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Journal of Clinical Oncology, Vol 26, No 9 (March 20), 2008: pp. 1562-1563 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.15.5499
Effects of Chemoradiation on Tumor-Host Interactions: The Immunologic SideDepartment of Radiation Oncology, New York University School of Medicine, New York, NY
Department of Pathology, New York University School of Medicine, New York, NY To the Editor: Drs Glynne-Jones and Hoskin have written an important article challenging the rationale for using neoadjuvant cisplatin-based chemotherapy in cancers potentially curable by concurrent chemoradiation.1 Their comprehensive review of the available clinical evidence compels the reader to abandon this investigational paradigm. We would like to suggest an additional hypothesis to explain the consistently inferior results when neoadjuvant platinum-based chemotherapy precedes radiation or a chemoradiotherapy regimen compared with a first-line approach of concurrent chemoradiation. Preclinical and clinical evidence support an immune-mediated component as part of the process of tumor cell death induced by radiotherapy and the most common chemotherapy agents.2,3 The classical morphologic classification of cell death has evolved to a more functional one, in the context of a system biology approach.4 For instance, either radiotherapy- or chemotherapy-induced apoptosis of tumor cells has been shown to carry concurrent effects on the immune microenvironment of the tumor. Either modality can cause the translocation of calreticulin from inside the cell to the cell surface, inducing a powerful "eat me" signal for dendritic and other antigen-presenting cells.2 In preclinical models, after exposure to ionizing radiation or agents like anthracyclines, etoposide, and cisplatin, dying tumor cells have been shown to release alarmin, a high-mobility group box 1 protein which provides danger signals alerting the immune system. This triggers a signaling cascade that results in effective antitumor immunity, enhancing the response to chemo- and radiotherapy.2,3 Substantial evidence in the field of autoimmunity indicates that a high load of dying cells is critical in inducing sufficient signals to antigen-presenting cells to activate the immune system of susceptible hosts.5 It is intriguing to consider whether the concomitant use of chemoradiation causes a tumor cell death that is both qualitatively and quantitatively different from that achieved by induction platinum-based chemotherapy alone, and is in fact, more likely to elicit antitumor immune responses. Concurrent radiation is likely to be a crucial ingredient. Preclinical evidence indicates that local radiation therapy has multiple effects on the immune microenvironment of the tumor, successfully harnessed when combined with specific immunotherapeutic strategies.6-9 It is conceivable that during chemoradiation, the type and intensity of the signals associated with cell death might result—in a subset of patients—in an immune-mediated destruction of the tumor. Local control would then be the result of a combination of cytocidal effects of chemotherapy and radiation as well as their collateral immune-mediated results. In this model, hosts achieving a successful immune response at the primary tumor site, particularly if it amounts to a pathologic complete response, could also derive systemic immunity, resulting in an immune targeting of distant micrometastases, with a consequent advantage in disease-specific survival.8 In addition to the intrinsic sensitivity of the cancer to the therapy, the inherited immune system of the hosts could also contribute to select the patients likely to benefit from a concurrent modality approach. A complete pathologic response to chemoradiotherapy could represent evidence for a successful in situ immunization against the tumor, as confirmed from its common association with an advantage in disease-free survival and overall survival. To further extrapolate the interplay with the immune system, a potential explanation for the disappointing effects on survival of an initial single-agent platinum-based chemotherapy can be attributed to a possible tolerogenic effect, because of inadequate bioavailability of the drug in bulky tumors typically characterized by high interstitial pressure,10 resulting in a modest cell death rate, with generation of tolerogenic signals to the immune system. Chronic exposure to low antigen dose is known to promote T cell anergy.11 Platinum compounds have immune-suppressive effects when tested at low dose in preclinical models, impairing T-cell function,12 whereas other chemotherapy agents might be devoid of such effects and can even be harnessed to enhance an immune response.13-15 To quote Glynne-Jones and Hoskin, "the small and meaningless reduction in size of the tumor" could carry the additional danger of further disabling the patient's immune recognition of the neoplastic process. In summary, a more integrated approach in clinical oncology is warranted, beyond the cytocidal scope of the currently used standard modalities. While consideration of the treatment effects on the tumor vasculature has been rapidly adopted, we find it peculiar that the inclusion of immunologic effects remains relatively neglected. Patients’ immune-genomic profile has already demonstrated to predict response to anthracycline, formally opening the door to this new dimension of cancer therapy.3 AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. ACKNOWLEDGMENTS S.C.F. is supported by Department of Defense Center of Excellence Award BC030282, by a grant from the Breast Cancer Research Foundation, and by National Institutes of Health (NIH) Grant No. 5P30CA016087-27. S.D. is supported by NIH Grant No. R01 CA113851, Research Scholar award RSG-05-145-01-LIB from the American Cancer Society, and by a grant from The Chemotherapy Foundation. REFERENCES
1. Glynne-Jones R, Hoskin P: Neoadjuvant cisplatin chemotherapy before chemoradiation: A flawed paradigm? J Clin Oncol 25:5281-5286, 2007 2. Obeid M, Tesniere A, Ghiringhelli F, et al: Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med 13:54-61, 2007[CrossRef][Medline] 3. Apetoh L, Ghiringhelli F, Tesniere A, et al: Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med 13:1050-1059, 2007[CrossRef][Medline] 4. Galluzzi L, Maiuri MC, Vitale I, et al: Cell death modalities: Classification and pathophysiological implications. Cell Death Differ 14:1237-1243, 2007[CrossRef][Medline] 5. Rovere-Querini P, Manfredi AA, Sabbadini MG: Environmental adjuvants, apoptosis and the censorship over autoimmunity. Autoimmun Rev 4:555-560, 2005[CrossRef][Medline] 6. Demaria S, Ng B, Devitt M-L, et al: Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. Int J Radiat Oncol Biol Phys 58:862-870, 2004[CrossRef][Medline] 7. Demaria S, Bhardwaj N, McBride WH, et al: Combining radiotherapy and immunotherapy: A revived partnership. Int J Radiat Oncol Biol Phys 63:655-666, 2005[CrossRef][Medline] 8. Demaria S, Kawashima N, Yang AM, et al: Immune-mediated inhibition of metastases following treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer. Clin Cancer Res 11:728-734, 2005 9. Demaria S, Formenti SC: Sensors of ionizing radiation effects on the immunological microenvironment of cancer. Int J Radiat Biol 83:1-7, 2007[CrossRef][Medline] 10. Fukumura D, Jain RK: Tumor microenvironment abnormalities: Causes, consequences, and strategies to normalize. J Cell Biochem 101:937-949, 2007[CrossRef][Medline] 11. Stamou P, de Jersey J, Carmignac D, et al: Chronic exposure to low levels of antigen in the periphery causes reversible functional impairment correlating with changes in CD5 levels in monoclonal CD8 T cells. J Immunol 171:1278-1284, 2003 12. Kouchi Y, Maeda Y, Ohuchida A, et al: Immunotoxic effect of low dose cisplatin in mice. J Toxicol Sci 21:227-233, 1996[Medline] 13. Emens LA, Jaffee EM: Leveraging the activity of tumor vaccines with cytotoxic chemotherapy. Cancer Res 65:8059-8064, 2005 14. Demaria S, Volm MD, Shapiro RL, et al: Development of tumor infiltrating lymphocytes in breast cancer after neoadjuvant paclitaxel chemotherapy. Clin Cancer Res 7:3025-3030, 2001 15. Lake RA, Robinson BW: Immunotherapy and chemotherapy–a practical partnership. Nat Rev Cancer 5:397-405, 2005[CrossRef][Medline] Related Reply
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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