Beltran_subbed.qxp 13/7/09 12:32 Page 44
Lung Cancer
like receptors (TLRs) expressed by AMDCs effectively help to circumvent parenchyma.
69
Recently, CXC-chemokine receptor 6 (CXCR6) and its ligand
the Th2-cell response, with subsequent production of effector memory were shown to be specifically expressed by human T cells and the lung
responses against the culprit stimulating antigens. These antigens are parenchyma suggesting that they may be involved in tissue-specific lung
readily transported to regional lymph nodes, the site at which promotion homing.
70
In conclusion, in physiological conditions the immune system,
of immunological memory occurs. Subsequently, activated DCs that with the effective and tight regulation of its differing subpopulations of
have migrated from the local lymph nodes acquire the ability to prime immune cells, exerts a status quo of surveillance that is able to
naïve T cells and induce immunological responses. These transformed T differentiate between potentially harmful pathogenic antigens and the
cells are able to selectively return to the initiating site of immunological other vast majority of non-harmful environmental antigens to which the
stimulus, a phenomenon referred to as tissue-specific homing.
60
This lungs are constantly exposed. Thus, damage to the lungs through
activity is possibly due to the ability of activated memory T cells to unnecessary immune responses is limited and local respiratory
upregulate tissue-specific adhesion molecules and chemokine homeostasis is maintained.
receptors that target their migration to non-lymphoid tissue sites while
downregulating lymphoid-tissue-homing receptors.
60
Although Rationale for Exploiting the
lymphocyte homing is also found in the respiratory system, the Immune System in Lung Cancer
mechanisms through which it occurs are not as clearly understood as it Traditionally, compared with, for example, melanomas, lung cancers
is in the case of the gastrointestinal tract and the skin.
61–66
Priming were thought not to contain many tumor-infiltrating lymphocytes, which
of T and B cells in Peyer’s patches and mesenteric lymph nodes for some time led to lung cancer being thought of as modestly
preferentially induces the expression of α
4
β
7
-integrin and CC- immunogenic.
71
This ethos is changing due to research in animal models
chemokine receptor 9 (CCR9); however, peripheral lymph-node primed T and also in human NSCLC specimens demonstrating significant
cells upregulate cutaneous leukocyte antigen CCR4 and CCR10.
61–64
infiltration of leukocytes in cancerous tissues (Yagui-Beltrán et al.,
unpublished data) Furthermore, CTLs against tumor-specific antigens
There is increasing research evidence that antigen-presenting DCs have been specifically isolated in lung cancer, all indicating that there is
process metabolites produced locally to program tissue-specific a role for immunotherapy in this disease.
72,73
Currently, there are several
lymphocyte homing. For example, in gut-associated lymphoid tissue clinical trials evaluating vaccine therapies in the management of lung
(GALT), resident DCs metabolize vitamin A to retinoic acid, which cancer: L-BLP25 (Stimuvax; Biomira, Alberta, CA),
74–76
BEC-2,
77,78
promotes α
4
β
7
-integrin and CCR9 expression by T cells.
62
In the skin, local belagenpumatucel-L (Lucanix; NovaRx Corporation, San Diego, CA),
79
DCs utilize vitamin D
3
metabolites to program T cells in regional lymph melanoma-associated antigen A3 immunotherapy,
80,81
granulocyte
nodes, which allows their migration to the epidermis.
65
In contrast, macrophage colony-stimulating factor (GM-CSF)-transduced allogenic
pulmonary-tissue-specific T-cell homing is less well understood; cancer cellular immunotherapy (GVAX; Cell Genesys Inc., South San
nevertheless, it is distinctive because it possesses two individual Francisco, CA),
82–85
1E10,
86
and PF-35126;
76
we will highlight aspects of the
circulatory systems, the first pertaining to the bronchial arteries most important trials in this article.
originating from the systemic circulation and that supplies the bronchial
tree, and the second being a low-pressure pulmonary circulatory system Recent high-throughput gene expression analyses have led to the
through the parenchyma of the lung. In addition, the central airways are identification of novel tumor-associated antigens. Tumor-specific
lined by mucosa that is an integral part of the mucosal-associated antigens can be obtained autologously from the patient’s malignant
lymphoid tissue (MALT). Depending on the site of induction—whether the lesion subsequent to surgical resection, or can be generated as
intestinal or the respiratory tract—distinct tissue-trafficking patterns for T recombinant proteins or from organ-specific tumor cell lines. Although
and B cells are observed in MALTs for various organs despite several an important aspect, tumor antigens in isolation may occasionally be
shared properties, such as IgA responses. For example, in the respiratory insufficient to elicit a clinically significant immune response. A variety of
system plasma-cell precursors that are primed in lymphoid tissues that approaches can be utilized to overcome these limitations, including the
home to the tracheo-bronchial mucosa express low levels of gut-homing use of genetically modified tumor cells, viral vectors, DNA-based
molecules CCR9 and α
4
β
7
-integrin but high levels of CCR10 and α
4
β
1
- strategies, and autologous DCs.
87
Bacillus Calmette-Guérin (BCG), which
integrin.
61
Moreover, the airway mucosal endothelial cells constitutively has been used non-specifically for immunotherapy of bladder cancer,
88
is
express CC-chemokine ligand 28 (CCL28) and vascular cell-adhesion the most widely used immunogenic adjuvant in lung malignancies.
89–91
molecule 1 (VCAM1).
61
Respiratory T cells have a different phenotype from The individual role of intrapleurally administered BCG in lung cancer has
gut-homing T cells.
67
In the lung parenchyma, leukocytes migrate through been assessed in several studies with no improvement to survival.
89–91
pulmonary capillaries. Research in both murine models and humans has Furthermore, Mycobacterium vaccae (SRL172) with concurrent
shown that memory CD8
+
T cells specifically target respiratory viruses chemotherapy has been examined as a non-specific immunogenetic
that accumulate in the lung parenchyma.
68
In non-inflammatory adjuvant without success, as shown by a phase III study in NSCLC with
conditions, the pulmonary vasculature expresses intercellular adhesion no effect on survival.
92
Modern techniques to boost immunotherapy
molecule 1 (ICAM1) and P-selectin; however, it does not express VCAM1. comprise mixing adjuvants with tumor cells and/or antigens prior to
Vascular retention and emergence of effector CD8
+
T cells to the normal administration. The strong immunogenic reaction to the adjuvant agents
mouse lung is mediated by the action of lymphocyte function-associated trigger APC responses, with subsequent breakdown of the adjuvant and
antigen 1 (LFA1)–ICAM1 and CCR5–CCR5-ligand interactions.
69
presentation of the antigens to T cells.
93
Biological adjuvants include
Furthermore, inhibition of P-selectin glycoprotein ligand 1 (PSGL1) diphteria toxoid, hemocyanin from marine mollusk Diodora cayenensis,
resulted in the decrease of T cells in both the alveoli and lung tetanus toxoid, and various plant extracts such as that derived from the
44 US ONCOLOGY
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