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Inhibiting C5a/C5aR axis reduces myeloid-derived suppressor cells and enhances PD-1 blockade therapy in lung cancer
Sherven Sharma,Steven Dubinett
- , 2017, DOI: 10.21037/13966
Abstract: In the US (1), and the world, lung cancer remains the leading cause of cancer death. Lung cancer causes more deaths than the next three most common cancers of the colon, breast and prostate combined. In the US an estimated 160,000 Americans and worldwide more than 1.1 million people die from lung cancer annually (2). Approximately 220,000 new cases occur every year in the US. Although previously thought to be non-immunogenic and non-responsive to immune-based therapies, recent ground-breaking studies in lung cancer with immune checkpoint blockade therapy reveal robust anti-tumor activity and durable responses in previously treated patients with progressive locally advanced or metastatic non-small cell lung cancer (NSCLC). This has also changed the treatment paradigm leading to immune checkpoint blockade as a frontline therapy for advanced stage lung cancer. Studies in NSCLC and melanoma patient-derived tumor specimens reveal that responses to immune checkpoint blockade therapy rely on tumor infiltration of activated T effector cells (3-7). Immune inhibitory molecules are upregulated on activated T cells in tumors causing a down regulation of anti-tumor activity. The programmed cell death protein 1 (PD-1; also known as CD279) is an inhibitory receptor that regulates immune responses. The PD-1 receptor interaction with the PD-L1 and PD-L2 ligands deliver inhibitory signals that regulate the balance between T cell activation and tolerance. Recent studies reveal responses in approximately 20% of NSCLC patients treated with inhibitors of the PD-1 checkpoint (3-6,8,9). Progress in our understanding of immune biology provide insights on the multiple pathways that modulate T cell and antigen presenting cell activities, hence PD-1/PD-L1 blockade alone is insufficient to address and mitigate all the deficiencies that contribute to the down regulation of anti-tumor immune responses in the tumor microenvironment (TME). This has led to concerted efforts into evaluating rational combinations with radiation therapy, chemotherapy, targeted therapy or vaccines to improve durable complete responses in cancer patients treated with PD-1/PD-L1 blockade therapy. Early investigations are encouraging suggesting that some of the combinations are more beneficial than monotherapy alone. With continued support of these research endeavors it is anticipated that increased immune based treatment options will be available for lung cancer. A number of combinations with PD-1/PD-L1 are under investigation for various cancer types. In this editorial we will focus on the combined efficacy
Indolence versus aggression in non-small cell lung cancer: defining heterogeneity to impact clinical outcomes
Avrum E. Spira,Brandon S. Grimes,Denise R. Aberle,Kostyantyn Krysan,Linh M. Tran,Stacy J. Park,Steven M. Dubinett
- , 2016, DOI: 10.21037/11283
Abstract: While important new findings in the treatment of advanced non-small cell lung cancer (NSCLC) have led to significant progress, it has been incremental. In the past 30 years, the five-year survival rate for lung cancer has increased by only 5% (1). Despite the major survival advantage conferred to patients with localized disease, only 17% of NSCLC diagnoses were made at stage I–II as of 2014 (2). For this reason, considerable efforts have historically focused on improving early detection through development of screening programs. Following the publication of the NCI-funded National Lung Screening Trial (NLST), the Centers for Medicare and Medicaid Services (CMS) added annual low-dose computed tomography (LDCT) as a preventive service benefit in 2015. This has led to a rapid expansion of lung cancer screening programs. The NLST demonstrated a 20% relative reduction in cancer-specific mortality with annual LDCT screening in high-risk patients and resulted in a much improved probability of early stage disease at diagnosis (3). Specifically, amongst patients with screen-detected lung cancers, approximately 70% were stage I–II at diagnosis and over 50% were stage IA (3). The observation that screen-detected lung cancer is more likely to be at an early, localized stage is consistent with the findings of other large-scale prospective screening studies. Thus, the implementation of lung cancer screening programs is expected to lead to a stepwise increase in early stage diagnoses
Myeloid-derived suppressor cell-dependent inhibition of B cell responses in non-small cell lung cancer
Rui Li,Steven M. Dubinett
- , 2019, DOI: 10.21037/tlcr.2019.04.10
Abstract: Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells with potent immune suppression activities. These cells are derived from the bone marrow (BM) and consist of two populations: polymorphonuclear MDSCs (PMN-MDSCs) and monocytic MDSCs (M-MDSCs), morphologically similar to neutrophils and monocytes, respectively. In mice, PMN-MDSCs are recognized as CD11b+Ly6ClowLy6G+, whereas M-MDSCs are CD11b+Ly6ChighLy6G？. In contrast, in humans, CD11b+CD14？CD15+CD33+ cells with low density are defined as PMN-MDSCs, while CD11b+CD14+CD15？CD33+HLA？DR？/low are markers for M-MDSCs (1). Accumulation of MDSCs is often dependent on persistent inflammation in the tumor microenvironment (TME) which provides signals for their expansion and pathological activation. Upon activation, MDSCs gain increased capacity to generate reactive oxygen species (ROS) and nitric oxide (NO), express high levels of arginase and PD-L1, and secrete a variety of tumor-promoting inflammatory factors, including IL-10, TGF-β and PGE2 (1). Under the influence of the TME, MDSCs fail to differentiate into mature myeloid cells, such as mature neutrophils, macrophages and dendritic cells (DCs) that could promote antitumor immune activities. Instead, MDSCs function as potent immune suppressors, diverting specific immune responses on multiple fronts (1)
Targeting myeloid-derived suppressor cells augments antitumor activity against lung cancer
Srivastava MK, Zhu L, Harris-White M, Huang M, St John M, Lee JM, Salgia R, Cameron RB, Strieter R, Dubinett S, Sharma S
ImmunoTargets and Therapy , 2012, DOI: http://dx.doi.org/10.2147/ITT.S32617
Abstract: rgeting myeloid-derived suppressor cells augments antitumor activity against lung cancer Review (768) Total Article Views Authors: Srivastava MK, Zhu L, Harris-White M, Huang M, St John M, Lee JM, Salgia R, Cameron RB, Strieter R, Dubinett S, Sharma S Published Date October 2012 Volume 2012:1 Pages 7 - 12 DOI: http://dx.doi.org/10.2147/ITT.S32617 Received: 28 July 2012 Accepted: 21 August 2012 Published: 12 October 2012 Minu K Srivastava,1,2 Li Zhu,1,2 Marni Harris-White,2 Min Huang,1–3 Maie St John,1,3 Jay M Lee,1,3 Ravi Salgia,4 Robert B Cameron,1,3,5 Robert Strieter,6 Steven Dubinett,1–3 Sherven Sharma1–3 1Department of Medicine, UCLA Lung Cancer Research Program, David Geffen School of Medicine at UCLA, Los Angeles, CA, 2Molecular Gene Medicine Laboratory, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, 3Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, 4Department of Medicine, University of Chicago, Chicago, IL, 5Department of Surgery, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, 6Department of Medicine, University of Virginia, Charlottesville, VA, USA Abstract: Lung cancer evades host immune surveillance by dysregulating inflammation. Tumors and their surrounding stromata produce growth factors, cytokines, and chemokines that recruit, expand, and/or activate myeloid-derived suppressor cells (MDSCs). MDSCs regulate immune responses and are frequently found in malignancy. In this review the authors discuss tumor-MDSC interactions that suppress host antitumor activities and the authors' recent findings regarding MDSC depletion that led to improved therapeutic vaccination responses against lung cancer. Despite the identification of a repertoire of tumor antigens, hurdles persist for immune-based anticancer therapies. It is likely that combined therapies that address the multiple immune deficits in cancer patients will be required for effective therapy. MDSCs play a major role in the suppression of T-cell activation and they sustain tumor growth, proliferation, and metastases. Regulation of MDSC recruitment, differentiation or expansion, and inhibition of the MDSC suppressive function with pharmacologic agents will be useful in the control of cancer growth and progression. Pharmacologic agents that regulate MDSCs may be more effective when combined with immunotherapies. Optimization of combined approaches that simultaneously downregulate MDSC suppressor pathways, restore APC immune-stimulating activity, and expand tumor-reactive T cells will be useful in improving therapy.
Systematic quantitative characterization of cellular responses induced by multiple signals
Ibrahim Al-Shyoukh, Fuqu Yu, Jiaying Feng, Karen Yan, Steven Dubinett, Chih-Ming Ho, Jeff S Shamma, Ren Sun
BMC Systems Biology , 2011, DOI: 10.1186/1752-0509-5-88
Abstract: We established and validated a data-driven mathematical approach to systematically characterize signal-response relationships. Our results demonstrate how mathematical learning algorithms can enable systematic characterization of multi-signal induced biological activities. The proposed approach enables identification of input combinations that can result in desired biological responses. In retrospect, the results show that, unlike a single drug, a properly chosen combination of drugs can lead to a significant difference in the responses of different cell types, increasing the differential targeting of certain combinations. The successful validation of identified combinations demonstrates the power of this approach. Moreover, the approach enables examining the efficacy of all lower order mixtures of the tested signals. The approach also enables identification of system-level signaling interactions between the applied signals. Many of the signaling interactions identified were consistent with the literature, and other unknown interactions emerged.This approach can facilitate development of systems biology and optimal drug combination therapies for cancer and other diseases and for understanding key interactions within the cellular network upon treatment with multiple signals.Understanding how multiple signals affect cellular functions is necessary in order to be able to understand and control these functions. Extensive studies have been done to address how the activation/inhibition of a particular cellular signaling pathway leads to a specific response. Several challenges limit the ability to study the simultaneous effects of multiple signaling. The complexity and lack of detailed knowledge of cellular systems prevent, in many cases, accounting for the effects of some unknown interactions among pathways or among non-primary signal targets. In addition, genetic or epigenetic alterations between otherwise similar cells can cause a significant difference in their respons
Pre-clinical characterization of GMP grade CCL21-gene modified dendritic cells for application in a phase I trial in Non-Small Cell Lung Cancer
Felicita Baratelli, Hiroko Takedatsu, Saswati Hazra, Katherine Peebles, Jie Luo, Pam S Kurimoto, Gang Zeng, Raj K Batra, Sherven Sharma, Steven M Dubinett, Jay M Lee
Journal of Translational Medicine , 2008, DOI: 10.1186/1479-5876-6-38
Abstract: In the current study, human monocyte-derived DC were differentiated by exposure to GM-CSF and IL-4 from cryopreserved mononuclear cells obtained from healthy volunteers. Transduction with clinical grade adenoviral vector encoding CCL21 (1167 viral particles per cell) resulted in secretion of CCL21 protein.CCL21 protein production from transduced DC was detected in supernatants (24–72 hours, 3.5–6.7 ng/4–5 × 106 cells). DC transduced with the clinical grade adenoviral vector were > 88% viable (n = 16), conserved their phenotype and maintained integral biological activities including dextran uptake, production of immunostimulatory cytokines/chemokines and antigen presentation. Furthermore, supernatant from CCL21-DC induced the chemotaxis of T2 cells in vitro.Viable and biologically active clinical grade CCL21 gene-modified DC can be generated from cryopreserved PBMC.Lung cancer is the leading cause of cancer-related death in the United States with a 5-year survival rate of only 15% [1]. Thus, development of new therapeutic strategies is required. The potential for the immune system to induce tumor regression has stimulated much research into development of vaccines to unmask tumor antigens, leading to a specific host immune response against the tumor [2]. However, the poor immunogenicity of human lung cancer due to low expression of major histocompatibility complex (MHC) antigens, a deficit in transporter-associated with antigen-processing, and lack of co-stimulatory molecules, have rendered most of the immunotherapeutic efforts ineffective [3]. In addition, tumor cell-derived inhibitory factors and immune suppressive cells such as T regulatory cells also impede the immune response to Non-Small Cell Lung Cancer (NSCLC) [4-7].Dendritic cells (DC) are the most potent antigen presenting cells (APC) capable of inducing primary immune responses [8]. DC express high levels of MHC and costimulatory molecules such as CD40, CD80, and CD86. DC also produce high levels of cytoki
Understanding the mechanisms of immune-evasion by lung cancer in the context of chronic inflammation in emphysema
Ramin Salehi-Rad,Steven M. Dubinett
- , 2019, DOI: 10.21037/jtd.2019.01.22
Abstract: Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disorder that constitutes the third leading cause of death worldwide. The presence of COPD is associated with an increased incidence of lung cancer, even after correction for the risk associated with cumulative tobacco exposure (1). Furthermore, the severity of COPD, as defined by the degree of airflow obstruction or the severity of radiographic emphysema, portends a worse prognosis in patients with lung cancer (2). Although our understanding of the pathophysiology of COPD and lung cancer is rapidly evolving, the underlying mechanisms of the epidemiologic link between COPD and lung cancer remain obscure (3). Accumulating evidence suggests that smoke-induced chronic airway inflammation could serve as a potential link between these two disease processes
The Role of PPAR in the Cyclooxygenase Pathway in Lung Cancer
Saswati Hazra,Katherine A. Peebles,Sherven Sharma,Jenny T. Mao,Steven M. Dubinett
PPAR Research , 2008, DOI: 10.1155/2008/790568
Abstract: Decreased expression of peroxisome proliferator activated receptor- (PPAR) and high levels of the proinflammatory enzyme cyclooxygenase-2 (COX-2) have been observed in many tumor types. Both reduced (PPAR) expression and elevated COX-2 within the tumor are associated with poor prognosis in lung cancer patients, and recent work has indicated that these signaling pathways may be interrelated. Synthetic (PPAR) agonists such as the thiazolidinedione (TZD) class of anti-diabetic drugs can decrease COX-2 levels, inhibit growth of non-small-cell lung cancer (NSCLC) cells in vitro, and block tumor progression in xenograft models. TZDs alter the expression of COX-2 and consequent production of the protumorigenic inflammatory molecule prostaglandin E2 (PGE2) through both (PPAR) dependent and independent mechanisms. Certain TZDs also reduce expression of PGE2 receptors or upregulate the PGE2 catabolic enzyme 15-prostaglandin dehydrogenase. As several COX-2 enzymatic products have antitumor properties and specific COX-2 inhibition has been associated with increased risk of adverse cardiac events, directly reducing the effects or concentration of PGE2 may provide a more safe and effective strategy for lung cancer treatment. Understanding the mechanisms underlying these effects may be helpful for designing anticancer therapies. This article summarizes recent research on the relationship between (PPAR), TZDs, and the COX-2/PGE2 pathways in lung cancer.
CXCR4 expression on circulating pan-cytokeratin positive cells is associated with survival in patients with advanced non-small cell lung cancer
Karen L Reckamp, Robert A Figlin, Marie D Burdick, Steven M Dubinett, Robert M Elashoff, Robert M Strieter
BMC Cancer , 2009, DOI: 10.1186/1471-2407-9-213
Abstract: We evaluated CXCR4 levels on circulating pan-cytokeratin positive cells from patients with NSCLC. NSCLC tumor and metastases were also assessed for the presence of CXCR4.Pan-cytokeratin positive cells were increased in the circulation of patients with NSCLC, as compared to normal control subjects. Patients with pan-cytokeratin +/CXCR4+ = 2,500 cells/ml had a significant improvement in median survival when compared with patients with pan-cytokeratin +/CXCR4+ >2,500 cells/ml (not achieved versus 14 weeks). CXCR4 expression was found on NSCLC tumors and at sites of tumor metastasis.This study suggests that CXCR4 may be a prognostic marker in NSCLC, and provides hypothesis-generating results, which may be important in determining metastatic potential. In future studies, we will prospectively evaluate the prognostic significance of pan-cytokeratin/CXCR4+ cells, and determine the mechanisms involved in the regulation of CXCR4 expression on tumor cells in a larger patient population.Approximately 213,380 new cases of lung cancer will be diagnosed and 160,390 deaths will occur from lung cancer during 2007. Lung cancer is the leading cause of cancer death among both men and women in the United States [1]. Nearly 60% of those diagnosed with lung cancer die within one year of their diagnosis, and the five-year survival for all patients with lung cancer is only 16%. This statistic has not improved significantly in the past 10 years. Surgical resection offers the most promising chance for cure in patients who present with early-stage disease, although the majority of patients will develop recurrence despite complete surgical resection. This is likely secondary to undetected microscopic metastatic disease at the time of surgery, and recently adjuvant chemotherapy has been shown to improve survival in some early-stage patients [2-4]. Identification of targeted treatments for micrometastatic disease could block tumor cell migration and improve outcomes in this devastating disease.C
Myeloid Suppressor Cell Depletion Augments Antitumor Activity in Lung Cancer
Minu K. Srivastava, Li Zhu, Marni Harris-White, Upendra Kar, Min Huang, Ming F. Johnson, Jay M. Lee, David Elashoff, Robert Strieter, Steven Dubinett, Sherven Sharma
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0040677
Abstract: Background Myeloid derived suppressor cells (MDSC) are important regulators of immune responses. We evaluated the mechanistic role of MDSC depletion on antigen presenting cell (APC), NK, T cell activities and therapeutic vaccination responses in murine models of lung cancer. Principal Findings Individual antibody mediated depletion of MDSC (anti-Gr1 or anti-Ly6G) enhanced the antitumor activity against lung cancer. In comparison to controls, MDSC depletion enhanced the APC activity and increased the frequency and activity of the NK and T cell effectors in the tumor. Compared to controls, the anti-Gr1 or anti-Ly6G treatment led to increased: (i) CD8 T cells, (ii) NK cells, (iii) CD8 T or NK intracytoplasmic expression of IFNγ, perforin and granzyme (iv) CD3 T cells expressing the activation marker CD107a and CXCR3, (v) reduced CD8 T cell IL-10 production in the tumors (vi) reduced tumor angiogenic (VEGF, CXCL2, CXCL5, and Angiopoietin1&2) but enhanced anti-angiogenic (CXCL9 and CXCL10) expression and (vii) reduced tumor staining of endothelial marker Meca 32. Immunocytochemistry of tumor sections showed reduced Gr1 expressing cells with increased CD3 T cell infiltrates in the anti-Gr1 or anti-Ly6G groups. MDSC depletion led to a marked inhibition in tumor growth, enhanced tumor cell apoptosis and reduced migration of the tumors from the primary site to the lung compared to controls. Therapeutic vaccination responses were enhanced in vivo following MDSC depletion with 50% of treated mice completely eradicating established tumors. Treated mice that rejected their primary tumors acquired immunological memory against a secondary tumor challenge. The remaining 50% of mice in this group had 20 fold reductions in tumor burden compared to controls. Significance Our data demonstrate that targeting MDSC can improve antitumor immune responses suggesting a broad applicability of combined immune based approaches against cancer. This multifaceted approach may prove useful against tumors where MDSC play a role in tumor immune evasion.
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