Ectopic Lymph Nodes Within Human Solid Tumors (2008)

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, DieuNosjean et al 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 tumorinfiltrating 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 al 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, particularly in the settings of autoimmune disease (eg, rheumatoid arthritis) and chronic inflammation. 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 naive T cells extranodally within a tumor mass, resulting in the generation of tumor-specific T cells and subsequent tumor regression. 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 al have classified as authentic ectopic follicles. Bell et al 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. Tolllike 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. Not all lymphoid aggregates within solid tumors may be beneficial to the antitumor response, as Aspord et al 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. 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. Perhaps most relevant to the current study by Dieu-Nosjean et al, 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. A similar correlation was recently reported for patients with colorectal cancer. As individuals who were not primary reviewers of the DieuNosjean et al 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 JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 26 NUMBER 27 SEPTEMBER 2