Immunodeficiency and cancer: prospects for correction

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Abstract

Cellular immunodeficiency is associated with human cancer. Extensive reviews on cancer of the head and neck, lung, esophagus and breast convince the author that for these diseases the immunodeficiency is reasonably well established yet the mechanisms are poorly understood. Evidence indicates that other tumors are similarly associated with cellular immune deficiency. The advent of recombinant cytokines and of antitumor monoclonal antibodies has served to focus attention toward direct tumoricidal mechanisms. As tumor antigens relating to cellular and humoral immune mechanisms are being defined and vaccine strategies are increasingly being attempted, it is critical to confront issues of the mechanism of anergy and effective immunorestoration in order to maximize the potential of cellular immune response to address these tumor antigens.

Intrinsic to this approach is the introduction of contrasuppressive therapy to alleviate the tumor-associated immune suppression. Encouraging attempts have been made with plasmapheresis, indomethacin, low-dose cyclophosphamide, anti CTLA-4, anti FAS ligand and, perhaps in the future, more judiciously applied chemotherapy.

In contrast to the popular notion that thymic involution cannot be reversed in the adult, studies from the author's laboratory indicate that in aged hydrocortisone stressed mice, a natural Type 1-cytokine mixture (IRX-2) hastens the reversal of thymic involution and promotes T-cell responses to cytokines and mitogens. Recombinant IL-1 and IL-2 by themselves, and in combination, were inactive. Similar positive effects were observed with oral zinc, zinc-thymulin and thymosin α1. The combination of a natural cytokine mixture (IRX-2) with thymosin α1 had a very large effect and increased the absolute number of peripheral T lymphocytes as measured in the spleen. In studies of combination immunotherapy in lymphocytopenic squamous cell head and neck cancer patients using IRX-2 (18 patients) and IRX-2 plus thymosin α1 (IRX-3) in IRX-2-refractory patients (7 patients), marked increases in CD45RA+ “naı̈ve” T cells (>250/mm3) were observed. These are among the first insights into how to generate T lymphocyte replacement in the adult.

These and many other experimental efforts point to ways to achieve more effective immunotherapy of human cancer in the future, particularly if tumor-induced immune deficiency can be effectively addressed.

Introduction

Cancer arises more frequently in a background of immunodeficiency [1], [2]. Leukemias and lymphomas are more frequent in children with primary immunodeficiency diseases (approximately 25% of patients). Cancer is also more frequent in patients receiving immunosuppressive therapy for transplantation (6% of patients). Patients with severe immunodeficiency associated with HIV infection have a high incidence of Kaposi's sarcoma (14%) and non-Hodgkins Lymphoma (3%).

Aging is also associated with HIV infection and AIDS is associated with cellular immune deficiency [3], [4] and an increased incidence of tumors of lung, GI tract, breast, ovary and prostate [5]. Considerable information indicates a broad spectrum of human immune reactions against the major tumors (e.g., head and neck, lung, breast, GI, ovary and cervix) as well as the more clearly immunogenic tumors like renal cell cancer and malignant melanoma [6], [7], [8], [9].

One of the most convincing pieces of evidence for human immune reactions lies in the phenomenon of tumor-associated or tumor-infiltrating lymphocytes (TALs, TILs) [10], [11], [12], [13], [14]. The presence of TILs in many tumors, particularly lung, head and neck SCC (H & N SCC), breast and malignant melanoma, have been demonstrated. Freshly isolated TILs from such tumors show poor proliferative responses to mitogens like phytohemagglutinin (PHA) and negligible cytotoxicity to autologous tumor targets cells; however, when these TILs are grown in interleukin-2 (IL-2), with or without autologous tumor cells, they expand and show preferential cytotoxicity for autologous tumor target cells. Similarly, TAL from around the tumor, from regional nodes or even from blood show similar characteristics. These observations reflect the fact that T cells of patients with cancer enter and recognize the tumor, that is, have a T-cell receptor (TCR) capable of reacting with the tumor but are paralyzed and incapable of function (T-cell anergy).

The capacity of the tumor to induce T-cell anergy is a complicated process but may involve induced alteration of the TCR [15]. The extant data indicate the presence of multiple human tumor antigens and multiple tumor-induced suppressive factors. It seems likely that the co-presentation of stimulatory and inhibitory factors contribute to T-cell anergy [16].

Other important evidence of immune reactions to cancer in the human lies in the high incidence of antibodies evident in the circulation which are reactive to tumors and in the tumor itself [17], [18], [19], [20], [21]. Tumor-specific antibodies have been described in breast cancer, H & N SCC and others. Antigen–antibody (Ag–Ab) complexes are increased in most patients, particularly with late-stage cancer [18], [22] and, in some cases, glomerular deposition of these complexes in the kidney has been demonstrated to include tumor antigens such as carcinoma embryonic antigen (CEA), Epstein–Barr Virus (EBV) or melanoma antigen. From the evidence, it would appear that humoral reactivity in human cancer is reflective of immunogenicity but does not provide an effective resistance mechanism.

In addition to the clinical demonstration of both humoral and cellular immune reactions to autologous tumors, a large body of evidence supports the definition of both serologically defined and T-cell antigens on human tumors. The advent of monoclonal antibody and Serex technologies has spawned a large number of antigens on multiple tumor types [23], [24], [25]. Similarly, a large number of T-cell antigens have been elucidated. The issue of antigenicity of human tumors is no longer in doubt, as it was in the 1970s.

For example, in malignant melanoma a series of antigens have emerged [7], [8] and a number of vaccine approaches [see Mitchell in this volume] have been initiated using melanoma cell lines with various adjuvants or autologous tumors transfected with cytokines or co-stimulating molecules like B7. Similar approaches have been initiated, including dendritic cell pulsing, to induce cell-mediated immune responses to various tumors.

Section snippets

Tumor-associated immune deficiency

The presence of antigenicity and the lack of effective immune response define the situation of tumor-induced immune subversion. Much has been written about this topic [17], [27], [29], [30], [31], [32], [33], [34], [35].

From the reviews, it would appear that for tumors like breast cancer and malignant melanoma, immune function at the time of diagnosis may be quite normal; whereas, in SCC of the aerodigestive tract (head and neck, lung and esophagus) and cervix, depressed immune functions are

Host-derived factors in immunosuppression

Immune complexes, as mentioned, are common in the circulation of patients with late stage cancer. As shown in breast cancer [32], these complexes participate in immunosuppression of T-cells. Historically, the significance of this finding has not generally been considered to be of great importance in delineating serologically defined tumor antigens nor in the immunosuppression attendant to human cancer.

Antigen–antibody complexes bind to the surfaces of Fc receptor-bearing cells like monocytes

Treatment-derived immunosuppression

Surgery is the most frequent primary treatment for cancer. Surgery and anesthesia are associated with transient suppression of the cellular immune system correlating with the degree of tissue trauma and lasting up to 3 weeks [73]. Nutritional deficiency is a compounding factor of the impact of surgery on the immune system. Radiotherapy is also suppressive for the cellular immune system and in H & N SCC induces progressive losses of CD4>CD8 T-cells which do not recover over months of observation

Prospects for correction of tumor-associated immune suppression

Advances in tumor immunology have redirected emphasis toward T-cell-mediated cytotoxicity and DTH as critical mechanisms of host resistance to cancer [6], [7], [8], [9], [10], [26], [32], [33], [34], [35], [76], [77], [78], [79], [80], [81]. The immunologic mechanisms underlying this type of resistance have been well worked out; however, only in the last decade have T-cell epitopes been demonstrated on human T-cells. Immunologic developments have focused on the TH1–TH2 paradigm as critical in

Our work on T-cell immunorestoration

Over the last 20 years we have sought to elucidate aspects of the thymus and its endocrine component, the thymic epithelial cells (TEC), in an attempt to discern immunopharmacologic strategies to reverse cellular immune deficiencies [101], [102]. These studies prompted animal studies using aged, hydrocortisone-stressed, thymicly involuted mice [103], [104], [105]. We observed that a natural cytokine mixture (containing IL-1, IL-2, IL-6, IL-8, IL-10, IL-12, GM+G CSF, TNFα+δIFN), thymosin α1,

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