Cancer researchers can almost feel the ground rumble beneath their feet as they walk through their clinics and laboratories. A veritable explosion of information has radically altered the way we think about cancer, and has introduced new concepts about treating or preventing this dreaded set of diseases. Traditional approaches such as surgery, radiation therapy, and chemotherapy retain their important roles as strategies to extirpate, lethally irradiate, or specifically destroy malignant cells. However, much has been learned about the ways malignancies functionabout the intracellular signaling, or "wiring" mechanisms that initiate or promote growth on a background of defined changes in genetic structure. Such insights have led to very important new treatment strategies directed against key proteins such as c-kit, c-abl, HER2/neu, CD20, and the epidermal growth factor receptor. As more pathways and nodal junctions are identified, it is likely that new treatments will continue to emerge for many cancers.
Interactions between cancers and their host environments offer new opportunities for therapy based on improved understanding of the nature of these interactions and the mechanisms that govern them. It is increasingly appreciated that malignant cells create tolerant neighborhoods in which they can function with limited interference. Cancer cells recruit host blood vessels, co-opt regional fibroblasts, and shape the local immune response to permit the essential conditions for their survival and success. Malignancies must receive nutrients, must evade destruction via host immune recognition, and must be able to locally invade and disseminate to distant sites. Understanding the mechanisms by which tumor cells manipulate the immune response remains an important challenge, but much has been learned. In this series of articles, entitled "Beyond Neutrophil Recovery: Manipulation of the Tumor Microenvironment by GM-CSF to Control Cancer," the clinical implications and exploitation of this information are discussed in considerable detail.
A number of factors influence the immune response to autologous tumors. A recent provocative article by Shankaran and colleagues has revived and modified the old concept of immune surveillance, providing new evidence that the immune response to autologous tumors is "shaped" during the evolution of the tumors. In this paradigm, autoreactive T cells are actually quite effective in identifying immunogenic tumor antigens; cells bearing such antigens are eliminated but variant tumor cells lacking these antigens survive. Through successive iterations of this process, the tumor cells that finally emerge are conditioned by these ordeals to be poorly immunogenic and superbly well adapted to survive the rigors of a vigorous and effective immune response. These battle-hardened tumor cells express few, if any, potent immunogens, and may elaborate factors that actively inhibit the immune response. For example, T-cell activation may be thwarted through the tumor cell-directed degradation of the T-cell receptor zeta chain. Alternatively, the amplitude of the T-cell response can be dampened through tumor cell production of transforming growth factor-beta or skewed through the secretion of Th2 cytokines such as interleukin-10 to inhibit the establishment of an environment conducive to cytotoxic T lymphocyte activation. These factors underscore the difficulties that are inherent to manipulating the host immune response toward an effective antitumor outcome. The contribution by Joyce Ohm and David Carbone elegantly reviews the phenomenon of immune dysfunction in cancer patients and shows how tumors can interact with the host microenvironment to produce a substance (in this case vascular endothelial growth factor) that produces immune inhibition by interfering with dendritic cell function. The elucidation of these and other important mechanisms has permitted the development of new treatment strategies, some of which employ drugs that already are in the therapeutic armamentarium.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) is one such drug. Originally developed to accelerate neutrophil recovery following myelosuppressive chemotherapy, GM-CSF also accelerates the recovery of mononuclear phagocytes and manipulates the functions of these cells in a variety of ways. For example, GM-CSF is a growth factor that participates in the in vitro expansion of dendritic cells; it is likely that this cytokine has equivalent effects in the in vivo setting. The contribution by Edmund Waller, Hilary Rosenthal, and Sagar Lonial illustrates the importance of having a sufficient number of dendritic cells in the setting of allogeneic bone marrow transplantation. They hypothesize that the improved outcomes in patients receiving more of the right type of dendritic cells facilitates the graft-vs-tumor effect thought to underlie much of the benefit of allogeneic bone marrow transplants.
Dendritic cells function as the key tumor antigen processors and initiators of adaptive antitumor immune responses. Not surprisingly, it is increasingly appreciated that there are multiple dendritic cell subpopulations, with defined functional differences based on cell of origin, state of differentiation, and local environmental factors. Clinical descriptions of this specialization are urgently needed in order to home in on the subpopulations that require immunologic manipulation. Richard Essner provides such descriptions in his contribution. He uses intraoperative lymphatic mapping and sentinel lymphadenectomy to isolate and study sentinel lymph nodes in patients with melanoma. Using reverse transcription polymerase chain reaction (RT-PCR) analysis he defines differences in dendritic cell expression of costimulatory molecules in sentinel nodes as compared with nonsentinel nodes. This provides important information regarding the need to overcome tumor-related immunosuppression at the site of primary tumors, but perhaps also in draining lymph nodes where the process of antigen presentation occurs.
A large body of research indicates that GM-CSF promotes the process of antigen presentation by antigen-presenting cells such as monocytes, macrophages, and dendritic cells. Numerous investigators have shown that immune responses to autologous tumors are facilitated by the elaboration of high concentrations of GM-CSF at tumor sites. Although there are differences depending upon the experimental systems employed, GM-CSF is the cytokine that most consistently promotes effective antitumor immune responses in animal model systems. Studies that test these concepts in human clinical trials are being performed. Even as these clinical studies accrue patients, much work remains before we will fully understand the mechanisms by which GM-CSF exerts these effects. Many different mechanisms may be in play; GM-CSF promotes a Th1 cytokine secretion profile at tumor sites, thus attacking tumor-derived immunosuppression and promoting the generation of productive, cytotoxic T lymphocytes. GM-CSF promotes phagocytosis, alters the expression and function of immune costimulatory molecules, and also reverses immunosuppression. Accordingly, it is possible that treatment with GM-CSF could modify the tumor microenvironment to favor the development of an effective antitumor immune response. In an accompanying article, Evelien Bodar, Jan Buter, Tanja de Gruijl, Elsken van der Wall, and Herbert Pinedo present intriguing data suggesting that adjuvant chemotherapy incorporating GM-CSF is associated with a favorable clinical outcome compared with similar chemotherapy without the use of the cytokine. While many possible explanations exist for this observation, the authors reasonably speculate that the immune modulatory effects of GM-CSF may be responsible for this observation. These preliminary observations will be formally tested in a randomized phase III clinical trial. Finally, Lynn Spitler describes, in her contribution, her experience using GM-CSF as adjuvant therapy for patients following the resection of high-risk melanoma.
Threads of information are slowly being woven together to create a tapestry of understanding regarding the ways in which the host environment can be subtly altered so it is inhospitable for tumor growth. These threads interconnect in surprising ways: a cytokine that accelerates neutrophil recovery also promotes antigen presentation by dendritic cells, while a molecule that promotes angiogenesis inhibits dendritic cell function. By snipping some threads and strengthening others a pattern that is fundamentally antagonistic to tumor growth is emerging. The challenge before clinical researchers is to learn how to translate this understanding into improved therapy. The rumbling under our feet does not mean that we are about to be swallowed up, but rather is notice that opportunity awaits and we had better get moving.