Unmasking the immune recognition of prostate cancer with CTLA4 blockade

Abstract

Although cancer cells can be immunogenic, tumour progression is associated with the evasion of immunosurveillance, the promotion of tumour tolerance and even the production of pro-tumorigenic factors by immune cells. Cytotoxic T lymphocyte-associated antigen 4 (CTLA4) represents a crucial immune checkpoint, the blockade of which can potentiate anti-tumour immunity. CTLA4-blocking antibodies are now an established therapeutic approach for malignant melanoma, and clinical trials with CTLA4-specific antibodies in prostate cancer have also shown clinical activity. This treatment may provide insights into the targets that the immune system recognizes to drive tumour regression, and could potentially improve both outcome and toxicity for patients with prostate cancer.

Figure 1. Immunotherapy for prostate cancer

Immunotherapy methodologies fall into two major camps: antigen-targeted immunotherapy and immunomodulatory immunotherapy. In antigen- targeted immunotherapy, tumour-associated antigens, such as prostate-specific antigen (PSA), prostatic acid phosphatase (PAP), prostate-specific membrane antigen (PSMA) and whole-cell vaccines, are introduced into the patient as a vaccine to elicit an immune response that targets the tumour. In immunomodulatory immunotherapy, the immune system, presumably primed by endogenous tumour-associated antigens, is potentiated either by blocking inhibitory immune effectors such as cytotoxic T lymphocyte-associated antigen 4 (CTLA4) and programmed cell death protein 1 (PD1) or by triggering immune activators such as OX40 and glucocorticoid-induced TNF receptor-related gene (GITR) using antibodies or agonists. This enables immune cells to become activated and to target the tumour. Conventional therapies such as radiation, chemotherapy or androgen deprivation contribute to the antigenic pool by increasing tumour cell death. Antigen-targeting and immunomodulatory immunotherapies have also been used in combinations in current clinical trials.

Figure 2. CTLA4-specific antibodies potentiate T_H cell-dependent B cell activation

Helper T (T_H) cells (T_H2 and follicular T helper cells) are activated through the co-stimulation of two signalling receptor complexes. The first signal involves the presentation of antigenic peptides on a T cell receptor (TCR) on T_H cells to major histocompatibility complex (MHC) II on antigen-presenting cells (APCs). The second signal occurs through the binding of CD28 molecules on T_H cells to the B7 molecules on APCs. T_H cells are also activated by interleukins (ILs) that are secreted by APCs. The B cell is also activated by activated T_H cells through co-stimulation. The first signal consists of the binding of antigenic peptide that is presented by the TCR on a T_H cell to MHC II expressed by the B cell. The second signal is given by the binding of a CD40 ligand on a T_H cell to a CD40 molecule that is expressed on the B cell. B cell-activating interleukins are also secreted by activated T_H cells. Activation of the B cell also requires the binding of the B cell receptor (BCR) to an antigenic peptide that is recognized by B cells. As cytotoxic T lymphocyte-associated antigen 4 (CTLA4)-specific antibodies increase T_H cell activation, T_H cells may subsequently increase B cell activation, resulting in the production of antibodies that recognize the targeted antigen.