Towards effective immunotherapy for lung cancer: simultaneous targeting of tumor-initiating cells and immune pathways in the tumor microenvironment

Abstract

ImmunotherapyVol. 1, No. 5 EditorialFree AccessTowards effective immunotherapy for lung cancer: simultaneous targeting of tumor-initiating cells and immune pathways in the tumor microenvironmentSteven Dubinett and Sherven SharmaSteven DubinettDivision of Pulmonary and Critical Care Medicine, UCLA Lung Cancer Program, School of Medicine at UCLA, 10833 Le Conte Avenue, Los Angeles, CA 90095-1690, USA. Veterans Affairs Greater Los Angeles Healthcare System, CA, USASearch for more papers by this authorEmail the corresponding author at ssharma@mednet.ucla.edu and Sherven Sharma† Author for correspondenceDivision of Pulmonary and Critical Care Medicine, UCLA Lung Cancer Program, School of Medicine at UCLA, 10833 Le Conte Avenue, Los Angeles, CA 90095-1690, USA. Veterans Affairs Greater Los Angeles Healthcare System, CA, USASearch for more papers by this authorEmail the corresponding author at ssharma@mednet.ucla.eduPublished Online:2 Sep 2009https://doi.org/10.2217/imt.09.56AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit New therapies are desperately needed for lung cancerLung cancer is the most common cause of cancer mortality worldwide for both men and women, causing approximately 1.2 million deaths per year [1]. With the existing therapeutic efforts, the long-term survival for lung cancer patients remains low with only 15% surviving for 5 years following diagnosis. Therefore, new therapeutic strategies are needed. One such approach is the development of immune therapy for lung cancer. Immune approaches for lung cancer remain attractive because although surgery, chemotherapy and radiotherapy alone or in combination produce response rates in all histological types of lung cancer, relapse is frequent. Immunologic targeting of lung cancer has the potential for nontoxic and specific therapy. Strategies that harness the immune system to react against tumors can be integrated with existing forms of therapy for optimal responses toward this devastating disease.Immune therapy for lung cancer has potential; however, there have not been improvements in survival with previous regimens. Tumor-induced immune suppression may have contributed to the limited efficacy of the approaches. Many tumors, including lung cancer, have the capacity to promote immune tolerance and escape host immune surveillance [2,3]. Tumors utilize numerous pathways to inhibit immune responses, including the elaboration of immune inhibitory cytokines as well as inducing host cells to release immune inhibitors [4–8]. Another important explanation for tumors that remain refractive to immune therapy is the concept of cancer stem cells. Cancer stem cells have tumor growth-initiating potential and treatment that is not directed to this target population may explain why tumors recur even after a sizeable shrinkage following therapy. Identification of the cell type capable of sustaining neoplastic growth and directing immune therapy to cells that possess tumor-initiating potential may improve current immune-based therapeutic approaches. Before cancer stem cells can serve as an immunotherapeutic target, further research is required to identify and separate cancer stem cells from normal stem cells and other cancer cells. Identification of the genetic signatures in cancer stem cells will unravel novel antigens for exploitation in immune therapy protocols with the eventual goal of eliminating residual disease and recurrence.Effective immunotherapeutic strategies for cancer will result from a basic understanding of the mechanisms that sustain tumor growth kinetics. Tumor growth and invasion into surrounding tissue promotes an inflammatory response that is important for tumor development and progression [9,10]. Dysregulated inflammation in cancer leads to hyporesponsiveness of the tumor. Strategies that reprogram the tumor niche could alter the inflammatory infiltrate in the tumor microenvironment making it permissive for immune destruction of tumors. It is likely that combination therapies that focus on methods to address the immune deficits in the lung cancer microenvironment will be required to develop effective therapies for this disease. From our understanding of host–tumor interactions, effective immune therapy for lung cancer must first enlist the host response to recognize tumors of poor immunogenicity by restoring effective tumor-antigen presentation; second, it must target the cancer stem cells; third, circumvent tumor-mediated immune suppression; and fourth, expand and maintain tumor-reactive effector-cell populations with gc homeostatic cytokines such as IL-7, IL-15 and IL-21. In a murine model of lung cancer, we found that systemic delivery of IL-7 restores T-cell activity by promoting CXCR3 ligand-dependent T-cell antitumor immune responses and significantly reduces tumor burden [11].Critical role of antigen presentation in cancer: T-cell tolerance versus T-cell primingEffective antitumor responses require antigen-presenting cells (APCs), lymphocyte and NK effectors [12–15], as well as the elaboration of effector molecules that promote antitumor activity [16]. Although lung cancer cells express tumor antigens, the limited expression of MHC antigens, defective transporter associated with antigen processing (TAP) and lack of costimulatory molecules, make them ineffective APCs [17]. Many tumors, including lung cancer, have the capacity to promote immune tolerance and escape host immune surveillance [2,3]. Tumors utilize numerous pathways to inhibit immune responses, including reduction in APC activity.The central importance of functional APCs in the immune response against cancer was well defined by Huang et al.[12]. The study revealed that even highly immunogenic tumors require host APCs for antigen presentation. Thus, host APCs, rather than tumor cells, present tumor antigen. This is consistent with a study indicating that CD8+ T-cell responses can be induced in vivo by professional APCs that present exogenous antigens in a MHC I-restricted manner [18]. This has been referred to as cross-priming or representation and may be critical for effective antitumor responses [19]. Dendritic cells (DCs) have been demonstrated to be the host APCs responsible for cross-priming by presenting epitopes obtained from apoptotic cells [18].However, in tumor-bearing hosts, there is a state of T-cell unresponsiveness [20–22]. The dominant mechanism underlying the development of antigen-specific T-cell unresponsiveness is thought to be through tumor-antigen processing and presentation by APCs [23]. The intrinsic APC capacity of tumor cells has little influence over T-cell priming versus tolerance, an important decision that is regulated by bone marrow-derived APCs. DCs, macrophages and B cells are all bone marrow-derived cells that express both MHC and the costimulatory molecules CD80 and CD86 and present tumor antigens to antigen-specific T cells.Several studies have shown that DCs play a critical role leading to T-cell tolerance versus T-cell priming [24–27], which is dictated by the environmental context in which the DCs encounter the antigen. Antigen capture by DCs in an inflammatory context triggers their maturation to a phenotype capable of generating strong immune responses, whereas antigen capture in a noninflammatory environment leads instead to the development of T-cell tolerance [24]. The tumor microenvironment not only fails to provide the inflammatory signals needed for efficient DC activation, but also inhibits DC differentiation and maturation through IL-10 [28] and VEGF [29]. DCs, which are pivotal for T-cell priming, remain immature and become dysfunctional in hosts bearing growing tumors, acquiring tolerogenic properties that induce T-cell tolerance to tumor antigens. Immature DCs (iDCs) have little or no expression of costimulatory molecules such as CD80, CD86 and CD40 on their surface and produce little or no IL-12, which is required to support T-cell proliferation. iDCs are unable to induce antitumor immune response but can induce T-cell tolerance. If APCs fail to provide an appropriate costimulatory signal for T cells, tolerance or anergy can develop [24,30]. The importance of restoring APCs with immune-stimulating activity in the tumor microenvironment is crucial. In a recent study, Dieu-Nosjean et al. retrospectively identified ectopic lymph node or tertiary lymphoid structures within human non-small-cell lung cancer specimens and demonstrated that there is a correlation of cellular content with clinical outcome [31]. The density of DC-Lamp, indicating mature DCs within these structures, is a predictor of long-term survival within their selected lung cancer patient population. The authors observed that a low density of tumor-infiltrating CD4+ and T-bet+ T lymphocytes present in tumors poorly infiltrated by DC-Lamp+ mature DCs appears to provide additional supporting evidence for the prognostic importance of an adaptive immune reaction to a solid tumor.We have previously demonstrated that elements from the tumor microenvironment can suppress DC function. We found that bone marrow derived DCs stimulated with granulocyte–macrophage colony-stimulating factor (GM-CSF) and IL-4 in the presence of tumor supernatants (TSNs) failed to generate antitumor responses and caused immunosuppressive effects that correlated with enhanced tumor growth. Functional analyses indicated that TSNs cause a decrement in DC capacity to process and present antigens, induce alloreactivity and secrete IL-12. The TSNs caused a reduction in cell surface expression of CD11c, DEC205, MHC I antigen, MHC II antigen, CD80 and CD86, as well as a reduction in TAP 1 and 2 proteins [32].Tumor host Treg & myeloid-derived suppressor cell downregulation of immune responsesIt is becoming increasingly clear that immune suppression through Tregs, MDSC and M2 macrophages has a crucial role in promoting tumor progression. The success of immune therapy for cancer will depend on integrating strategies that downregulate immune suppression.In addition to reduced APC activity, T cells accumulate in lung cancer tissues but fail to respond because high proportions of tumor-infiltrating lymphocytes (TILs) are Tregs [33]. CD4+CD25+ Treg cell activities increase in lung cancer, and play a role in suppressing antitumor immune responses. Treg cells actively downregulate the activation and expansion of self-reactive lymphocytes [34]. Given that many tumor-associated antigens recognized by autologous T cells are antigenically normal self-constituents, Treg cells engaged in the maintenance of self-tolerance may impede the generation and activity of antitumor reactive T cells [34,35]. Depletion of Tregs has been shown to augment the generation of specific immune T cells in tumor draining lymph nodes [36], and enhance vaccine-mediated antitumor immunity in cancer patients [37]. Thus, reducing the number or activity of Tregs in the tumor-bearing host may induce effective tumor immunity by activating tumor-specific as well as nonspecific effector cells [38–40]. Treg cells are known to suppress DC function via TGF-β and IL-10 [41]. Recent clinical studies indicate that high levels of tumor infiltration by activated CD8+ T cells combined with a low number of Tregs is a significant positive prognostic factor for cancer patient survival [42–45].In addition to Tregs, tumor growth is accompanied by an increase in the number of Gr+CD11b+ myeloid-derived suppressor cells (MDSCs) having strong natural suppressive activity in cancer patients [46,47] or tumor-bearing mice [48–50]. In murine tumor models, 20–40% of the splenocytes are MDSCs compared with 2–4% in normal mice. In addition, MDSCs are found in the tumor tissues, bone marrow and lymph nodes of tumor-bearing mice [51]. It has been demonstrated that these immune suppressive cells are capable of inhibiting the T-cell proliferative response induced by alloantigens [52], CD3 ligation [53], or various mitogens [54,55], and can also inhibit IL-2 utilization [56] as well as NK cell activity [47]. The studies indicate that progressive tumor growth leads to an increase in the MDSCs involved in the downregulation of T-cell responses. MDSCs, in addition to inducing tumor-specific T-cell tolerance, also cause the development of Tregs. MDSCs in tumor bearing hosts reduce the number and activation of T cells through several mechanisms, including depletion of L-arginine by arginase-1, production of reactive oxygen species and reactive nitrogen oxide species by inducible nitric oxide synthase [51,57]. Elimination of MDSCs in cancer patients prior to immune therapy is most likely to prove beneficial.Another tumor-infiltrating phenotype, tumor-associated macrophages (TAMs) are an important cellular compartment of the tumor niche with the ability to modulate tumor growth kinetics. TAMs are derived from circulating monocytes that are recruited to tumors by chemotactic factors such as CCL2, VEGF and M-CSF [58,59]. In some cases, macrophages can represent 50% of the cellularity within a tumor [9,60]. The type of TAMs infiltrating the tumor correlates with favorable or unfavorable prognoses [61]. The M1 (classically activated) macrophages have a potent antigen-presentation function and stimulate a type 1 immune response that leads to tumor rejection, tissue destruction and host defense. M1 macrophages produce proinflammatory cytokines, such as IL-12, IL-23, TNF-α, IL-6, and IL-1 [9,61]. By contrast, M2 (alternatively activated) macrophages are thought to promote tumor formation by enhancing wound healing and tissue remodeling via inhibition of type 1 immune responses by secretion of IL-10 and TGF-β.Future of immune therapy for lung cancerCancer immunotherapy offers an attractive therapeutic addition, delivering treatment of high specificity, low toxicity and prolonged activity. The future of immune therapy for cancer holds promise with novel combined approaches that simultaneously target cancer-initiating stem cells, restore APC immune-stimulating activity, expand tumor-reactive T cells and downregulate suppressor pathways to generate effective therapy. The optimal way to integrate novel immune targeted combinations will be the major focus of future studies and will require a coordinated and cooperative multidisciplinary effort by the international scientific community. Objective cancer regressions and extensions in survival should be correlated with multiple predictive and prognostic molecular and cellular biomarkers of response. This information will prove useful in improving therapy.Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. 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This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.PDF download