Cancer and the Immune System

Introduction

The immune system has a well-established role in human cancers. Recently, many advances in the treatment of cancer have been due, in part, to manipulation of the immune system. This module provides users with a brief overview of the history of cancer immunotherapies and includes a description of a newer hallmark of cancer – evasion from the immune system. The module concludes with an explanation of the theories of immune surveillance, immunoediting and the cancer-immunity cycle.

Brief History of Cancer Immunotherapy Approaches and Theories

Using the immune system to fight cancer and other diseases is a not a new concept. In the late 1800s, injection of Streptococcus bacteria into tumors was found by German physicians W. Busch and Friedrich Fehleisen and confirmed in 1909 by American surgeon William B. Coley, MD, to reduce tumor burden in sarcoma and melanoma patients. For Coley’s report on the early use of bacteria to treat cancer and what became known as Coley’s Toxins. Around the same time in Berlin, Paul Ehrlich developed the “side chain,” or “receptor” theory, suggesting that cells had proteins that could recognize and bind to molecules he termed “antigens.” His theory paved the way for the concept of drug-specific receptors and thus, immunotherapy (Figure 2-5). Ehrlich is responsible for postulating that a host immune defense may prevent neoplastic cells from developing into tumors in 1909.

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Several decades later in the early 1950s, Lewis Thomas first introduced the idea that the immune system could recognize cancer from neoantigens on and released by tumor cells, and Ludwick Gross later demonstrated the ability to mount an immune response against sarcoma in mice via intradermal immunization. Sir Frank Mac Farlane Burnet further developed the immune surveillance theory. Burnet and Thomas are both credited with contributing to the immune surveillance theory in cancer.

In a seminal paper published in 1975 in Nature, Argentinian Cesar Milstein, PhD, and his German post-doctoral student Georges Kohler announced the discovery of monoclonal antibodies. Recall from, the Immune System, antigens are foreign substances that induce immune response. Antibodies are proteins produced by immune cells (lymphocytes) in response to and counteracting antigens. In cancer therapy, monoclonal antibodies are laboratory-produced molecules designed to recognize and bind to a neoantigen. Monoclonal antibodies function in multiple ways. For example, some monoclonal antibodies block the link between cancer cells and proteins that may promote cancer cell growth, while other monoclonal antibodies may carry chemotherapeutic drugs directly into a cancer cell. Milstein and Kohler won the Nobel Prize in physiology and medicine in 1984 for their contribution to science.

Around the same time Milstein and Kohler were publishing data on their discovery of monoclonal antibodies, Donald L. Morton, MD, completed his study of 151 melanoma patients treated with Bacillus Calmette-Guerin (BCG). BCG is an attenuated version of a bacteria (Mycobaterium bovis) that is related to the bacteria that causes tuberculosis. Adjuvant injections of BCG directly into tumors resulted in regression of melanoma in 91% of patients. BCG was also successfully administered in non-muscle invasion bladder cancer patients and is still used today.

Cytokines are soluble proteins that are secreted by different types of cells, both immune and nonimmune, that have an impact on the immune system and are thought to be involved with immune surveillance. Cytokines are pleiotropic, meaning that each cytokine has multiple biological properties, and redundant, meaning they may share biological actions. Many different families of cytokines have been identified for potential use as cancer therapy, starting with discovery of the first interferons in the late 1950s and interleukins in the 1970s. Other cytokine families include tumor necrosis factor, transforming growth factor beta and the extended IL-1 families. Of note, in the 1980s, the first immunotherapy cancer treatment IL-2 was approved by the FDA for the treatment of kidney cancer and melanoma.

Various approaches to immune therapy continue to be developed. Adoptive cell therapy uses a patient’s own blood and tumor to fight cancer. T cells from the blood and tumor are treated in the lab with substances to help them better target the cancer cells. Chimerical antigen receptor T cell (CAR T) and tumor infiltrating lymphocyte (TIL) are two types of adoptive cell therapy. In addition to adoptive cell therapies, immune checkpoint inhibitors and cancer vaccines are at the forefront of cancer immunotherapy, with research advances changing standard practice at an unprecedented rate.

In 2018, James P. Allison, PhD, and Tasuku Honjo, MD, PhD, received a Nobel prize “for their discovery of cancer therapy by inhibition of negative immune regulation.” Their pioneering work on the CTLA-4 (Allison) and PD-1 (Honjo) immune checkpoints in the 1990s proved that these pathways act as “brakes” on the immune system. Their research showed that inhibition of these checkpoint pathways allows T cells to more effectively eradicate cancer cells. This led to the development of immune checkpoint inhibitors, the first class of immunotherapeutic drug that showed clinical benefit across a wide range of cancers, including both solid tumors and hematologic malignancies.

A Hallmark of Cancer – Evasion of Immune Destruction

In 2000, the seminal paper “The Hallmarks of Cancer” was published by Douglas Hanahan, PhD, and Robert A. Weinberg, PhD, in the journal Cell. The authors provide evidence to support a multistep progression of alterations that drive normal cells into malignant cells that can survive, proliferate and spread. Hanahan and Weinberg proposed six acquired capabilities of cancer (Figure 2-6). Briefly, these capabilities include evading apoptosis; self-sufficiency in growth signals; insensitivity to anti-growth signals; tissue invasion and metastasis; limitless replicative potential; and sustained angiogenesis. Importantly, in this manuscript published nearly two decades ago, Hanahan and Weinberg forecast that the immune system could serve as “active collaborators” in the initiation and progression of cancer (Figure 2-7).

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The original “The Hallmarks of Cancer” paper was updated in 2011. The revised manuscript “The Hallmarks of Cancer: The Next Generation” was expanded to include two emerging hallmarks: deregulating cellular energetics and evasion of immune destruction. Additionally, Hanahan and Weinberg describe enabling characteristics: genome instability and tumor-promoting inflammation (Figure 2-8).

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Typically, we think of our immune system as an ally; however, our immune system actually plays a role in promoting tumor growth. Tumor-promoting inflammation refers to early innate immune mechanisms driven by the tumor itself to promote tumor growth. One of the best described mechanisms is the role played by macrophages during early carcinogenesis in promoting angiogenesis and tissue remodeling without triggering anti-tumor immunity. This mechanism is actively promoted by the tumor through production of cytokines/chemokine and modulators of metabolic pathways (e.g., IDO and Arg1) rather than neoantigen recognition and lymphocyte involvement. In most solid tumors, various cells are found in the evolving tumor microenvironment and can contribute to inflammation (Figure 2-9)

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Hanahan and Weinberg go on to briefly describe the theory of immune surveillance and describe how some solid tumors seem to avoid detection by the immune system. Mouse models have been used to demonstrate that carcinogen-induced tumors were more likely to develop or grow more rapidly when mice were immunodeficient, especially when cytotoxic T lymphocytes (CTLs), helper T cells or natural killer (NK) cells were deficient. Several studies of human colon and ovarian tumors demonstrated that tumors with high infiltration of CTLs and NK cells had better prognosis. Evidence supporting the immune evasion hallmark continues to be published in journals across tumor sites, including, but not limited to, breast, lung, melanoma and lymphoma.

Immuno-oncology Theories – Immunoediting and Immune Surveillance

Immunoediting is a theory that describes the transformation of normal cells to clinically-detectable cancer. The theory implies that while the human immune system protects from cancer, it also drives the development of tumors that will undergo immunogenic “sculpting” and may survive immune cell attacks. Proposed by Gavin P. Dunn, MD, PhD, and Robert Schreiber, PhD, the immunoediting process consists of three phases, often referred to as the “3 Es”: elimination, equilibrium and escape (Figure 2-10).

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Elimination

Both innate and adaptive immune cells play a role in immune surveillance. In this phase, growing tumors are completely eliminated by the immune system.

Equilibrium

Some cancer cells may not be controlled by the innate and adaptive immune cells during elimination. When this occurs, the cells able to survive elimination replicate with new variants that may be more resistant to the immune response. During this phase, cancer remains clinically undetectable and is dormant. Patients whose tumors are in equilibrium may either revert to elimination or progress on to the escape phase.

Escape

In this phase, cancer cells have escaped the immune system and are replicated, leading to clinically detectable tumors. Immune escape can be facilitated through various mechanisms: the immune system may not recognize tumor cells; the cells may become resistant to immune cell attacks; or inflammation and the tumor microenvironment may lead to increased immunosuppression. The tumor microenvironment may contain many (inflamed tumors) or few (non-inflamed tumors) immune cells.

It is well established that the immune system continually scans the body for threats and then, when appropriate, mounts an immune response. This process is known as immune surveillance. The immune surveillance theory is strongly supported by the increased incidence of cancers in immunocompromised individuals. Immune surveillance is the first phase (elimination) of the immunoediting process, outlined by Dunn and Schreiber and described in more detail below.

The basis of the immune surveillance theory is that tumors produce antigens that may evoke an immune response. Tumor-specific antigens (found exclusively on tumor cells) or tumor-associated antigens (found on both tumor and normal cells but overexpressed on tumor cells) may trigger the immune system response.

When a patient’s immune system is functioning properly and able to mount appropriate responses to antigens, the patient is considered to be immunocompetent. Patients whose immune systems are not able to respond appropriately to antigens are referred to as immunodeficient or immunocompromised. Most often, cancer occurs in those without any obvious immunodeficiency, suggesting that tumor cells have adapted ways to escape immune surveillance.

Cancer-Immunity Cycle

The cancer-immunity cycle is a process initiated by the release of cancer cell antigens that concludes with the destruction of cancer cells. Daniel S. Chen, MD, PhD, and Ira Mellman, PhD, detail the steps of the cancer-immunity cycle in a manuscript published in the journal Cell Press in 2013. A summary of the steps described by Chen and Mellman is found below.

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• Step 1 – Neoantigens are released by tumors as they die off and are captured by the antigen-presenting dendritic cells, which process the antigens to produce peptides that bind to major histocompatibility complex (MHC).
• Step 2 – Peptides bound to MHC-I and MHC-II molecules are presented to T cells. CD4⁺ T cell receptors can recognize the peptide-MHC-II molecules.
• Step 3 – Effector T cells are primed and activated to respond to the tumor antigens presented. Three classes of antigens with high tumor specificity may be identified by T cells: antigens produced from mutated cells, cancer-germline genes and viral genes.
• Step 4 – Activated T cells move to the tumor site and infiltrate the tumor.
• Step 5 – Activated T cells bind to cancer cells. T cells are able to recognize cancer cells as foreign based on the antigens they released earlier, specifically binding to cancer cells through the interaction between the T-cell receptor and its cognate antigen bound to MHC-I on the surface of the cancer cells.
• Step 6 – Activated T cells kill cancer cells. T cells eliminate cancer cells by activating a series of steps that lead to cell death. The dying cancer cell releases additional cancer-specific neoantigens (Step 1) to continue the cycle and amplify the anticancer response.

As the cycle continues, more and more tumor antigens are released during cell death, thereby strengthening the immune response of the T lymphocytes. Stimulatory factors promote immunity, whereas inhibitory checkpoint proteins, such as CTLA-4 and PD-L1, work at different steps of the cycle to reduce immune activity and, in this manner, also prevent autoimmune responses. A central goal of immunotherapy is to trigger the cancer-immunity cycle without harming normal cells; thus, many immunotherapeutic agents target steps in the cancer-immunity cycle.

Video 2-1

Video 2-1: Edward S. Kim, MD, explains how drugs targeting the cancer-immunity cycle are making it into the clinic.