The immune system not only defends against the immediate consequences of infection with pathogens, but may also help in warding off cancer. As we have seen, the adaptive immune system is purged of many self-reactive B and T cells by negative selection. Self-reactive lymphocytes that escape this process are usually silenced because they are not provided with the appropriate (co)stimulatory signals. Conditions that lead to severe immunosuppression, such as a genetic lesion in the RAG somatic recombination machinery or immunodeficiency caused by infection with HIV, confer an increased risk of cancer, not only for cancers caused by transforming viruses but also for those elicited by carcinogens. This observation establishes a role for the immune response in keeping precancerous cells in check.

Recall that B and T cells require activation not only via their antigen-specific receptors, but also by a second, co-stimulatory signal (e.g., engagement of CD28 on T cells). Withholding of this co-stimulatory signal silences, or anergizes, any self-reactive lymphocyte that escaped deletion in the course of T-cell selection. Because tumor cells are exceedingly similar to the progenitors that give rise to them (see Chapter 24), with only those few mutations (“driver mutations”) required to cause cancer, it is not immediately obvious how immune recognition aids in the eradication of (pre)malignanT cells before they have chance to grow into larger tumors. Nonetheless, somatic mutations—even those that are adventitious and do not directly contribute to causing cancer—can create so-called neo-antigens in the developing tumor cell that may be recognized by antigen-specific receptors. Chemical mutagens, as experienced by heavy smokers who expose their lungs to tobacco products, not only cause mutations in genes that then drive tumorigenesis, but also cause mutations in other genes (passenger mutations), providing a rich spectrum of altered gene products to which the developing immune system was never exposed. If there is no immune tolerance for these mutagen-induced neo-antigens, they may serve as targets for recognition by the host’s immune system.

Often the deregulation of gene expression that accompanies a transformed phenotype results in re-expression of differentiation antigens characteristic of a much earlier developmental state. If these differentiation antigens were expressed at a stage of development when the immune system had not yet fully matured, immune tolerance for such differentiation antigens may not have been established. These antigens may therefore be targets for immune recognition. Finally, the levels of certain gene products may no longer be properly regulated in cancer cells and may begin to exceed a threshold required for immune recognition, notwithstanding the fact that they are proteins normally made by the host, albeit at much reduced levels.

In summary, because cancer can be considered a disease caused first and foremost by mutations, whose effects are modified by epigenetic events (see Chapter 24), there is the potential for immune recognition of cancer cells. Furthermore, in much the same way that an immune response against a virus or a bacterium can result in the outgrowth of variants that are no longer recognized by the immune system, selective pressure exerted by the immune system may also lead to variants of cancer cells that have lost expression of a possible tumor antigen. For example, many colon cancers show reduced levels, if not complete loss of expression, of class I MHC products, and are thus rendered invisible to cytotoxic T cells.

The tumor microenvironment is composed of stromal cells: fibroblasts and myeloid-derived cells, including macrophages. Lymphocytes are known to invade tumors, as do neutrophils. The interplay between tumor cells and the microenvironment in which these cells reside can create immunosuppressive conditions that preclude a successful anti-tumor immune response, even if the tumor cells themselves are sufficiently antigenically distinct to be recognized as such. Important players in establishing an immunosuppressive environment are molecules now referred to as immunological checkpoints, such as CTLA4, the expression of which increases as T cells undergo full activation and maturation. Normally, CTLA4 would play a role in terminating an immune response, but its expression on tumor-specific T cells would compromise their anti-tumor activity. Moreover, the thymus and peripheral lymphoid compartments produce Treg cells, which are capable of suppressing the activity of other T cells. An abundance of Treg cells would keep other T cells from attacking a tumor. By the same logic, these Treg cells may keep potentially self-reactive T cells in check as a means of preventing the onset or reducing the severity of autoimmune disease.

Two key inhibitors of immune responses are PD-1 on T cells and PD-L1 on T-cell targets. This pair of proteins inhibits T-cell function. A spectacular breakthrough in the treatment of cancer is the use of antibodies that target the inhibitory CTLA4 and PD-1 proteins. Some 30–50 percent of patients with metastatic melanoma, refractory to other forms of therapy, respond to treatment with these antibodies, which has resulted in complete remissions and even cures. Similar approaches are under way to treat different forms of lung and renal cancer. Treatment with anti-CTLA4 apparently broadens the repertoire of cytotoxic T cells capable of recognizing tumor antigens as well as suppressing the activity of Treg cells. Treatment with anti-PD-1 enhances |T-cell recognition of tumors. It is perhaps ironic that smokers with the heaviest exposure to tobacco products may benefit the most from these forms of treatment because of the high mutational load in their cancers.