Editorial

 

Interleukins and colon cancer

 

Tumor development is interpreted as a phenomenon escaping immunosurveillance. Furthermore, tumor tissue seems to have little immunogenic power. However, a variable proportion of lymphocytic infiltration may be identified in tumors, and colorectal cancer is an example of a tumor with considerable T-cell infiltration overall, which seems to be associated with a better prognosis (1,2). In fact, in both human gastric and human rectal cancers, infiltrating lymphocytes are predominantly of the Th1 and cytotoxic-1 T-cell types, with gamma-interferon predominating over other Th2-dependent cytokines including IL-4, which may be important for anti-tumoral immune response (3). For example: while studying these immunologic issues in human colorectal cancer, tumors expressed CCR5 -in association with its ligand: RANTES- and CXCR3 (Th1 markers) in marginal tumor infiltrates; CCR4 (Th2 marker) expression was rarer, which would indicate recruitment of Th1 cells and both CD8 and CD4+ cytotoxic T cells towards tumoral tissue (4).

The role of specific cytokines -including chemokines- in immune defense against tumor development and extension is being currently assessed by multiple studies oriented towards the design of effective immunobiologic anti-tumoral therapies. Most of them are experimental, albeit a number of therapeutic attempts in humans already exist in view of the not-so-good prospects of surgery, radiotherapy, and chemotherapy for advanced-stage tumors.

However, specific cytokines may on occasion encourage tumor growth and particularly tumor spread, as is the case with IL-1ß and TNFa, which are released for instance during surgery and may activate adhesion molecules (ICAM-1 and VCAM-1, and their ligands LFA-1 and VLA-4) at the lung's vascular endothelium, thus promoting pulmonary metastasis (5). In a study carried out in patients with colon carcinoma serum IL-6, TNFa and PCR levels were seen to correlate with prognosis in terms of tumor mass and survival (6), while IL-6 and TGFa levels, and to a lesser extent TNFa levels, were seen to correlate with quality of life (7). Regarding the liver, experimental studies have suggested that Kupffer cells may well release IL-6, IL-10 and TNFa when stimulated by carcinoembrionary antigen (CEA). This may induce ICAM-1 expression and a greater potential for neoplastic cell retention within sinusoids, thus resulting in colon carcinoma metastases to the liver (8).

Regarding cytokines, IL-2 and IL-12 are most involved in immunobiological anti-tumoral response (9). As for IL-2, its local administration in transplanted colon carcinoma induced a macrophage response with tumor necrosis, while systemic administration had no effect other than notable adverse events (10). Other authors identified a rejection of specific colon tumors in mice following vaccination using dendritic cells loaded with anti-idiotype 3H1 antibodies (which mimics carcinoembrionary antigen, CEA). This is consistent with the induction of antigen-specific CD8+ T cells that may express IL-2, gamma-interferon, and TNFa (11). One study attempted immune therapy using IL-2-activated lymphocytes from the excised tumor in patients undergoing hepatectomy for colon carcinoma metastases, together with a systemic infusion of IL-2. Besides side effects, only a small percentage of patients responded during follow-up for 5 years (12).

In contrast, many positive results have been obtained with IL-12, as well as with IL-23 and IL-27, both of them belonging in the family of the former cytokine (13,14). Indeed, IL-12 is a heterodimeric cytokine primarily released by antigen-presenting cells (macrophages, dendritic cells, and B lymphocytes), which promote proliferation and activation of NK and cytotoxic T cells. The anti-tumoral mechanism of action of IL-12 is not clearly understood, but seems to depend on the activation of these cells in addition to their anti-angiogenic and angiostatic effects. Considering also its toxic effects when systemically administered, vectors -particularly adenoviral- are being used to deliver this cytokine within the tumor or tumor-invaded tissue, thus avoiding systemic effects. For example, IL-12 gene transfection to an adenoviral vector in the mouse liver provided protection against primary and metastatic tumors. Furthermore, the effect was seen to be mediated by NK cells, which were severely activated regarding cytolitic activity and gamma-interferon production, with the latter being seemingly a major mediator of anti-tumoral protection. Adoptive transference of NK cells from previously transfected mice similarly provided protection against colorectal cancer metastasis to the liver (15). Another experiment in rats with multiple experimental colon cancer metastases to the liver included the intraportal injection of IL-12 in association with a retroviral vector, which resulted in significant reduction of tumor bulk, together with neoplastic tissue infiltration by CD8+ and NKT T cells; the latter's anti-angiogenic effects were highlighted (16). Intralesional inoculation of an HSV mutant for immunogenesis in an experimental colon tumor resulted in a local immune response that was increased by the local or systemic administration of recombinant IL-12, with a complete regression of inoculated tumors and metastases in 67 and 79%, respectively, of animals, which opens up new research perspectives into the treatment of metastatic disease (17). An oligodeoxynucleotide with immunogenic effects (CpG ODN) induced necrosis and lymphocytic infiltration in experimental colon tumors; mouse survival increased, and the expression of specific cytokines such as IL-6 and GMC-SF, as well as the expression of a number of chemokines (CXCL1, CCL2, and CCL3), which may modulate tumor growth by affecting angiogenesis, immune response activation and/or cell proliferation, was demonstrated (18). NK-cell activation has also been studied with the administration of autologous HSPs (heat shock proteins) from patients with colorectal cancer, which increase IL-12 production and exert cytotoxic effects (19).

Other studies (20) show how intradermically inoculated murine colon tumors are eradicated by the intralesional administration of IL-12-producing dendritic cells (using "in vitro" transfection with adenoviral vectors); this seemed to be mediated by CD8+ T cells, but CD4+ and NK cells, which are stimulated to release gamma-interferon as an anti-tumoral mediator, were also seen to play a role. This effect increased upon the systemic administration of anti-CD137 (4-1BB) monoclonal agonist antibodies, as CD137 is an antigen of both activated T cells and NK cells. Regarding this synergic effect of IL-12 and anti-CD137 agonist antibodies, other experimental studies (21) demonstrate that NK cells play a vital role, as through gamma-interferon production they induce the activation and expansion of dendritic cells, which deserves investigation in relation to anti-tumoral immune therapy.

In a human Phase I trial, intratumoral administration (for primary or metastatic liver tumors) of an adenoviral vector coding for human IL-12 genes increased tumor infiltration with T lymphocytes (CD4 and CD8+), albeit only a moderate antitumoral effect was achieved, which was somewhat larger for primary tumors (22).

In this issue of our Journal, Coca et al. (23) present a study in rats with experimental colon cancer where tumor frequency and bulk were smaller in rats treated before tumor inductor administration by intraperitoneal IL-12 injection, which they associate with a higher density of NK cells within infiltrates. Concurrent IL-2 administration was not protective, possibly -as the authors themselves state- because of the smaller IL-12 dose that was administered to the combination therapy group as a result of side effects. In this respect, the option of directed immune therapy using vectors to facilitate higher drug concentrations locally, with the result of fewer systemic adverse events, should again be offered.

A. Caro-Patón Gómez

School of Medicine. Service of Digestive Diseases.
Hospital Universitario Río Hortega. Valladolid, Spain

 

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