Oncogenic cancer/testis antigens: prime candidates for immunotherapy

Abstract

Recent developments have set the stage for immunotherapy as a supplement to conventional cancer treatment. Consequently, a significant effort is required to further improve efficacy and specificity, particularly the identification of optimal therapeutic targets for clinical testing. Cancer/testis antigens are immunogenic, highly cancer-specific, and frequently expressed in various types of cancer, which make them promising candidate targets for cancer immunotherapy, including cancer vaccination and adoptive T-cell transfer with chimeric T-cell receptors. Our current understanding of tumor immunology and immune escape suggests that targeting oncogenic antigens may be beneficial, meaning that identification of cancer/testis antigens with oncogenic properties is of high priority. Recent work from our lab and others provide evidence that many cancer/testis antigens, in fact, have oncogenic functions, including support of growth, survival and metastasis. This novel insight into the function of cancer/testis antigens has the potential to deliver more effective cancer vaccines. Moreover, immune targeting of oncogenic cancer/testis antigens in combination with conventional cytotoxic therapies or novel immunotherapies such as checkpoint blockade or adoptive transfer, represents a highly synergistic approach with the potential to improve patient survival.

Keywords: cancer/testis antigen; immunotherapy; oncogenesis.

Figure 1. Shared characteristics between germ cells and cancer cells

Germ cells and cancer cells share many features that are absent in most other cell types, suggesting that germ cell programs contribute to cancer development and progression. In addition to cancer/testis antigen expression, these characteristics include proliferation, migration, colonization and meiosis/genomic instability.

Figure 2. Oncogenic functions of cancer/testis antigens

Tumorigenesis involves acquisition of a specific set of essential capabilities (as described in the ‘Hallmarks of cancer’ by Hanahan and Weinberg”[20, 21]). These include uncontrolled growth, resistance to death (apoptosis), the potential to migrate and grow at distant sites (invasion and metastasis), the ability to induce the growth of new blood vessels (induce angiogenesis), etc. Underlying these hallmarks is genomic instability, which generates the genetic variation that accelerates their acquisition. Cancer/testis antigens confer several of these important capabilities to cancer cells, suggesting that they are directly implicated in tumorigenesis.

Figure 3. Cancer immunotherapies targeting cancer/testis antigens

The goal of therapeutic cancer immunotherapy is to reverse immune escape of tumor cells by overcoming tolerance and increasing numbers of tumor-reactive T cells. This can be accomplished by boosting existing immune responses to tumor antigens, and cancer/testis antigens have proved useful as targets due to high tumor-specificity and immunogenicity. Currently two types of cancer/testis antigen-specific immunotherapy are used: vaccination and adoptive transfer. Vaccination stimulates the patient's intrinsic immune response to cancer/testis antigens expressed by their tumor by administration of immunogenic peptides/proteins loaded on dendritic cells or in combination with adjuvants. Cancer/testis antigens are also popular targets for adoptive transfer wherein recombinant T-cell receptors specific for cancer/testis antigen epitopes are inserted into patient T cells, which are then expanded and transferred back to patients. Targeting oncogenic cancer/testis antigens in vaccination and adoptive transfer regimens may greatly reduce the risk of outgrowth of escape variants.

Figure 4. Targeting oncogenic cancer/testis antigen in combination with other therapies

A. Chemotherapy may only kill the bulk of tumor cells, leaving chemoresistant cells. Since several cancer/testis antigens have been demonstrated to inhibit apoptosis in cancer cells and lower the response to cytotoxic anti-cancer drugs, targeting cancer/testis antigens in combination with chemotherapy may be effective. B. DNA methyltranferase (DNMT) inhibitors, which have been approved for treatment of hematologic malignancies, can induce cancer/testis antigen expression in cancer cells and reverse intratumoral heterogeneity. Thus, treatment with DNMT inhibitors may boost the effect of vaccines targeting oncogenic cancer/testis antigens. C. The foremost limitation to expanding adoptive transfer of T cells to treatment of multiple types of human cancer is the need for sufficient numbers of tumor-infiltrating T cells. Vaccination with cancer/testis antigens expressed in the tumor can increase these numbers in cancer types wherein such cells are sparse. Thus, the combination of adoptive transfer and cancer/testis antigen vaccination may be beneficial. D. Tumor antigen vaccination can enhance the effect of immune-checkpoint blockade, and directing the immune response to antigens important for the tumor cells, such as oncogenic cancer/testis antigens, may further enhance the effect of this combination treatment.