Cancer immunology is extremely complex with numerous interactions between the tumor and the host. It is time for those that treat cancer, especially surgeons, to learn more about these complex interactions. We need to know more about host immunity and immunosuppressive mechanisms which are not directly related to the disease, but caused by stress and therapy of the disease. The diagnosis of cancer initiates stress that can be very detrimental to the host immune system. Most cancer physicians (surgical, medical, and radiation oncologist) do not appreciate the impact on host cell mediated immunity (CMI) caused by cancer therapy, and definitely do not know how devastating, psychic stress is on host immunity. This communication is an attempt to bring awareness to this problem.
R. L. Elliott and J. F. Head, “Host Immunity Ignored in Clinical Oncology: A Medical Opinion,” Cancer Biotherapy and Radiopharmaceuticals, Vol. 20, 2005, pp. 123-125. doi:10.1089/cbr.2005.20.123
I. J. Elenkov, R. L. Wilder, G. P. Chrousos and E. S. Vizi, “The Sympathetic Nerve—An Integrative Interface between Two Supersystems: The Brain and the Immune System,” American Pharmaceutical Review, Vol. 52, 2000, pp. 595-638.
S. Ben-Eliyahu, “The Promotion of Tumor Metastasis by Surgery and Stress: Immunological Basis and Implications for Psychoneuroimmunology,” Brain, Behavior, and Immunity, Vol. 17, No. 1, 2003, pp. 27-36. doi:10.1016/S0889-1591(02)00063-6
M. Urosevic and D. Reinhard, “Human Leukocyte Antigen-G and Cancer Immunoediting,” Cancer Research, Vol. 68, No. 3, 2008, pp. 627-630. doi:10.1158/0008-5472.CAN-07-2704
J. L. McCoy, R. Rucker and J. A. Petros, “Cell-Mediated Immunity to Tumor-Associated Antigens is a Better Predictor of Survival in Early Stage Breast Cancer than Stage, Grade or Lymph Node Status,” Breast Cancer Research and Treatment, Vol. 60, No. 3, 2000, pp. 227-234. doi:10.1023/A:1006405504158
R. L. Elliott, J. F. Head and J. L. McCoy, “Comparison of Estrogen and Progesterone Receptor Status to Lymphocyte Immunity against Tumor Antigens in Breast Cancer Patients,” Breast Cancer Research and Treatment, Vol. 30, 1994, pp. 299-304. doi:10.1007/BF00665971
J. F. Head, F. Wang, R. L. Elliott and J. L. McCoy, “Assessment of Immunologic Competence and Host Reactivity against Tumor Antigens in Breast Cancer Patients: Prognostic Value and Rationale of Immunotherapy Development,” Annals of the New York Academy of Sciences, Vol. 609, 1993, pp. 340-342. doi:10.1111/j.1749-6632.1993.tb44024.x
P. Eschwège, F. Dumas, P. Blanchet, V. Le Maire, G. Benoit, A. Jardin, B. Lacour and S. Loric, “Haematogenous Dissemination of Prostatic Epithelial Cells during Radical Prostatectomy,” The Lancet, Vol. 346, 1989, pp. 1528-1530.
K. Yamaguchi, Y. Takagi, S. Aoki, M. Futamura and S. Saji, “Significant Detection of Circulating Cancer Cells in the Blood by Reverse Transcriptase-Polymerase Chain Reaction during Colorectal Resection,” Annals of Surgery, Vol. 232, No. 1, 2000, pp. 58-65. doi:10.1097/00000658-200007000-00009
J. Folkman, “What is the Evidence that Tumors Are Angiogenesis Dependent,” Journal of National Cancer Institution, Vol. 82, No. 1, 1990, pp. 4-6. doi:10.1093/jnci/82.1.4
Br. Zetter, “Angiogenesis and Tumor Metastasis,” Annual Review of Medicine, Vol. 49, 1998, pp. 407-424. doi:10.1146/annurev.med.49.1.407
R. Abramovitch, M. Marikovsky, G. Meir and M. Neeman, “Stimulation of Tumor Growth by Wound-Derived Growth Factors,” British Journal of Cancer, Vol. 79, No. 9-10, 1999, pp. 1392-1398. doi:10.1038/sj.bjc.6690223
S. O. Hofer, G. Molema, R. A. Hermens, H. J. Wanebo, J. S. Reichner and H. J. Hoekstra, “The Effect of Surgical Wounding on Tumor Development,” European Journal of Surgical Oncology, Vol. 25, No. 3, 1999, pp. 231-243. doi:10.1053/ejso.1998.0634
R. L. Elliott, X. Jiang, J. Phillips, B. Barnett and J. F. Head, “Human Leukocyte Antigen G Expression in Breast Cancer: Role in Immunosuppression,” Cancer Biotherapy and Radiopharmaceuticals, Vol. 26, No. 2, 2000, pp. 153-157. doi:10.1089/cbr.2010.0924
C. Sietses, R. H. Beelen, S. Meijer and M. A. Cuesta, “Immunological Consequences of Laparoscopic Surgery, Speculations on the Cause and Clinical Implications,” Langenbecks Archives of Surgery, Vol. 384, No. 3, 1999, pp. 250-258. doi:10.1007/s004230050200
E. Faist, C. Schinkel and S. Zimmer, “Update on the Mechanisms of Immune Suppression of Injury and Immune Modulations,” World Journal of Surgery, Vol. 20, No. 4, 1996, pp. 454-459. doi:10.1007/s002689900071
R. Melamed, E. Rosenne, K. Sakhar, Y. Schwartz, N. Abudarham and S. Ben-Eliyahu, “Marginating Pulmonary-NK Activity and Resistance to Experimental Tumor Metastasis: Suppression by Surgery and the Prophylactic Use of a Beta-Adrenergic Antagonist and a Prostaglandin Synthesis Inhibitor,” Brain, Behavior, and Immunity, Vol. 19, 2005, pp. 114-126. doi:10.1016/j.bbi.2004.07.004
M. Baum, R. Demicheli, W. J. M. Hrushesky and M. Retsky, “Does Surgery Unfavourably Perturb the “Natural History” of Early Breast Cancer by Accelerating the Appearance of Distant Metastases,” European Journal of Cancer, Vol. 41, 2005, pp. 508-515. doi:10.1016/j.ejca.2004.09.031
W. J. M. Hrushesky, A. Z. Bluming, S. A. Guber and R. Sothern, “Menstrual Influence on Surgical Care of Breast Cancer,” Lancet, Vol. 2, 1989, pp. 949-952. doi:10.1016/S0140-6736(89)90956-2
K. Bove, D. W. Lincoln, P. A. Wood and W. J. M. Hrushesky, “Fertility Cycle Influence on Surgical Breast Cancer Cure,” Breast Cancer Research and Treatment, Vol. 75, No. 1, 2002, pp. 65-72. doi:10.1023/A:1016543222323
D. Little, M. Regan, R. M. Keane and D. Bouchier-Hayes, “Perioperative Immune Modulation,” Surgery, Vol. 114, No. 1, 1993, pp. 87-91.
J. Wu and L. L. Lanier, “Natural Killer Cells and Cancer,” Advances in Cancer Research, Vol. 90, 2003, pp. 127-156. doi:10.1093/jnci/90.1.30
B. L. Andersen, W. B. Farrar, D. Golden-Kreutz, L. A. Kutz, R. MacCallum, M. E. Courtney and R. Glaser, “Stress and Immune Responses after Surgical Treatment for Regional Breast Cancer,” Journal of the National Cancer Institute, Vol. 90, No. 1, 1998, pp. 30-36. doi:10.1093/jnci/90.1.30
A. Taketomi, M. Shimada, K. Shiabe, K. Kajiyama, T. Gion and K. Sugimachi, “Natural Killer Cell Activity in Patients with Hepatocellular Carcinoma: A New Prognostic Indicator after Hepatectomy,” Cancer, Vol. 83, No. 1, 1998, pp. 58-63. doi:10.1002/(SICI)1097-0142(19980701)83:1 3.0.CO;2-A
H. Takeuchi, Y. Maeharo, E. Tokunaga, T. Koga, Y. Kakeji and K. Sugimachi, “Prognostic Significance of Natural Killer Cell Activity in Patients with Gastric Carcinoma: A Multivariate Analysis,” The American Journal of Gastroenterology, Vol. 96, No. 2, 2001, pp. 574-578. doi:10.1111/j.1572-0241.2001.03535.x
A. Riesco, “Five-Year Cancer Cure: Relation to Total Amount of Peripheral Lymphocytes and Neutrophils,” Cancer, Vol. 25, 1970, pp. 135-140. doi:10.1002/1097-0142(197001)25:1 3.0.CO;2-9
L. A. Fumagalli, J. Vinke, W. Hoff, E. Ypma, F. Brivio and A. Nespoli, “Lymphocyte Counts Independently Predict Overall Survival in Advanced Cancer Patients: A Biomarker for IL-2 Immunotherapy,” Journal of Immunotherapy, Vol. 26, No. 5, 2003, pp. 394-402. doi:10.1097/00002371-200309000-00002
G. Di Lorenzo, P. M. Esposito, A. Drago, P. Di Blasi, G. Candore, C. Balisteri, F. Listi and C. Caruso, “Effects of in vitro Treatment with Fluticasone Propionate on Natural Killer and Lymphokine-Induced Killer Activity in Asthmatic and Healthy Individuals,” Allergy, Vol. 56, No. 4, 2001, pp. 323-327. doi:10.1034/j.1398-9995.2001.00879.x
M. Dokur, N. Boyadjieva and D. K. Sarkar, “Catecholaminergic Control of NK Cell Cytolytic Activity Regulatory Factors in the Spleen,” Journal of Neuroimmunology, Vol. 151, No. 1-2, 2004, pp. 148-157. doi:10.1016/j.jneuroim.2004.03.003
S. Ben-Eliyahu, G. G. Page, R. Yirmiya and G. Shakhar, “Evidence that Stress and Surgical Interventions Promote Tumor Development by Suppressing Natural Killer Cell Activity,” International Journal of Cancer, Vol. 8, No. 6, 1999, pp. 880-888. doi:10.1002/(SICI)1097-0215(19990315)80:6 3.0.CO;2-Y
S. Ben-Eliyahu, G. Shakhar, G. G. Page, V. Stefanski and K. Shakhar, “Suppression of NK Cell Activity and of Resistance to Metastasis by Stress: A Role For Adrenal Catecholamines and Beta-Adrenoceptors,” Neuroimmunomodulation, Vol. 8, No. 3, 2000, pp. 154-164. doi:10.1159/000054276
N. K. Ellis, G. P. Duffie, M. R. Young and H. T. Wepsi HT, “The Effects of 16,16-Dimethyl PGE2 and Phosphodiesterase Inhibitors on Con A Blastogenic Responses and NK Cytotoxic Activity of Mouse Spleen Cells,” Journal of Leukocyte Biology, Vol. 47, No. 4, 1990, pp. 371-377.
M. M. Whalen and A. D. Bankhurst, “Effects of Beta-Adrenergic Receptor Activation, Cholera Toxin and Forskolin on Human Natural Killer Cell Function,” Biochemical Journal, Vol. 272, No. 2, 1990, pp. 327-331.
E. Rosenne, G. Shakhar, R. Melamed, Y. Schwartz, A. Erdreich-Epstein and S. Ben-Eliyahu, “Inducing a Mode of NK-Resistance to Suppression by Stress and Surgery: A Potential Approach Based on Low Dose of Poly I-C to Reduce Postoperative Cancer Metastasis,” Brain, Behavior, and Immunity, Vol. 21, No. 4, 2007, pp. 395-408. doi:10.1016/j.bbi.2006.12.002
X. P. Jiang, D. C. Yang, R. L. Elliott and J. F. Head, “Vaccination with a Mixed Vaccine of Autogenous and Allogeneic Breast Cancer Cells and Tumor Associated Antigens CA15-3, CEA and CA125—Results in Immune and Clinical Response in Breast Cancer Patients,” Cancer Biotherapy and Radiopharmaceuticals, Vol. 15, No. 5, 2000, pp. 495-505. doi:10.1089/cbr.2000.15.495
K. Greenfeld, R. Avraham, M. Benish, Y. Goldgarb, E. Rosenne, Y. Shapira, T. Rudich and S. Ben-Eliyahu, “Immune Suppression While Awaiting Surgery and Following It: Dissociations between Plasma Cytokine Levels, Their Induced Production, and NK Cell Cytotoxicity,” Brain, Behavior, and Immunity, Vol. 21, 2007, pp. 503-513. doi:10.1016/j.bbi.2006.12.006
Y. Schwartz, R. Avraham, M. Benish, E. Rosenne and S. Ben-Eliyahu, “Prophylactic IL-12 Treatment Reduces Postoperative Metastasis: Mediation by Increased Numbers but not Cytotoxicity of NK Cells,” Breast Cancer Research and Treatment, Vol. 107, 2008, pp. 211-223. doi:10.1007/s10549-007-9540-9
Y. Goldfab, M. Benish, E. Rosenne, R. Melamed, B. Levi, A. Glasner and S. Ben-Eliyahu, “CpG-C Oligodeoxynucleotides Limit the Deleterious Effects of Beta-Adrenoceptor Stimulation on NK Cytotoxicity and Metastatic Dissemination,” Journal of Immunotherapy, Vol. 32, No. 2, 2009, pp. 280-291. doi:10.1097/CJI.0b013e31819a2982
R. L. Elliott, X. P. Jiang and J. F. Head, “Reversal of Immune Suppression in Cancer by Manipulation of Tumor Iron Metabolism,” Journal of Immunotherapy, Vol. 33, 2010, p. 869.
X. P. Jiang, R. L. Elliott, B. G. Barnett and J. F. Head, “The Regulation of the Cytolytic Function Natural Killer Cells on the MCF-7 Human Breast Cancer Cell Line by Iron,” AACR Special Conference on Tumor Immunology: Basic and Clinical Advances, Vol. 1, 2010, p. 101.
R. L. Elliott, “Combination Cancer Immunotherapy “Expanding Paul Ehrlich’s Magic Bullet Concept,” In Press.