Understanding the Immune System, Mechanisms of Suppression in Cancer

Understanding the Immune System, Mechanisms of Suppression in Cancer

Speakers at the Pre-Annual Meeting Education Session, “The Immune System and Cancer,” on June 2, discussed the nuts and bolts of and current thinking about immunology and cancer and the implications for future research and therapy.

Dr. Zihai Li
Zihai Li, MD, PhD, of the Medical University of South Carolina, presented “The Structure and Organization of the Immune System”; Justin Kline, MD, of The University of Chicago Hospital, discussed the “Basic Principles of Tumor Immunology”; and session chair Howard L. Kaufman, MD, FACS, of Rutgers Cancer Institute of New Jersey, outlined the “Mechanisms of Immune Suppression.”

In his presentation, Dr. Kaufman noted that 1984 Nobel Prize winner Niels Jerne, MD, predicted in 1969 that immunology would be completely solved within the following 50 years. “It is very interesting that as we approach the 50-year mark, we are understanding a lot more about immunology.”      

Breaking Down the Immune System

In his discussion about the structure and organization of the immune system, Dr. Li said that “immunity is balanced by tolerance to achieve homeostasis, and all cancers share the hallmark of immune evasion via multiple tolerogenic ways.” The goal of cancer immunology is to prevent and cure cancer by “tipping the balance towards immunity in a tumor-specific way,” he said.

In his look at the “big picture concepts” of the immune system, Dr. Li said that understanding the structure and organization of the immune system requires an appreciation of the differences between innate immunity and adaptive immunity, the principles of immune recognition, and the differences among the key immune cells: T cells, B cells, and dendritic cells.

Innate immunity, he said, is activated by germline encoded pattern-recognition receptors, and it dictates adaptive immunity. Antigen receptors of T and B cells are generated by somatic gene rearrangement, Dr. Li explained. T cells, developed in the thymus, include two major subsets: CD4 and CD8. T-cell receptors are highly polymorphic and, with major histocompatibility complex (MHC) molecules, recognize antigenic peptides. B lymphocytes develop in the bone marrow and include two major subsets: B1 and B2 cells. The B-cell receptors, however, recognize naked antigens and differentiate into plasma cells to produce antibodies of isotypes.

Dendritic cells are the “most potent cells” in cross-presenting exogenous antigens to MHC I and II molecules and increase expression of MHC I and II upon activation, he said. These cells express high levels of pattern recognition receptors, co-stimulatory molecules, and inhibitory molecules, including immune checkpoints. They have high motility and migration potential from the peripheral organs to lymphoid tissues and exhibit specialization of function over time. In other words, they can shift from an antigen-capturing mode to a T cell–sensitizing mode, which is crucial for immune regulation, Dr. Li said.

Detailing Tumor Immunology

In his presentation, Dr. Kline noted that the immune system, which developed to fight infections, can also recognize and kill cancer cells. The antigens in the form of mutated or overexpressed proteins that are expressed by cancers are seen as foreign to T cells. However, even though immune responses are generated against cancer in some patients, these responses are often suppressed and ineffective.

Each step of the cancer-immunity cycle requires coordination of numerous factors that are both stimulatory and inhibitory in nature, Dr. Kline explained. Stimulatory factors promote immunity, but inhibitors help keep the process in check and will reduce immune activity and/or prevent autoimmunity. Immune checkpoint proteins, such as CTLA4, can inhibit the development of an active immune response by acting primarily at the level of T-cell development and proliferation. These are distinguished from immune factors such as PD-L1, which can have an inhibitory function that primarily acts to modulate active immune responses in the tumor bed.

One hypothesis undergoing analysis is that cancer immunogenicity relies on genetic changes that drive tumorigenesis, he said. Some cancers driven by viruses may have high antigenicity, whereas cancers driven by oncogene activation/tumor suppressor inactivation have low antigenicity.

Examining Immune Suppression       

Dr. Kaufman outlined the mechanisms of suppression in his presentation. “We know that the immune system uses a series of molecular, soluble, and cellular factors to regulate the responses. Cancers have used these pathways to promote their own survival and progression, and targeting these suppressant pathways is an important strategy. The future will be not only looking at how to block some of these suppressant pathways to turn the immune system back on but also combining it with other elements that turn the immune system on in the first place.”

Suppression of the immune response originates with dendritic cells. These cells activate T cells by a “complex molecular mechanism where the peptides are presented by the MHC molecules and are recognized by T-cell receptors, and these T cells can differentiate into various types. For example, Th1, which is very good at clearing viral infections and good at clearing some cancers as well, can become a Th2 type cell that helps regulate B-cell function and antibody production that can effectively deal with bacterial-type infections but is not so good with cancer,” Dr. Kaufman said.

These dendritic cells also produce many molecules and soluble factors, which can influence the response. One of the signals involved in getting the immune system activated is believed to originate from these soluble factors, such as cytokines and chemokines that are released and can either directly or indirectly influence the immune response.

The immune response can be modulated at the molecular level, by soluble factors, and at the cellular level. “This is critical because all of these suppressant mechanisms seem to be operative,” explained Dr. Kaufman. “But cancer has developed some really sly mechanisms for dysregulating these immune suppressant features.” Cancer utilizes suppressive pathways to promote tumor cell survival and cancer progression, and “targeting these suppressive pathways is an important strategy to improve immunotherapy,” he said.

One target for restoring immunity is regulatory T cells. Recent research has found that tumor-associated macrophages have a dual effect in cancer immunity, including stimulating an anti-tumor response. However, in the setting of hypoxia—and possibly with other cytokines such as interleukin (IL)-10—the macrophage will take on a different phenotype, a pro-tumor macrophage, which can lead to a chronic inflammatory situation where angiogenesis is stimulated and tumor growth is promoted, he said.

Myeloid-derived suppressor cells, which have been widely discussed, produce IL-10 and inhibit “all the kinds of cells you would want to inhibit to get a good immune response. Instead they tend to favor the generation of regulatory T cells in a more Th2 type or M2 type macrophage response.”

A variety of approaches are currently in drug development that will target these M2 macrophages or the myeloid-derived suppressor cells, he said, adding that he anticipates more research targeting the macrophages.

A variety of cells are involved in innate immunity and in adaptive immunity, and some, such as T cells and natural killer T cells, are at the intersection of both. “Many of these, if not all of these, have been implicated in cancer,” Dr. Kaufman said. “There is a lot to be learned from these cells, and a better delineation of their role in cancer and understanding how we can target these cells to get the right complement is going to be an important area to overcome immune suppression in cancer.”

Many soluble factors are associated with tumors. Some may favor clearance of tumors, such as interferon-gamma. A number of proinflammatory cytokines, however, have been implicated as having a negative effect and promoting tumor growth, such as IL-10, transforming growth factor (TGF)-ß, VEGF, IL-35, and IL-23, he said. The way some factors, such as granulocyte macrophage colony-stimulating factor, work is still not clearly understood, Dr. Kaufman said.

IL-10 plays a complex role in cancer. It is typically assumed to be a suppressant cytokine that shuts down the immune system, he said. But recent reports suggest that under certain situations IL-10 may promote T-cell responses and may be beneficial in treating cancer. In secondary lymphoid organs, Dr. Kaufman explained, IL-10 inhibits the cross-presentation of tumor-associated antigens (TAA) to T cells and favors the development of regulatory T cells with powerful immunosuppressive functions.

By contrast, high levels of IL-10 within the tumor microenvironment may favor immune-mediated tumor rejection by enhancing cytotoxicity and migration of cytotoxic T lymphocytes.

“One might hypothesize that IL-10 effects on the anticancer immune response can be different depending on the site of IL-10 production. In particular, although IL-10 overexpression within the tumor microenvironment might be beneficial for cancer immune rejection, an IL-10-dominant cytokine profile in secondary lymphoid organs likely hinders the adaptive immune reaction toward TAA, thus compromising the secondary immune response,” he said.

Dr. Kaufman believes that these considerations may have “profound implications in the design of the next generation of anticancer immunotherapeutic strategies.”

The cytokine TGF-ß is being scrutinized for drug development, according to Dr. Kaufman. TGF-ß has many effects, not just on the immune system but also on angiogenesis and inflammation, and it can impact metabolic functions in the host. Targeting TGF-ß may be problematic, he explained, but a variety of approaches can be used to do this, some of which are in clinical development.

– Kathy Holliman