Immune Suppression and Colorectal Cancer (Excerpts) Posted 11/16/2006 (MEDSCAPE.com) C. Evans; A. G. Dalgleish; D. Kumar Summary Background: Advances in immunology and molecular biology have shown that colorectal cancer is potentially immunogenic and that host immune responses influence survival. However, immune surveillance and activation is frequently ineffective in preventing and/or controlling tumour growth. Aim: To discuss potential ways in which colorectal cancer induces immune suppression, its effect upon prognosis and avenues for therapeutic development. Method: A literature review was undertaken for evidence of colorectal cancer-induced immune suppression using PubMed and Medline searches. Further studies were identified from the reference lists of identified papers. Results: Immune suppression occurs at a molecular and cellular level and can result in a shift from cellular to humoral immunity. Several mechanisms for immune suppression have been described affecting innate and adaptive immunity with suppression linked to poorer clinical outcome. Conclusions: Colorectal cancer causes direct inhibition of the host's immune response with a detrimental effect upon prognosis. Immunotherapy offers a therapeutic strategy to counteract these effects with promising results seen particularly in precancerous conditions and early tumours. This review strongly suggests that immunotherapy should be incorporated into adjuvant therapeutic trials for stage 2 tumours and be considered as adjuvant treatment in conjunction with standard chemotherapy regimes for advanced disease. Impaired NK Activity Natural killer cells are critical to innate immunity, performing an immunosurveillance function through recognition of altered or missing self on damaged, infected, or transformed malignant cells.[189] They can act against tumour initiation, growth and metastasis; suppressing tumour cells through a variety of effector mechanisms, including the perforin/granzyme-containing granule-mediated pathway, death-receptor pathway and IFN-ã-mediated pathway.[190] Patients with colorectal cancer have suppressed NK cell activity,[191-195] which is an important prognostic factor for the development of distant metastases,[192-194] and is reversed postcurative resection.[195] The modulation of NK responses is believed to occur through downregulating surface expression of the NK's activating NKG2D receptors and chemokine CXCR1 receptors.[166, 196] Conclusion This review highlights the many mechanisms whereby colorectal cancer induces immune suppression and how this relates to clinical prognosis. Suppression begins at a molecular and cellular level and can result in a fundamental shift in immune function detectable in the systemic circulation. It is apparent that tumours use many different strategies to escape host immune responses and create an environment in which tumour cells can survive and proliferate. Here, we argue that the many mechanisms deployed strongly suggest that the immune system is capable of being very effective in containing colorectal tumours. Moreover, randomized-clinical trials have reported significant clinical benefits for an autologous cell-based vaccine[19, 20] and preoperative cytokine protocols have also been reported to make a significant difference.[28, 29] We therefore propose that the case for further studies with cancer vaccine and other immunotherapy candidates is overwhelming for Dukes' B disease and should be incorporated with standard adjuvant therapies for more advanced disease. Of note is the fact that current adjuvant regimens are remarkably non-immunosuppressive and would therefore be ideal for combination studies.[214] Aliment Pharmacol Ther. 2006;24(8):1163-1177. Prof. D. Kumar, Colorectal Surgery Unit, St James Wing (Level III), St George's Hospital, Blackshaw Road, London SW17 0QT, UK. E-mail: dkumar@sgul.ac.uk Thanks to MEDSCAPE.com References: 19. Vermorken JB, Claessen AM, van Tinteren H, et al. Active specific immunotherapy for stage II and stage III human colon cancer: a randomised trial. Lancet 1999; 353: 345–50. 20. Hoover HC Jr, Brandhorst JS, Peters LC, et al. Adjuvant active specific immunotherapy for human colorectal cancer: 6.5-year median follow-up of a phase III prospectively randomized trial. J Clin Oncol 1993; 11: 390–9. 28. Brivio F, Lissoni P, Alderi G, Barni S, Lavorato F, Fumagalli L. Preoperative interleukin-2 subcutaneous immunotherapy may prolong the survival time in advanced colorectal cancer patients. Oncology 1996; 53: 263–8. 29. Brivio F, Lissoni P, Fumagalli L, et al. Pre-operative IL-2 immunoprophylaxis of cancer recurrence: long-term clinical results of a phase II study in radically operable colorectal cancer. Oncol Rep 1999; 6: 1205–7. 166. Lee JC, Lee KM, Kim DW, Heo DS. Elevated TGF-beta1 secretion and down-modulation of NKG2D underlies impaired NK cytotoxicity in cancer patients. J Immunol 2004; 172: 7335–40. 189. Hsu KC, Dupont B. Natural killer cell receptors: regulating innate immune responses to hematologic malignancy. Semin Hematol 2005; 42: 91–103. 190. Smyth MJ, Hayakawa Y, Takeda K, Yagita H. New aspects of natural-killer-cell surveillance and therapy of cancer. Nat Rev Cancer 2002; 2: 850–61. 192. Koda K, Saito N, Oda K, et al. Natural killer cell activity and distant metastasis in rectal cancers treated surgically with and without neoadjuvant chemoradiotherapy. J Am Coll Surg 2003; 197: 254–60. 193. Koda K, Saito N, Takiguchi N, Oda K, Nunomura M, Nakajima N. Preoperative natural killer cell activity: correlation with distant metastases in curatively research colorectal carcinomas. Int Surg 1997; 82: 190–3. 194. Kondo E, Koda K, Takiguchi N, et al. Preoperative natural killer cell activity as a prognostic factor for distant metastasis following surgery for colon cancer. Dig Surg 2003; 20: 445–51. 195. Espi A, Arenas J, Garcia-Granero E, Marti E, Lledo S. Relationship of curative surgery on natural killer cell activity in colorectal cancer. Dis Colon Rectum 1996; 39: 429–34. 196. Doubrovina ES, Doubrovin MM, Vider E, et al. Evasion from NK cell immunity by MHC class I chain-related molecules expressing colon adenocarcinoma. J Immunol 2003; 171: 6891–9. 214. Weiner LM, Hudes GR, Kitson J, et al. Preservation of immune effector cell function following administration of a dose-intense 5-fluorouracil-chemotherapy regimen. Cancer Immunol Immunother 1993; 36: 185–90. 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