Elsevier

Seminars in Immunology

Volume 47, February 2020, 101394
Seminars in Immunology

Review
Antibodies specific for disease-associated antigens (DAA) expressed in non-malignant diseases reveal potential new tumor-associated antigens (TAA) for immunotherapy or immunoprevention

https://doi.org/10.1016/j.smim.2020.101394Get rights and content

Abstract

Immune responses to a large number of mutated and non-mutated tumor antigens have been studied in an attempt to unravel the highly complex immune response to cancer. Better understanding of both the effectors and the targets of successful immunosurveillance can inform various immunotherapeutic approaches, which can strengthen or replace natural immunosurveillance that a tumor has managed to escape. In this review we highlight targets of antibodies generated in the context of diseases other than cancer, such as asthma, allergies, autoimmune disorders, inflammation and infections, where the antibody presence correlates either with an increased or a reduced lifetime risk of cancer. We focus on their target antigens, self-molecules abnormally expressed on diseased cells or cross-reactive with exogenous antigens and found on cancer cells as tumor associated antigens (TAA). We refer to them as disease-associated antigens (DAA). We review 4 distinct categories of antibodies according to their target DAA, their origin and their reported impact on cancer risk: natural antibodies, autoantibodies, long-term memory antibodies and allergy-associated antibodies. Increased understanding and focus on their specific targets could enable a more rational choice of antigens for both therapeutic and preventative cancer vaccines and other more effective and less toxic cancer immunotherapies.

Introduction

Immunosurveillance and elimination of cancer is an important function of the immune system. Even when tumors manage to escape immune control, the presence of immune infiltrates in the primary tumors is associated with lower recurrence rates or longer progression-free survival, suggesting continued immunosurveillance [1]. Immunosurveillance is acting on the earliest premalignant lesions and can result in one of three potential outcomes: tumor elimination, considered to be the most frequent outcome; equilibrium, where the tumor and the immune system interact over a long period of time without evidence of clinical disease; and escape, where the tumor escapes immune control and becomes a clinical disease [2]. The ability to escape from immune recognition and control is now recognized as an important hallmark of cancer [3].

A lot that is known about anti-tumor immunity is derived from the failed phase of immunosurveillance and this knowledge has led to immunotherapies designed to help the immune system regain control of the disease, establish an equilibrium or achieve complete cancer elimination [4]. These therapies, known as checkpoint inhibitors, have shown impressive results but still in a relatively small number of patients and restricted to only a few cancer types [[5], [6], [7]]. Immunoprevention is another anti-cancer immune-based strategy, still very early in development, that aims to strengthen natural immunosurveillance and lower the likelihood of cancer escape [8]. In the context of infectious diseases, prevention through vaccination has had an enormous impact on improved health around the world [9]. However, with many deadly infectious diseases under control, cancer is becoming a leading cause of death with the newest and most successful therapies available only in the most affluent countries due to their high costs. Thus, a successful effort to develop vaccines for the prevention of various cancers might result in a victory similar to the one observed over infectious diseases.

The major barrier to the development of preventative cancer vaccines has been the lack of antigens that would be predictably expressed on future tumors and against which immune responses elicited through vaccination would be safe, destroying arising tumors but not normal tissues. In this review, we highlight target antigens of antibodies that are present constitutively or elicited in immunological contexts other than cancer, such as acute inflammatory states, infections, auto-immune diseases or allergies. Some of their target antigens, to which we refer to as disease-associated antigens (DAA), could be highly appropriate for the development of safe preventative cancer vaccines or therapies because they undergo transient changes in expression and post-translational modifications similar to what is observed on malignant cells where they are considered to be tumor-associated antigens (TAA).

Section snippets

Tumor antigens recognized by the immune repertoire of cancer patients

An all-out effort using state-of-the-art cellular and molecular techniques to study immune responses in cancer patients against their tumors, resulted in the discovery and characterization of hundreds of molecules of different types recognized on tumors by human T cells and antibodies [10]. The first category of molecules are the tumor-specific antigens that include mutated neoantigens unique to each tumor [11], products of oncogene mutations such as K-ras and N-ras, or gene translocations and

Anti-tumor immune repertoire of healthy individuals with no history of cancer

T cells recognizing well-known TAA have been be found in healthy individuals who never experienced cancer. For instance, a study observed that healthy HLA‐A*0201‐positive individuals showed a similar mean frequency of CD8+ cells recognizing a tyrosinase peptide YMDGTMSQV than melanoma patients [31]. Similarly, T cells against melanA/MART-1 were found in 8 % of healthy donors, albeit 95 % were naïve compared to melanoma patients where one-third of these T cells were of the effector memory type [

Targeting DAA/TAA for cancer therapy

Targeted therapies are the focus of much research in oncology. The development of biological therapies, such as monoclonal antibodies (mAbs) and T cells that target specific tumor antigens, has given hope for improvement of survival in many cancers [123]. Anti-cancer antibodies function through various mechanisms including antibody-dependent cellular cytotoxicity (ADCC), phagocytosis (ADCP) or complement-independent cytotoxicity (CIC), which can lead to promotion of new immune responses and

Acknowledgment

This work was funded by NIH/NCI grant 5R35CA210039 to OJF.

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