James H. Finke

Molecular Mechanisms of Immune Dysfunction in Renal Cell Carcinoma

The development of an effective host immune response against neoplastic cells requires activation of T cells following recognition of tumor-associated antigens expressed on the appropriate antigen presenting cells (1). The generation of a cell-mediated cellular response typically involves CD8+ T cells that recognize peptides presented by MHC class I whereas CD4+ T cells recognize peptides presented by major histocompatibility complex (MHC) class II along with the appropriate costimulatory molecules (B7.1 and B7.2). Activation of the Th1 CD4+ cells leads to the production of cytokines such as interleukin-2 (IL-2) that provides a critical signal for clonal expansion of antigen activated lymphocytes. IL-2 signaling also upregulates expression of effector molecules (granzyme B and pore forming protein) requisite for the cytolytic function of CD8+ T cells. Another critical cytokine is gamma-interferon (IFNγ), produced by both Th1 CD4+ and a subset of CD8+ T cells, that further promotes the development of a cellular response by enhancing MHC and costimulatory molecule expression as well as by activating macrophages. Activation of T-cell immunity is dependent on normal intracellular signaling through the T-cell receptor and subsequent downstream induction of a variety of transcriptional factors that regulate gene expression of cytokines, chemokines, and receptors involved in T-cell responses (1, 2).

Immunologic Response to Renal Cell Carcinoma

Based on more than 50 years of intensive research, we have come to the understanding that the ability of a host to reject an established tumor lesion depends on whether a cellular antitumor immune response can be effectively generated and maintained in that individual (1–5). Murine tumor models readily demonstrated, that with few exceptions, the ability to confer protective antitumor immunity to naive mice is associated with the adoptive transfer of immune lymphocytes (6–10). In marked contrast, the adoptive transfer of serum from tumor-immune animals into naive mice failed to confer resistance to tumor progression (10,11). The critical nature of cellular antitumor immunity in the prevention and treatment of human malignancy has also been substantiated.

Interactions Between Chemokines and Other Cytokines in Host Response to Tumor

This chapter focuses on interactions between chemokines and other cytokines that influence the nature of the host response to tumor. The basic structural and functional features of chemokines are presented in Chapters 1 and 2 in this volume, and a general discussion of these issues is therefore not provided here. The functional repertoire of the chemokine family is, however, known to encompass much beyond its ability to promote directed migration of leukocytes (1–4). Since the cooperative potential of individual chemokines for modulating host response to tumor is likely to be heavily influenced by the functional potential of each molecule, it is appropriate to provide a brief overview of such activities.

Biology of renal cell carcinoma

This text presents the proceedings of the third International Symposium on the Biology of Renal Cell Carcinoma. Topics covered in the areas of molecular biology of renal cell carcinoma include: cytogenetics, genetic approaches to therapy of renal cell carcinoma, immunology of renal cell carcinoma - T-cell anergy, and new approaches with renal cell carcinoma - cytokines.

CD4+ T-Cell-Mediated Immunity to Cancer

A major clinical focus has been dedicated to the design and application of immunotherapies for the promotion of antitumor cytotoxic T lymphocyte (CTL) responses (1,2). In their purest form, such strategies take the form of adoptively transferred, enriched populations of tumor-reactive CD8+ T cells. These approaches have occasionally been shown to be capable of mediating the regression of lesions in cancer patients (3). However, more often, high circulating frequencies of such cancer-specific CD8+ T cells fail to provide any demonstrable clinical benefit, despite the co-application of supportive biologic response modifiers, such as interleukin-2 (IL-2) (4,5). Although it is not the purpose of this chapter to survey all of the potential mechanisms that may underlie the ineffectiveness of such immune effector cells in situ, one must consider deviation in the functional antitumor CD4+ T “helper” compartment as a major confounding variable.

Optimizing T-Cell Adoptive Immunotherapy to Overcome Tumor Evasion

The normal immune system has the capacity to develop tolerant relationships with strongly antigenic environments, including the placenta and the bacteria-laden large intestine (1–3). Such chronic tolerance is as important to the immune system as its capacity to destroy pathogens, since it is essential that the host does not reject a growing fetus or loops of bowel that house commensual bacteria. A vast array of physiological immunosuppressive factors, including interleukin (IL)-10, transforming growth factor-β (TGF-β), and cyclic adenosine 5′ monophosphate (cAMP)-elevating prostaglandins, contribute to the induction and maintenance of such tolerance, and are variously produced by T lymphocytes themselves and/or by ambient host cells such as macrophages (4–12).

Alterations in T-Cell Signaling Pathways and Increased Sensitivity to Apoptosis

Despite the presence of antigens on tumors, studies suggest that that the antitumor immune response is attenuated. Well-recognized immune dysfunction in T cells of tumor-bearing hosts is most pronounced in tumor-infiltrating lymphocytes (TIL), and is characterized by impaired proliferation and reduced cytotoxic effector function (1). Some in vivo gene expression studies suggest that in the tumor microenvironment, there is minimal induction of inflammatory responses involving the expression of IFN-γ and IL-2 mRNA,(2,3) In a subset of patients, diminished T-cell function has also been observed in the peripheral blood, which is mostly associated with reduced production of TH1 type cytokines (e.g., IFN-γ) following stimulation of peripheral-blood T cells with mitogens or anti-CD3 antibody (4).

Principles of Antitumor Immunity and Tumor-Mediated Immunosuppression

A quarter of a century ago, a series of discoveries alerted investigators to the possibility that the immune system could be successfully harnessed to cure cancer. Intratumor injection of bacterial extracts such as Bacille Calmette-Guerin (BCG) or Corynebacterium parvum proved sufficient to induce local rejection of mouse tumors, and, in some cases, led to systemic acquisition of specific antitumor immunity (1,2). Melanoma patients whose tumor nodules were injected with such bacterial adjuvants frequently experienced local tumor regressions, sometimes with downstream tumor regressions at sites of lymphatic drainage and, rarely, even distant metastases (1,3–6). At approximately the same time, it was discovered that individual melanoma patients had evidence of peripheral blood T cells that could directly kill their own tumor cells in culture, and such in vitro killer T cell reactivity sometimes correlated to spontaneous clinical remissions (7).Furthermore, with the discovery of interleukin (IL)-2 (also known as a T cell growth factor) in the late 1970s, the prospect of raising vast numbers of antitumor killer T cells for therapeutic reinfusion appeared imminent and inevitable (8).