Both innate and adaptive immune responses to tumors can be detected in patients and experimental animals, and various immune mechanisms can kill tumor cells in vitro. The challenge for tumor immunologists has been to determine which of these mechanisms may contribute significantly to protection against tumors and to develop therapies that enhance these effector mechanisms in ways that are tumor specific. Recent technical advances in characterizing tumor antigen-specific immune responses and data from studies of cancer patients treated with drugs that stimulate T cells have indicated that CTLs are the most important contributors to host immune defense against tumors. In this section, we will review the evidence for antitumor immunity mediated by T cells and other immune effector mechanisms.
T Lymphocytes
The principal mechanism of immune protection against tumors is killing of tumor cells by CD8+ CTLs (Fig. 1). The ability of CTLs to provide effective antitumor immunity in vivo is clearly seen in animal experiments using carcinogen-induced and DNA virus-induced tumors. It is possible that CTLs per form a surveillance function early in the development of cancers by recognizing and killing potentially malignant cells that express peptides that are derived from mutant proteins and are presented in association with MHC class I (MHC-I) molecules. Tumor-specific CTLs can be isolated from animals and humans with established tumors and, as discussed earlier, there is evidence that the prognosis of human tumors, including common types such as colon carcinomas, is more favorable when more T cells, and specifically CD8+ CTLs, are present within the tumor (see Fig. 2D). Importantly, the inability to detect functional tumor-specific CTLs in some patients may be because of regulatory mechanisms exploited by the tumor to suppress CTL responses, and new therapies that block these regulatory mechanisms lead to the development of strong CTL responses against the tumor.
Fig1. Cytotoxic T-lymphocyte (CTL) response against tumors. Tumor antigens are picked up by host dendritic cells, and responses are initiated in secondary lymphoid organs. Tumor-specific CTLs migrate back to the tumor and kill tumor cells. CD4+ T-cell responses against tumors involve similar initiating steps to generate tumor-specific helper T cells, but the antitumor effector mechanisms are different. Other mechanisms of tumor immunity are not shown.
Fig2. Lymphocytic inflammation associated with tumors. Certain tumor types more frequently have associated lymphocytic infiltrates, including medullary breast carcinoma (A) and malignant melanoma (B). Red arrows indicate malignant cells. Yellow arrows indicate lymphocyte-rich inflammatory infiltrates. Immunohistochemical staining of resected tumors can be used to enumerate different types of T cells associated with the tumor, such as an infiltrate of CD8+ T cells in a colonic carcinoma (C). The tumor cells appear blue and the CD8+ T cells appear brown. Intermediate (Int) and high (Hi) density of CD3+ T cells within the tumor, detected in this way, is associated with longer disease-free survival than tumors with low (Lo) numbers of these cell types (D). Meta-analysis of data from 200 studies of about 25,000 patients with different cancer types showed that the presence of CD8+ T cells, tertiary lymphoid structures, and M1 macrophages correlated with better prognosis, whereas the presence of M2 macrophages correlated with worse prognosis (not shown). C, Courtesy Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts. D, From Mlecnik B, Lugli A, Bindea G, et al. Multicenter international study of the consensus Immunoscore for the prediction of relapse and survival in early-stage colon cancer. Cancers (Basel). 2023;15:418.
CD8+ T-cell responses specific for tumor antigens may require cross-presentation of the tumor antigens by dendritic cells (DCs). Most tumor cells are not derived from antigen presenting cells (APCs) nor do the tumor cells usually express costimulatory molecules needed for naive T-cell activation, so they are unlikely to be able to activate naïve T cells on their own. Thus, to initiate antitumor CD8+ T-cell responses, tumor antigens have to be presented by DCs, the best APCs for trans porting tumor antigens to the T-cell zones of secondary lymphoid organs and for activating naive T cells. DCs at the site of a tumor can ingest tumor cells or their protein antigens, carry the tumor antigens to lymph nodes, and colocalize with naive CD8+ T cells. Furthermore, the DCs can deliver the ingested proteins from phagosomes into the cytosol so that they are processed by proteasomes into peptides that are then displayed bound to MHC-I molecules for recognition by CD8+ T cells (Fig. 3). This process of cross-presentation, or cross priming, is mainly carried out by the cDC1 subset of DCs, as described in earlier chapters in the context of initiating CD8+ responses to viruses. DCs also express costimulators, and these or helper T cells that are activated at the same time provide the signals needed for differentiation of naive CD8+ T cells into tumor-specific CTLs. Once effector CTLs are generated, they are able to recognize and kill the tumor cells without a requirement for costimulation.
Fig3. Activation of tumor-specific CD8+ T cells by cross-presentation. Protein tumor antigens, or the cancer cells that produce the antigen, are ingested by dendritic cells (DCs) into endocytic vesicles. The anti gens are then delivered into the cytosol, where they are processed in proteaasomes and enter the major histocompatibility complex class I (MHC-I) antigen presentation pathway, resulting in the display of tumor peptides bound to MHC-I displayed on the DC surface, along with costimulatory molecules. Naive CD8+ T cells specific for these peptide-MHC antigens can then be activated. Peptides derived from the ingested tumor antigens may also be displayed by MHC class II molecules and recognized by CD4+ T cells (not shown). APCs, Antigen-presenting cells.
CD4+ helper T cells contribute to antitumor immune responses by several mechanisms. CD4+ T-cell responses to tumor antigens are commonly found in animal models and patients with cancer, and the presence of Th1 cells, like CTLs, in human tumors correlates with good prognosis. Some studies show a therapeutic benefit of adoptive transfer of tumor antigen-specific CD4+ T cells into the host. The antitumor effects of Th1 cells may reflect their known role in enhancing CD8+ T-cell responses and activating macrophages through the secretion of interferon-γ (IFN-γ). IFN-γ can increase tumor cell MHC-I expression and sensitivity to lysis by CTLs. The importance of IFN-γ in tumor immunity is demonstrated by the finding of increased incidence of tumors in knockout mice lacking this cytokine, its receptor, or IFN-γ induced signaling molecules.
The demonstration that the numbers of different types of T cells within resected tumors correlates with the likelihood of developing metastatic disease has led to the idea that determining an immune score for cancers may be useful to assess prognosis and direct treatment options. This has been most thoroughly studied in some medical centers in cases of colon cancer, in which a score is given to tumors based on the number of CD45RO+ memory T cells and CD8+ CTLs in the margins of resected tumors. A low score predicts a higher chance for relapse, metastases, and death within 5 years compared with tumors with a high score, even when comparing tumors with no evidence of lymph node or distant metastases at the time of resection. In some studies, the immune score was found to have greater prognostic value than the histologic evaluation of the tumor. Current research is focused on expanding the use of immune scores for a wider range of tumors and broadening the analyses of resected tumors to include more subsets of immune cells by immunohistochemistry and other methods. Additional immune/inflammatory gene expression patterns of individual tumors are also being studied and may supplement immune scores.
Antibodies
Tumor-bearing hosts often produce antibodies against various tumor antigens, but the significance of these antibodies in protecting against cancers is unknown. Antibodies may kill tumor cells by activating complement or by antibody-dependent cell mediated cytotoxicity, in which Fc receptor–bearing natural killer (NK) cells or macrophages mediate the killing. However, there is little evidence that humoral immune responses against tumors have a significant effect in preventing the development or progression of tumors. Nonetheless, the presence of B cells in tumor infiltrates and the formation of tertiary lymphoid structures with germinal centers in tumors correlates with good prognosis. This may reflect a protective role for local production of antitumor antibodies or just a marker of a robust immune response that includes antitumor effector T cells. Antitumor monoclonal antibodies are used to provide passive immunity against tumors, discussed later.
Natural Killer Cells
NK cells are capable of killing many types of tumor cells and may contribute to immune surveillance against cancers. Some studies have indicated that people with defects in NK cell function or numbers caused by genetic mutations or with lower than normal NK cell numbers or activity without known genetic defects are at higher risk than the general population for devel oping certain types of virus-induced tumors. Mouse studies also have shown that genetic defects in NK cell function or depletion of NK cells by antibodies enhances tumor growth and metastases. Although these findings support a contribution of NK cells to immune surveillance, these cells usually represent only a small fraction of the inflammatory infiltrates present in most human and mouse tumors, and their role in immune eradication of established tumors is not clear.
Tumor cells become susceptible to killing by NK cells when they downregulate the expression of MHC-I or they upregulate the expression of ligands that bind activating NK cell receptors. NK cells express inhibitory receptors that bind MHC-I molecules expressed on healthy cells. As we will see later, some tumors lose expression of MHC-I molecules as a result of selection against MHC-I-expressing cells that are readily killed by CTLs. This loss of MHC-I molecules makes the tumors particularly good targets for NK cells. In addition, many tumors express ligands for the NKG2D activating receptor on NK cells, such as MIC-A, MIC-B, and ULB, and NKG2D signaling can override inhibitory signals from MHC-I binding receptors. As mentioned earlier, NK cells may be activated to kill tumor cells coated with antitumor antibodies by antibody-dependent cell mediated cytotoxicity. The tumoricidal capacity of NK cells is increased by cytokines, including interleukin-2 (IL-2), IL-15, and IL-12, and the antitumor effects of these cytokines in vivo are partly attributable to stimulation of NK cell activity.
Macrophages
Macrophages are capable of both inhibiting and promoting the growth and spread of cancers, depending on their activation state. Classically activated M1-like macrophages, dis cussed in Chapter 10, can kill many types of tumor cells. How macrophages are activated by tumors is not known. A possible mechanism is recognition of damage-associated molecular pat terns from dying tumor cells by macrophage innate immune receptors. The tumor-killing function of macrophages may be enhanced by IFN-γ produced by tumor-specific Th1 cells, CTLs, and NK cells. This may be why a large number of Th1 cells in some tumors correlates with a good prognosis. M1 macrophages can kill tumor cells by mechanisms that they also use to kill infectious organisms, including the liberation of lysosomal enzymes, nitric oxide, and reactive oxygen species. We will discuss how M2 macrophages promote tumor growth later.
The Role of Innate and Adaptive Immunity in Promoting the Development of Tumors
Although much of the emphasis in tumor immunology has been on the role of the immune system in eradicating tumors, it is clear that the immune system may also contribute to the development of some solid tumors. In fact, chronic inflammation has long been recognized as a risk factor for the development of tumors in many different tissues, especially those affected by chronic inflammatory diseases such as Barrett esophagus and ulcerative colitis. Some cancers associated with infections are also considered to be an indirect result of the tumor-promoting effects of the chronic inflammatory states that are induced by the infectious organisms. These include gastric carcinoma and lymphoma in the setting of chronic Helicobacter pylori infection and hepatocellular carcinomas associated with chronic hepatitis B and C virus infections. Although the mechanisms by which chronic inflammation can promote tumor development are not well understood, several possibilities are supported by data in rodent models.
Myeloid cells of the innate immune system are considered the most direct tumor-promoting culprits among immune cells. They may contribute to malignant transformation of cells by generating free radicals that cause DNA damage and lead to mutations in tumor suppressor genes and oncogenes. Some data suggest that cells of the innate immune system, including mast cells, neutrophils, and macrophages, secrete soluble factors that promote cell cycle progression and survival of tumor cells.
The tumor-promoting effects of the immune system are paradoxical and a topic of active investigation at present. A major problem is that the nature of the tumor-promoting immune stimuli varies among different tumors, and a cell type that pro motes some tumors may inhibit others. As a result, it has been difficult to definitively establish the most important tumor promoting mechanisms. These effects of chronic inflammation are theoretically targets for pharmacologic intervention because there is a large variety of effective antiinflammatory drugs already available. The challenge for oncologists is to achieve a beneficial balance in which protective antitumor immune responses are not compromised while potentially harmful tumor-promoting inflammatory reactions are controlled.
