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Ruben Pio
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MS 26 - Re-Modeling Microenvironment Mimicking Human Cancer (ID 548)
- Event: WCLC 2017
- Type: Mini Symposium
- Track: Biology/Pathology
- Presentations: 1
- Moderators:P. Yang, C. Mascaux
- Coordinates: 10/18/2017, 14:30 - 16:15, Room 502
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MS 26.02 - Innate Immune Microenvironment (ID 7765)
14:50 - 15:10 | Presenting Author(s): Ruben Pio
- Abstract
- Presentation
Abstract:
A better understanding of the interaction between tumors and the immune microenvironment has led to the successful development of immunotherapies for tumors traditionally considered poorly immunogenic, such as non-small cell lung cancer (NSCLC). Clinically approved immunotherapies for lung cancer are based on antibodies able to reactivate cytotoxic T cells by targeting the PD-1/PD-L1 immune checkpoint. However, the substantial proportion of tumors refractory to these treatments, together with the limited predictive value of PD-L1 expression, evidences the existence of additional immune suppressive regulatory systems. This calls for a more detailed understanding of the immune cell landscape related to lung tumors. Some studies have begun to dissect the details of immune cell distribution in lung cancer lesions using multiscale immune profiling strategies. Along with adaptive immune alterations in T cells, significant innate immune cell changes have been identified (1). We have recently reviewed the role played by the innate immune system in supporting tumor-promoting activities and an immunosuppressive microenvironment (2). Innate immunity includes soluble components and immune cell populations, such as myeloid cells. Specific subpopulations of myeloid cells have been identified as specialized immunosuppressive cells. These myeloid-derived suppressor cells (MDSCs) are immature myeloid cells arrested in different stages of differentiation. The recognition of these cells as a defined cell lineage remains controversial, but their cancer-specific phenotypic and functional characteristics are manifest (3). Chronic inflammation factors released by tumors induce the accumulation of these immature cells in the bone marrow, which are released to the circulation and recruited to tumors. MDCSs are thought to be major contributors to T-cell exhaustion. They deplete the tumor microenvironment of amino acids essential for T cell proliferation (e.g. arginine) and produce immunosuppressive cytokines (e.g. IL10 and TGFβ). Increased levels of MDSCs have been described in patients with NSCLC, are associated with poor prognosis and can mediate resistance to chemotherapy (4). Interestingly, in tumor models, accumulation of MDSCs has been proposed as a contributor to the incapacity of the anti-PD-1/PD-L1 blockade to completely reverse the suppressive activity (5). Therefore, stimulation of effector T cells while blocking the immunosuppressive activity of MDSCs represents a rational immunotherapy combination potentially effective for lung cancer. Several agents used in conventional cancer chemotherapy (e.g. gemcitabine, 5-fluorouracil or cyclophosphamide) have been found to reduce MDSC numbers and can be used to deplete this cell subpopulation. However, the use of these drugs results in a profound and unpredictable remodeling of the myeloid cell compartment in the tumor stroma, and careful evaluation of the appropriate timing and dosing is required (6). An alternative strategy recently proposed by us to successfully reverse the tumor immunosuppressive microenvironment is based on the inhibition of the complement system, another essential element of innate immunity. The complement system has developed as a first defense against pathogens or unwanted host elements. The three major pathways of complement activation (the classical, alternative, and lectin pathways) converge in the cleavage of C3 into C3b. C3b deposition leads to the formation of C3 convertases that amplify both opsonization and the complement response, and eventually promote C5 convertase formation and assembly of the membrane attack complex. In addition, enzymatic cleavage of C3 and C5 releases C3a and C5a, two multifunctional immunomodulators. Traditionally, tumor-associated complement activation has been considered as part of the body’s immunosurveillance against cancer. However significant work in recent years has identified new and surprising activities for complement within the tumor microenvironment. In the context of chronic inflammation, complement elements can promote an immunosuppressive response, induce angiogenesis, and activate cancer-related signaling pathways. In the seminal study that shifted the paradigm, Markiewski et al. reported that complement deficiencies were associated with impaired tumor growth in a syngeneic model of cervical carcinoma (7). This study demonstrated that the immunomodulator C5a, generated after complement activation within the tumors, is able to hamper antitumor CD8 T cell-mediated responses. Importantly, this activity was associated with the accumulation of MDSCs in the tumor stroma. In the case of lung cancer, reduction of tumor growth after blockade of the C5a receptor-1 (C5aR1) is accompanied by a decrease in the expression of immunosuppressive molecules and, again, a diminution in the percentage of MDSCs (8). These studies reveal the important role played by C5a/C5aR1 signaling in tumor immunity, and point to this pathway as a potential therapeutic target in the context of checkpoint inhibition. To support this hypothesis, we have recently evaluated the therapeutic efficacy of the combined administration of anti-PD-1 and anti-C5a drugs in a variety of syngeneic models of lung cancer. We demonstrated that the combination of C5a and PD-1 blockade synergistically impairs lung cancer growth and metastasis. This therapeutic effect is accompanied by a negative association between the frequency of CD8 T cells and MDSCs within the tumors, which may result in a more complete reversal of CD8 T-cell exhaustion (9). These studies suggest that inhibition of complement may overcome tumor resistance in cancer immunotherapy, providing support for the clinical evaluation of anti-PD-1 and anti-C5a drugs as a novel combination therapeutic strategy for lung cancer. In conclusion, immunotherapy strategies tailored to restore innate immune modifications might recondition the tumor immunosuppressed niche, strengthening anti-tumor T cell immunity after immune-checkpoint blockade. A more comprehensive knowledge of the dynamic spatiotemporal interactions between the tumors and the microenvironment would be required to predict response, facilitate further investigations in this field, and extend the benefit of immunotherapies to most patients. References 1. Lavin Y et at. Cell 2017;169:750-765. 2. Berraondo P et al. Immunol Rev 2016;274:290-306. 3. Escors T et al. Oncoimmunology 2013;2:e26148. 4. Huang A et al. Cancer Immunol Immunother 2013;62:1439-1451. 5. Youn JI et al. J Immunol 2008;181:5791-5802. 6. Berraondo P et al. Cancer Res 2007;67:8847-8855. 7. Markiewski MM et al. Nat Immunol 2008;9:1225-1235. 8. Corrales L et al. J Immunol 2012;189:4674-4683. 9. Ajona D et al. Cancer Discov 2017;7:694-703.
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P2.02 - Biology/Pathology (ID 616)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.02-061 - Two Novel Protein-Based Prognostic Signatures Improve Risk Stratification of Early Lung ADC and SCC Patients (ID 9518)
09:30 - 09:30 | Author(s): Ruben Pio
- Abstract
Background:
The development of robust, feasible and clinically useful molecular classifiers for early stage NSCLC patients to assess the risk of developing post-resection recurrence is an unmet medical need. Here we identified and validated the clinical utility of two different histotype-specific protein-based prognostic signatures to stratify the five-year risk of lung cancer recurrence or death in patients with either early lung adenocarcinoma (ADC) or early squamous cell carcinoma (SCC). The signatures are based on the immunohistochemical detection of three and five proteins, for ADC and SCC respectively
Method:
A total number of 562 lung cancer patients were included in this study (n=350 for ADC and n=212 for SSC). A training cohort was used to assess the value of the prognostic signatures based on immunohistochemical (IHC) detection (n=239 ADC and n=117 SSC). The prognostic signatures were developed by Cox regression analysis and were comprised of three and five proteins, respectively for ADC and SCC. Overfitting and optimism were quantified and calibrated by internal validation by applying shrinkage and bootstraping combination. The performance of the models was externally validated in a second cohort of 111 and 95 patients with stage I-II lung ADC and SCC, respectively.
Result:
The prognostic indexes (PIs) generated by the models were significant predictors of five-year outcome for disease-free survival: [P<0.001, HR=2.88 (95% CI, 1.77-4.69)] for ADC and [P<0.001; HR=2.97 (95% CI, 1.84-4.79)] for SCC; and overall survival: [P<0.001, HR=4.04 (95% CI, 2.30-7.10)] for ADC and [P=0.006; HR=1.86 (95% CI, 1.20-2.88)] for SCC, independently of other clinicopathological parameters. The prognostic ability of both PIs was externally validated in the second cohort of early stage lung cancer patients (P<0.05). The molecular classifiers added significant information to pathological stage. Combined models including both PIs and the pathological stage (CPIs) improved the risk stratification in both cases (P<0.001). Moreover, using the CPI value we were able to select the group of stage I-IIA patients who could obtain a benefit from platinum-based adjuvant chemotherapy treatment (P<0.05) in both histological subtypes.
Conclusion:
This study identifies and validates two protein-based prognostic signatures that accurately identify early lung cancer patients with high risk of recurrence or death. More importantly, the proposed models may be valuable tools to identify the subset of stage I-IIA patients for whom adjuvant chemotherapy could be beneficial.
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P3.07 - Immunology and Immunotherapy (ID 723)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.07-007 - Blockade of the Complement C5a/C5aR1 Axis Impairs Lung Cancer Bone Metastasis (ID 8958)
09:30 - 09:30 | Presenting Author(s): Ruben Pio
- Abstract
Background:
The complement system, a central part of innate immunity, is implicated in the maintenance of a favorable microenvironment for lung cancer progression. In particular, several studies have demonstrated a tumor-promoting role for the immune regulator C5a, but its direct impact on growth and dissemination of lung cancer cells is poorly understood. In this study we aimed to investigate the contribution of the C5a/C5aR1(CD88) axis to the malignant phenotype of NSCLC cells, particularly to skeletal colonization, a preferential lung metastasis site.
Method:
The association between C5aR1 expression and clinical outcome was assessed at both the mRNA and protein levels by in silico and immunohistochemistry analyses, respectively. The mRNA levels of C5aR1 were also determined in a panel of 45 cell lines representing the main lung cancer subtypes. The expression of the receptor was validated by flow cytometry. The functional significance of C5aR1 expression in NSCLC cells was evaluated using lentiviral gene silencing and drug inhibition in in vivo models of lung cancer bone metastasis. In vitro functional assays for signaling, migration, invasion, metalloprotease activity and osteoclastogenesis were also performed.
Result:
High levels of C5aR1 in primary human NSCLC tumors were significantly associated with shorter recurrence-free survival and overall survival both at the mRNA and protein levels. Many lung cancer cell lines expressed C5aR1 mRNA. C5aR1 was also detected by flow cytometry on the cell surface of representative lung cancer cell lines. Moreover, addition of C5a to cultured cells led to phosphorylation of p42/44 MAPK and translocation of NF-kB to the nucleus, demonstrating the functionality of the receptor. Silencing of C5aR1 in A549 and H460 lung cancer cells did not affect proliferation, but led to a substantial reduction in skeletal metastatic burden and osteolysis in in vivo models. C5aR1 pharmacological blockade also reduced the osseous metastatic activity of lung cancer cells in vivo. Moreover, metalloproteolytic, migratory and invasive tumor cell activities were modulated in vitro by C5aR1 stimulation or gene silencing. This effect was associated with decreased osteoclastogenic activity in vitro, which was rescued by exogenous addition of the chemokine CXCL16.
Conclusion:
Disruption of C5aR1 signaling in lung cancer cells abrogates osseous colonization through a CXCL16-mediated mechanism. This study reinforces the role played by the C5a/C5aR1 axis in lung cancer progression, and supports its potential use as a novel therapeutic target.
