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Journal of Clinical Oncology, Vol 26, No 27 (September 20), 2008: pp. 4369-4370 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.17.6149
Ectopic Lymph Nodes Within Human Solid TumorsAnatomic Pathology and Cutaneous Oncology, H. Lee Moffitt Comprehensive Cancer Center, Tampa, FL It is well accepted that growing, human solid tumors are infiltrated by immune cells. The literature is replete with information characterizing the nature of these infiltrating host cells in a wide variety of distinct tumor types. In particular, the notable presence of in situ lymphocytes and antigen-presenting dendritic cells has provided evidence that certain human tumors can be recognized as foreign and elicit an immune response in patients with cancer. Possibly with the exception of melanoma, the prognostic value of the presence of tumor-infiltrating immune cells in patients with cancer is the subject of much debate. The basic observation has, in part, triggered a notable effort to develop and use immune-based treatment strategies in cancer, which include vaccines, adoptive transfer of tumor-reactive T cells, immunostimulatory biologic agents (such as recombinant cytokines and cytosine-phosphate-guanosine oligodeoxynucleotides), and molecules known to unleash functionally reactive T cells (eg, anti–cytotoxic T lymphocyte 4; anti–programmed death-1). In their article in this issue of Journal of Clinical Oncology, Dieu-Nosjean et al1 have retrospectively identified ectopic lymph node or tertiary lymphoid structures within human non–small-cell lung cancer (NSCLC) specimens and demonstrated that there is a correlation of their cellular content with clinical outcome. The authors have termed these structures tumor-induced bronchus-associated lymphoid tissue (Ti-BALT), which seem to be follicle-like and contain germinal centers, similar to those in secondary lymphoid follicles of lymph nodes. Of interest, the investigators demonstrated that the density of DC-Lamp+, mature dendritic cells within these structures is a predictor of long-term survival within their selected lung cancer patient population. This finding suggests that Ti-BALT have clinical relevance and participate in the host's antitumor immune response. The authors’ further observation that a low density of tumor-infiltrating CD4+ and T-bet+ T lymphocytes are present in tumors poorly infiltrated by DC-Lamp+ mature dendritic cells seems to provide additional supportive evidence for the prognostic importance of an adaptive immune reaction to a solid tumor. The concept of ectopic lymph nodes or tertiary lymphoid structures within solid tumors is becoming appreciated and is now further developed by Dieu-Nosjean et al1 in the context of lung cancer, the most common and one of the deadliest forms of human cancer. The formation of extranodal tertiary lymphoid follicles and lymphoid cell aggregates has been already noted in nonmalignant conditions,2,3 particularly in the settings of autoimmune disease (eg, rheumatoid arthritis) and chronic inflammation.4-6 There has been some earlier suggestion of the existence of similar structures in solid tumors as well. As examples, it has been reported in murine tumor models that dendritic cells genetically modified to secrete the potent molecule secondary lymphoid tissue chemokine/C-C motif ligand-21 can produce lymphoid cell aggregates and, importantly, prime naïve T cells extranodally within a tumor mass, resulting in the generation of tumor-specific T cells and subsequent tumor regression.7 This approach is now being extended to the clinic in patients with melanoma (Weber et al, unpublished data). Other studies of breast tumor–infiltrating lymphocytes have shown that B-cell aggregates contain interdigitating CD21+ follicular dendritic cells, which Coronella-Wood et al8,9 have classified as authentic ectopic follicles. Bell et al10 reported that in breast carcinoma tissue, immature dendritic cells reside within the tumor, whereas mature dendritic cells are located in peritumoral areas. In some cases, CD4+ T-cell clustering around the mature dendritic cells was observed, thus resembling the dendritic cell/T-cell clusters of secondary lymphoid organs, which are characteristic of ongoing immune reactions. Toll-like receptor 4 has been shown to be expressed by human dendritic cells, and patients with breast cancer who carry a toll-like receptor 4 loss-of-function allele experience relapse more quickly after radiation therapy or chemotherapy than do those carrying the normal allele.11 Not all lymphoid aggregates within solid tumors may be beneficial to the antitumor response, as Aspord et al12 have recently shown that the growth of human breast cancer can be facilitated by targeting dendritic cells to prime interleukin 13–secreting CD4+ T cells within the tumor mass. The presence of relatively high numbers of dendritic cell subpopulations may have prognostic value in ovarian tumors.13 In addition, it has been shown that ovarian tumor-specific recruitment of T-regulatory cells can foster immune privilege and is associated with reduced survival.14 Perhaps most relevant to the current study by Dieu-Nosjean et al,1 tumor-infiltrating S100+ dendritic cell aggregates in human lung cancers have been related to the appearance of apoptotic tumor cells; high density of S100+ dendritic cells could also be associated with enhanced survival for patients with lung cancer.15,16 A similar correlation was recently reported for patients with colorectal cancer.17 As individuals who were not primary reviewers of the Dieu-Nosjean et al1 report, one of the aspects of the current work that, in our opinion, needs further investigation is the pathogenesis of the tertiary lymphoid structures or ectopic lymph nodes. Are these structures and their cellular composition specific for the cancer only? The observation that similar structures are present in nonmalignant conditions raises the question of the existence of a new type of localized, functional immune response. Is it possible that a mechanism is operative for the ectopic generation of lymph node–like structures in anatomic areas where an adaptive immune response is needed? For example, the observation of bronchus-associated lymphoid tissue in inflammatory lung diseases and autoimmune diseases begs the question of whether their cellular composition is similar to, or different from, the Ti-BALT associated with NSCLC tumors or with other solid tumor types. Studies in rheumatoid arthritis have shown that CD40L+ and CD8+ T cells are required for the formation of so-called ectopic germinal centers18 and that they are capable of strongly inducing B-cell proliferation and the production of antibodies.19 These cell phenotypes do not seem to be present in tumor-associated, tertiary lymphoid structures.9 It would be also important to study whether a relationship exists between smoking history and the formation of malignant- and nonmalignant-associated bronchus-associated lymphoid tissue, even though no "distinguishable clinical (including smoking history) characteristics ... between patients with DC-Lamp–high versus DC-Lamp–low tumors" are noted by Dieu-Nosjean et al1 in their current article. Finally, it would be appropriate to examine a significant number of routine lung sections, not just biopsies, from nonmalignant areas of patients with cancer, and also from patients with nonmalignant conditions, to assess the incidence of DC-Lamp and Ti-BALT in such individuals. We believe the time has come to ascertain whether direct correlates exist between the functional activities of lymphocytes residing in ectopic lymph node structures within human solid tumors, their tumor specificity, and predictions of clinical outcome. What is needed is a demonstration that by sensitive in vitro immunologic monitoring assays, the function(s) of not only T cells but also B cells isolated from these follicles could predict the clinical course of the disease and have relevance to patient survival. The field should now move away from descriptive analyses to more direct measurements of immune functions within such intratumoral lymphoid aggregates. Given the work of Dieu-Nosjean et al,1 NSCLC seems to be a worthy candidate to lead the way. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Conception and design: James Mulé Collection and assembly of data: Domenico Coppola, James Mulé Manuscript writing: Domenico Coppola, James Mulé Final approval of manuscript: James Mulé ACKNOWLEDGMENTS We thank Jeff Weber, MD, PhD, for review and helpful suggestions. REFERENCES
1. Dieu-Nosjean MC, Antoine M, Danel C, et al: Long-term survival for patients with non–small-cell lung cancer with intratumoral lymphoid structures. J Clin Oncol 26:4410-4417, 2008 2. Singh P, Coskun ZZ, Goode C, et al: Lymphoid neogenesis and immune infiltration in aged liver. Hepatology 47:1680-1690, 2008[CrossRef][Medline] 3. Carragher DM, Rangel-Moreno J, Randall TD: Ectopic lymphoid tissues and local immunity. Semin Immunol 20:26-42, 2008[CrossRef][Medline] 4. Timmer TC, Baltus B, Vondenhoff M, et al: Inflammation and ectopic lymphoid structures in rheumatoid arthritis synovial tissues dissected by genomics technology: Identification of the interleukin-7 signaling pathway in tissues with lymphoid neogenesis. Arthritis Rheum 56:2492-2502, 2007[CrossRef][Medline] 5. Takemura S, Braun A, Crowson C, et al: Lymphoid neogenesis in rheumatoid synovitis. J Immunol 167:1072-1080, 2001 6. Olszewski WL: De novo lymph node formation in chronic inflammation of the human leg. Ann NY Acad Sci 979:166-177, 2002[Medline] 7. Kirk CJ, Hartigan-O'Connor D, Mulé JJ: The dynamics of the T-cell antitumor response: Chemokine-secreting dendritic cells can prime tumor-reactive T cells extranodally. Cancer Res 61:8794-8802, 2001 8. Coronella JA, Spier C, Welch M, et al: Antigen-driven oligoclonal expansion of tumor-infiltrating B cells in infiltrating ductal carcinoma of the breast. J Immunol 169:1829-1836, 2002 9. Coronella-Wood JA, Hersh EM: Naturally occurring B-cell responses to breast cancer. Review. Cancer Immunol Immunother 52:715-738, 2003[CrossRef][Medline] 10. Bell D, Chomarat P, Broyles D, et al: In breast carcinoma tissue, immature dendritic cells reside within the tumor, whereas mature dendritic cells are located in peritumoral areas. J Exp Med 190:1417-1426, 1999 11. 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] 12. Aspord C, Pedroza-Gonzalez A, Gallegos M, et al: Breast cancer instructs dendritic cells to prime interleukin 13-secreting CD4+ T cells that facilitate tumor development. J Exp Med 204:1037-1047, 2007 13. Eisenthal A, Polyvkin N, Bramante-Schreiber L, et al: Expression of dendritic cells in ovarian tumors correlates with clinical outcome in patients with ovarian cancer. Hum Pathol 32:803-807, 2001[CrossRef][Medline] 14. Curiel TJ, Coukos G, Zou L, et al: Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10:942-949, 2004[CrossRef][Medline] 15. Kurabayashi A, Furihata M, Matsumoto M, et al: Distribution of tumor-infiltrating dendritic cells in human non-small cell lung carcinoma in relation to apoptosis. Pathol Int 54:302-310, 2004[CrossRef][Medline] 16. Zeid NA, Muller HK: S100 positive dendritic cells in human lung tumors associated with cell differentiation and enhanced survival. Pathology 25:338-343, 1993[Medline] 17. Nagorsen D, Voigt S, Berg E, et al: Tumor-infiltrating macrophages and dendritic cells in human colorectal cancer: Relation to local regulatory T cells, systemic T-cell response against tumor-associated antigens and survival. J Transl Med 5:62, 2007[CrossRef][Medline] 18. Kang YM, Zhang X, Wagner UG, et al: CD8 T cells are required for the formation of ectopic germinal centers in rheumatoid synovitis. J Exp Med 195:1325-1336, 2002 19. Hermann P, Van-Kooten C, Gaillard C, et al: CD40 ligand positive CD8+ T cell clones allow B cell growth and differentiation. Eur J Immunol 25:2972-2977, 1995[Medline] Related Article
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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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