 macrophages to sustain CTL inhibition. CAF, cancer-associated fibroblast; MDSC, myeloid-derived suppressor cell; CTL, cytotoxic T lymphocyte; LT, lymphotoxin; SDF-1, stromal cell-derived factor 1; ROS, reactive oxygen species; iNOS, inducible nitric oxide synthase; PD-L1, programmed death-ligand 1; S100A9, S100 calcium-binding protein A9.

Figure 2

Immunogenomic subgroups and immunotherapeutic treatment strategies for PCa. Five immunogenomic subgroups of PCa are described. The inner ring (red) indicates the immune infiltrate characterised in each subgroup to date. Distinct immune populations are present in different genomic subtypes of PCa, indicating individual immune microenvironments to consider when designing immunotherapeutic treatment approaches. The outer ring (green) indicates potential treatment strategies for each subgroup. dMMR, microsatellite unstable/mismatch repair-deficient; PTEN, PTEN-deficient; HRD, homologous recombination-deficient; CDK12, CDK12-mutated; SPOP, SPOP-mutated; ADT, androgen deprivation therapy; ICB, immune checkpoint blockade.