Chapter Two - The Role of Neoantigens in Naturally Occurring and Therapeutically Induced Immune Responses to Cancer

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Abstract

Definitive experimental evidence from mouse cancer models and strong correlative clinical data gave rise to the Cancer Immunoediting concept that explains the dual host-protective and tumor-promoting actions of immunity on developing cancers. Tumor-specific neoantigens can serve as targets of spontaneously arising adaptive immunity to cancer and thereby determine the ultimate fate of developing tumors. Tumor-specific neoantigens can also function as optimal targets of cancer immunotherapy against established tumors. These antigens are derived from nonsynonymous mutations that occur during cellular transformation and, because they are foreign to the host genome, are not subject to central tolerance. In this review, we summarize the experimental evidence indicating that cancer neoantigens are the source of both spontaneously occurring and therapeutically induced immune responses against cancer. We also review the advances in genomics, bioinformatics, and cancer immunotherapy that have facilitated identification of neoantigens and have moved personalized cancer immunotherapies into clinical trials, with the promise of providing more specific, safer, more effective, and perhaps even more generalizable treatments to cancer patients than current immunotherapies.

Introduction

After decades of controversy, the ability of the immune system to influence cancer development and progression has now become apparent (Grivennikov et al., 2010, Mantovani et al., 2008, Schreiber et al., 2011, Shankaran et al., 2001). Two parallel lines of investigation, one focused on assessing naturally occurring immune responses to developing cancers and the other focused on immunotherapy-induced durable responses to established tumors have ultimately led to unequivocal resolution of this long-standing argument. These independent approaches have demonstrated the importance of tumor-specific neoantigens as critical targets of antitumor immune responses (Schumacher & Schreiber, 2015). Immune recognition of neoantigens has the potential to destroy developing cancers before they become clinically apparent, shape the immunogenicities of cancer cells rendering them more fit to grow progressively in an immunocompetent environment, and ultimately to facilitate the immune elimination of growing tumors when manipulated in the appropriate therapeutic manner. The concept that neoantigens may be optimal targets for cancer immunotherapy is a very old one dating back to the 1940s and steadily evolving since that time (Table 1). The evolution of this idea has undergone a dramatic acceleration with the advent and employment of next generation sequencing and computational approaches which have made it possible to predict cancer specific mutations that function as neoantigens for adaptive immunity (Gubin, Artyomov, Mardis, & Schreiber, 2015). The analyses of therapeutically active neoantigens has also led to the realization that both major histocompatibility complex (MHC) class I (MHC I) and MHC class II (MHC II) epitopes are required for effective antitumor immune responses. These developments now leave cancer immunologists and clinical oncologists poised to develop truly personalized treatment approaches against established cancers with the goal of increasing specificity and eliminating toxicity compared to the current therapies. The focus of this review is to summarize the key experimental evidence that has led to a paradigm shift in thinking about immune system–cancer interactions resulting in the current excitement over using neoantigens as tumor-specific targets for immune control of cancer.

Section snippets

Cancer Immunoediting as an Encompassing Model of Immune System–Tumor Interactions

The dual host-protective and tumor-promoting actions of the immune system on developing cancers have been codified as a process termed “Cancer Immunoediting” (Fig. 1; Schreiber et al., 2011, Shankaran et al., 2001). Cancer Immunoediting initiates after cellular transformation has occurred and intrinsic tumor suppressor mechanisms have been circumvented. In its most complex form, Cancer Immunoediting is comprised of three phases: Elimination, Equilibrium, and Escape. In the Elimination phase,

Antigenic Targets of Cancer Immunoediting

A central tenet of Cancer Immunoediting is that recognition of tumor antigens by T cells drives the immunological sculpting of cancers. Tumor antigens can be divided into three broad categories: (a) tumor-associated antigens (TAA), (b) cancer-germline/cancer testis antigens (CTA), and (c) tumor-specific antigens (TSAs) (Coulie et al., 2014, Heemskerk et al., 2013).

TAA are comprised of proteins encoded by genes encoded in the normal genome that may represent either normal differentiation

Setting the Groundwork: Genomic Approaches to Cancer Antigen Identification

Advances in next generation sequencing allowed for whole genome sequencing of cancers and a better understanding of the mutational landscape present in many cancers (Koboldt, Steinberg, Larson, Wilson, & Mardis, 2013). In 2008, James Allison and Bert Vogelstein performed in silico analysis combining breast and colorectal cancer-sequencing data with epitope prediction algorithms and hypothesized that breast and colorectal cancers accumulate unique HLA epitopes (Segal et al., 2008). They proposed

Developing Cancer Immunotherapies Based on Genomic Identification of Tumor-Specific Neoantigens

Using neoantigens for therapeutic benefit has significant conceptual advantages over the use of TAA. The former are expressed exclusively by transformed cells and therefore are similar to foreign proteins in that they are not subject to central immunological tolerance. Perhaps equally important, neoantigens are tumor specific and therefore targeting them obviates concerns about cytotoxicity toward healthy tissue. Indeed, accumulating data suggest that neoantigens are important components of

Neoantigens as Therapeutic Targets in Human Cancer

As our understanding of the dual functions of the immune system to both eliminate and sculpt the development of progressively growing tumors evolved, so too did the capacity to use the immune system as a therapeutic tool to control cancer. The recognition that tumor antigens were key to the immune system's capacity to discriminate between cancer cells and normal self formed the basis for many early clinical vaccine trials targeting TAA and subsequently CTA as antigens. While occasional

Concluding Remarks

Two parallel lines of investigation, one focused on the identification of endogenous immune responses to cancer, and the other on defining antigens that serve as therapeutically useful targets for immunotherapies, have both led to the same conclusion that tumor-specific neoantigens are ideal targets for immunotherapy. Where does the field go from here? The currently available bioinformatics approaches to identify neoantigens are clearly successful, but it is now apparent that the majority of in

Acknowledgments

We are grateful to T. Noguchi for constructive criticism and comments. R.D.S. receives research support from the National Cancer Institute (RO1 CA043059, RO1 CA190700, U01 CA141541), the Cancer Research Institute, the WWWW Foundation, the Siteman Cancer Center/Barnes-Jewish Hospital (Cancer Frontier Fund), Bristol-Myers Squibb Inc., Janssen and Stand Up to Cancer. J.P.W. is supported by a T32 training grant in hematology (5T32HL007088-40) from the National Heart, Lung, and Blood Institute.

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