Cancer Immunology, Immunotherapy

Our medical research library holds 21 studies published in Cancer Immunology, Immunotherapy (1993–2025). Each entry links to the study's record on PubMed and, where there is one, to the publisher's page and a free full text. 21 have an abstract, the authors' own summary as PubMed records it: open "Abstract" to read it.

About the journal

• Publisher: Springer Verlag
• Published: 1982 to the present, Germany
• Language: English
• ISSN: 0340-7004 (print), 1432-0851 (electronic)
• Continues: Cancer Immunology and Immunotherapy
• Its record in the NLM Catalog

2020s

• DNA methylation-regulated HLA-C expression modulates immune responses and metabolic alterations to influence prognosis in mesothelioma. H. Zhang, L. Yu, Y. Guo, et al. 2025;74(5):158. PubMed · Publisher · Free full text

  Abstract

  Background: Malignant mesothelioma is a highly aggressive cancer with a poor prognosis and limited therapeutic options. The tumor microenvironment (TME) plays a pivotal role in driving tumor progression, with immune cells influencing disease outcomes. However, the molecular mechanisms underpinning mesothelioma's progression remain insufficiently understood. HLA-C, a class I major histocompatibility complex (MHC) molecule, has been implicated in immune modulation and cancer progression, but its specific role in mesothelioma has yet to be thoroughly investigated.

  Methods: This study employed a comprehensive multi-omics approach, integrating single-cell RNA sequencing, expression quantitative trait loci (eQTL) analysis, and Mendelian randomization (MR), to elucidate the role of HLA-C in mesothelioma progression. We first analyzed HLA-C expression within the TME, with particular focus on immune cells, especially macrophages. Survival analysis was conducted using data from the TCGA mesothelioma cohort to assess the clinical relevance of HLA-C expression. We utilized mediated MR analysis to investigate the impact of DNA methylation on HLA-C expression, identifying key mediators such as inflammatory cytokines, immune cell populations, blood cell types, and metabolites that could potentially influence patient prognosis.

  Results: HLA-C was predominantly expressed in macrophages, T cells, and NK cells within the TME, and higher expression levels were associated with improved patient survival. MR analysis revealed that DNA methylation regulates HLA-C expression, which in turn impacts mesothelioma outcomes. Mediated MR analysis, encompassing 91 inflammatory cytokines, 731 immune cell populations, 91 blood cell types, and 1400 metabolites, highlighted several critical mediators of HLA-C's effect on prognosis, including IL-10, CD33 expression on CD33dim HLA DR- myeloid cells, the reticulocyte perturbation response, and the ADP-to-citrate ratio. Gene set enrichment analysis (GSEA) showed significant enrichment of immune-related and inflammatory pathways in patients with high HLA-C expression.

  Conclusion: HLA-C, regulated by DNA methylation, plays a central role in mesothelioma prognosis by modulating immune responses, inflammatory cytokines, blood cell populations, and metabolic processes within the TME. Our findings suggest that HLA-C could serve as both a prognostic biomarker and a potential therapeutic target for mesothelioma, offering new insights into the molecular mechanisms driving this aggressive cancer.

  © 2025. The Author(s).

• Fractionated low-dose radiotherapy primes the tumor microenvironment for immunotherapy in a murine mesothelioma model. R.A. D'Alonzo, S. Keam, S. Gill, et al. 2025;74(2):44. PubMed · Publisher · Free full text

  Abstract

  Combination immune checkpoint inhibitors (nivolumab and ipilimumab) are currently a first-line treatment for mesothelioma; however, not all patients respond. The efficacy of treatment is influenced by the tumor microenvironment. Murine mesothelioma tumors were irritated with various radiotherapy doses. Radiotherapy induced vasculature changes were monitored by power Doppler and photoacoustic ultrasound and analyzed via mixed-effects models. Tissue staining was used to investigate the immune cell infiltrate of tumors. The optimal radiotherapy schedule was combined with immune checkpoint inhibitors, and the survival of mice was analyzed. Using low-dose, low-fraction radiotherapy allowed favorable modification of the murine mesothelioma tumor microenvironment. Irradiating tumors with 2 Gy × 5 fractions significantly improved blood flow and reduced hypoxia, consequently increasing the presence of CD8+ and regulatory T cells in the tumor. Understanding the transient nature of these changes is crucial for optimizing the timing of therapeutic delivery. The combination of radiotherapy with dual immunotherapy (anti-PD-1 plus anti-CTLA-4) proved highly curative when administered concurrently. A diminishing rate of cures was noted with an increasing delay between radiotherapy and subsequent immunotherapy. Concurrent low-dose, low-fraction radiotherapy emerges as a translatable approach for improving the efficacy of immune checkpoint inhibitors in patients.

  © 2024. The Author(s).

• Dose-escalation, tolerability, and efficacy of intratumoral and subcutaneous injection of hemagglutinating virus of Japan envelope (HVJ-E) against chemotherapy-resistant malignant pleural mesothelioma: a clinical trial. K. Sakura, M. Kuroyama, Y. Shintani, et al. 2024;73(12):243. PubMed · Publisher · Free full text

  Abstract

  The hemagglutinating virus of Japan envelope (HVJ-E) is an inactivated Sendai virus particle with antitumor effect and inducing antitumor immunity. However, its dosage and efficacy have not been verified. We conducted a phase I clinical study on chemotherapy-resistant malignant pleural mesothelioma (MPM) aiming to determine the recommended dosage for a phase II study through dose-limiting toxicity and evaluate HVJ-E's preliminary efficacy. HVJ-E was administered intratumorally and subcutaneously to the patients with chemotherapy-resistant MPM. While no serious adverse events occurred, known adverse events of HVJ-E were observed. In the preliminary antitumor efficacy using modified response evaluation criteria in solid tumors (RECIST) criteria, three low-dose patients exhibited progressive disease, while all high-dose patients achieved stable disease, yielding disease control rates (DCRs) of 0% and 100%, respectively. Furthermore, the dose-dependent effect of HVJ-E revealed on DCR modified by RECIST and the baseline changes in target lesion size (by CT and SUL-peak; p < 0.05). Comparing targeted lesions receiving intratumoral HVJ-E with non-injected ones, while no clear difference existed at the end of the study, follow-up cases suggested stronger antitumor effects with intratumoral administration. Our findings suggest that HVJ-E could be safely administered to patients with chemotherapy-resistant MPM at both study doses. HVJ-E exhibited some antitumor activity against chemotherapy-resistant MPM, and higher doses tended to have stronger antitumor effects than lower doses. Consequently, a phase II clinical trial with higher HVJ-E doses has been conducted for MPM treatment. Trial registration number: UMIN Clinical Trials Registry (#UMIN000019345).

  © 2024. The Author(s).

• Functional enhancement of mesothelin-targeted TRuC-T cells by a PD1-CD28 chimeric switch receptor. D. McCarthy, M. Lofgren, A. Watt, et al. 2023;72(12):4195-4207. PubMed · Publisher · Free full text

  Abstract

  T cells expressing a mesothelin (MSLN)-specific T cell receptor fusion construct (TRuC®), called TC-210, have demonstrated robust antitumor activity in preclinical models of mesothelioma, ovarian cancer, and lung cancer. However, they are susceptible to suppression by the programmed cell death protein 1 (PD-1)/programmed cell death protein ligand 1 (PD-L1) axis and lack intrinsic costimulatory signaling elements. To enhance the function of anti-MSLN TRuC-T cells, chimeric switch receptors (CSRs) have been designed to co-opt the immunosuppressive PD-1/PD-L1 axis and to deliver a CD28-mediated costimulatory signal. Here, we report that coexpression of the PD1-CD28 CSR in TRuC-T cells enhanced T cell receptor signaling, increased proinflammatory effector cytokines, decreased anti-inflammatory cytokines, and sustained effector function in the presence of PD-L1 when compared with TC-210. Anti-MSLN TRuC-T cells engineered to coexpress PD1-CD28 CSRs comprising the ectodomain of PD-1 and the intracellular domain of CD28 linked by the transmembrane domain of PD-1 were selected for integration into an anti-MSLN TRuC-T cell therapy product called TC-510. In vitro, TC-510 showed significant improvements in persistence and resistance to exhaustion upon chronic stimulation by tumor cells expressing MSLN and PD-L1 when compared with TC-210. In vivo, TC-510 showed a superior ability to provide durable protection following tumor rechallenge, versus TC-210. These data demonstrate that integration of a PD1-CD28 CSR into TRuC-T cells improves effector function, resistance to exhaustion, and prolongs persistence. Based on these findings, TC-510 is currently being evaluated in patients with MSLN-expressing solid tumors.

  © 2023. The Author(s).

• Pre-treatment soluble PD-L1 as a predictor of overall survival for immune checkpoint inhibitor therapy: a systematic review and meta-analysis. Á. Széles, T. Fazekas, S. Váncsa, et al. 2023;72(5):1061-1073. Meta-analysis · Systematic review PubMed · Publisher · Free full text

  Abstract

  Introduction: Immune checkpoint inhibitors (ICI) such as anti-PD-L1 and anti-PD-1 agents have been proven to be effective in various cancers. However, the rate of non-responders is still high in all cancer entities. Therefore, the identification of biomarkers that could help to optimize therapeutic decision-making is of great clinical importance. Soluble PD-L1 (sPD-L1) and PD-1 (sPD-1) are emerging blood-based biomarkers and were previously shown to be prognostic in various clinical studies.

  Objective: We aimed to evaluate the prognostic relevance of sPD-L1 and sPD-1 in patients with different tumor entities who underwent ICI therapy.

  Methods: We searched for articles in PubMed via Medline, Embase, Scopus, and Cochrane databases. The primary outcome was overall survival (OS) and progression-free survival (PFS); furthermore, we analyzed on-treatment serum level changes of sPD-L1 and sPD-1 during ICI therapy.

  Results: We synthesized the data of 1,054 patients with different cancer types from 15 articles. Pooled univariate analysis showed that elevated levels of sPD-L1 were significantly associated with inferior OS (HR = 1.67; CI:1.26-2.23, I2 = 79%, p < 0.001). The strongest association was found in non-small cell lung cancer, whereas weaker or no association was observed in melanoma as well as in renal cell and esophageal cancers. Pooled multivariate analysis also showed that elevated levels of sPD-L1 correlated with worse OS (HR = 1.62; CI: 1.00-2.62, I2 = 84%, p = 0.05) and PFS (HR = 1.71; CI:1.00-2.94, I2 = 82%, p = 0.051). Furthermore, we observed that one or three months of anti-PD-L1 treatment caused a strong (27.67-fold) elevation of sPD-L1 levels in malignant mesothelioma and urothelial cancer.

  Conclusions: We found significantly inferior OS in ICI-treated cancer patients with elevated pre-treatment sPD-L1 levels, but this association seems to be tumor type dependent. In addition, sPD-L1 increases during anti-PD-L1 therapy seems to be therapy specific.

  © 2022. The Author(s).

• Assessment of interferon-γ in pleural fluid as a prognostic factor of survival in malignant pleural mesothelioma. B. Dozin, G. Carbotti, S. Roncella, et al. 2021;70(11):3349-3355. PubMed · Publisher · Free full text

  Abstract

  Backgound: Literature reports suggest that the host immune system may control Malignant Pleural Mesothelioma (MPM) growth, although its activity is limited by regulatory mechanisms. In this retrospective study, we analyzed the levels of pro-inflammatory (IL-1, IL-6, TNF), immune-regulatory (IL-10) and Th1/CTL-related cytokines (IL-12p70, IFN-γ) in the pleural exudate and their relationship with overall survival (OS) in MPM.

  Methods: Cytokines were quantified by multiplexed immunoassay. Concentrations were dichotomized with respect to the median value. Correlation between cytokine level and OS was assessed using univariate (Kaplan-Meier curves) and multivariate (Cox regression) analyses.

  Results: Regarding outcome, tumor histology, therapies undergone and IFN-γ were independent prognostic factors of OS in a 72 MPM training cohort. Notably, high concentrations of IFN-γ halved death probability (HR of high vs low IFN-γ concentration = 0.491, 95%CI 0.3-0.8, p = 0.007). Also in patients with epithelioid histology and those receiving at least one line of therapy, high IFN-γ level was an independent factor predictive of OS (HR of high vs low IFN-γ concentration were 0.497, p = 0.007 and 0.324, p = 0.006, respectively). However, these data were not confirmed in a 77 MPM validation cohort, possibly due to the low IFN-γ levels encountered in this population, and the heterogeneous distribution of disease stages between the training and the validation cohorts. None of the other cytokines showed any effect on survival.

  Conclusions: High level of IFN-γ in pleural effusion may be associated with better survival in MPM patients and potentially serve as a prognostic biomarker. Larger prospective studies are needed to ascertain this hypothesis.

  © 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

• Enhanced anti-tumor efficacy of IL-7/CCL19-producing human CAR-T cells in orthotopic and patient-derived xenograft tumor models. S. Goto, Y. Sakoda, K. Adachi, et al. 2021;70(9):2503-2515. PubMed · Publisher · Free full text

  Abstract

  Chimeric antigen receptor (CAR)-T cell therapy has impressive efficacy in hematological malignancies, but its application in solid tumors remains a challenge. Multiple hurdles associated with the biological and immunological features of solid tumors currently limit the application of CAR-T cells in the treatment of solid tumors. Using syngeneic mouse models, we recently reported that CAR-T cells engineered to concomitantly produce interleukin (IL)-7 and chemokine (C-C motif) ligand 19 (CCL19)-induced potent anti-tumor efficacy against solid tumors through an improved ability of migration and proliferation even in an immunosuppressive tumor microenvironment. In this study, for a preclinical evaluation preceding clinical application, we further explored the potential of IL-7/CCL19-producing human CAR-T cells using models that mimic the clinical features of solid tumors. Human anti-mesothelin CAR-T cells producing human IL-7/CCL19 achieved complete eradication of orthotopic pre-established malignant mesothelioma and prevented a relapse of tumors with downregulated antigen expression. Moreover, mice with patient-derived xenograft of mesothelin-positive pancreatic cancers exhibited significant inhibition of tumor growth and prolonged survival following treatment with IL-7/CCL19-producing CAR-T cells, compared to treatment with conventional CAR-T cells. Transfer of IL-7/CCL19-producing CAR-T cells resulted in an increase in not only CAR-T cells but also non-CAR-T cells within the tumor tissues and downregulated the expression of exhaustion markers, including PD-1 and TIGIT, on the T cells. Taken together, our current study elucidated the exceptional anti-tumor efficacy of IL-7/CCL19-producing human CAR-T cells and their potential for clinical application in the treatment of patients with solid tumors.

  © 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.

2010s

• Immune checkpoint blockade therapy of mesothelioma: a clinical and radiological challenge. L. Calabrò, A. Morra, R. Cornelissen, et al. 2018;67(8):1317-1324. Review PubMed · Publisher · Free full text

  Abstract

  Treatment of malignant pleural mesothelioma (MPM) represents a highly unmet medical need. Here, we discuss the results and therapeutic potential of first- and second-generation immunomodulatory antibodies targeting distinct immune checkpoints for the treatment of MPM, as well as their prospective therapeutic role in combination strategies. We also discuss the role of appropriate radiological criteria of response for MPM and the potential need of ad hoc criteria of disease evaluation in MPM patients undergoing treatment with immunotherapeutic agents.

• The PD-L1/PD-1 pathway promotes dysfunction, but not "exhaustion", in tumor-responding T cells from pleural effusions in lung cancer patients. H. Prado-Garcia, S. Romero-Garcia, A. Puerto-Aquino, et al. 2017;66(6):765-776. PubMed · Publisher · Free full text

  Abstract

  Malignant pleural effusions are frequent in patients with advanced stages of lung cancer and are commonly infiltrated by lymphocytes and tumor cells. CD8+ T cells from these effusions have reduced effector functions. The programmed death receptor 1(PD-1)/programmed death ligand 1 (PD-L1) pathway is involved in T-cell exhaustion, and it might be responsible for T-cell dysfunction in lung cancer patients. Here, we show that PD-L1 is expressed on tumor cell samples from malignant effusions, on lung cancer cell lines, and, interestingly, on MRC-5 lung fibroblasts. PD-L1 was up-regulated in lung cancer cell lines upon treatment with IFN-gamma, but not under hypoxic conditions, as detected by RT-qPCR and flow cytometry. Blockade of PD-L1 on tumor cells restored granzyme-B expression in allogenic CD8+ T cells in vitro. Remarkably, pleural effusion CD8+ T cells that responded to the tumor antigens MAGE-3A and WT-1 (identified as CD137+ cells) were lower in frequency than CMV pp65-responding CD8+ T cells and did not have an exhausted phenotype (PD-1+ TIM-3+). Nonetheless, tumor-responding CD8+ T cells had a memory phenotype and expressed higher levels of PD-1. A PD-L1 blocking antibody increased the expression of granzyme-B and perforin on polyclonal- and tumor-stimulated CD8+ T cells. Taken together, our data show that rather than being exhausted, tumor-responding CD8+ T cells are not completely differentiated into effector cells and are prone to negative regulation by PD-L1. Hence, our study provides evidence that lung cancer patients respond to immunotherapy due to blockade of the PD-L1/PD-1 pathway.

• CTLA-4 in mesothelioma patients: tissue expression, body fluid levels and possible relevance as a prognostic factor. S. Roncella, S. Laurent, V. Fontana, et al. 2016;65(8):909-17. PubMed · Publisher · Free full text

  Abstract

  CTLA-4 function as a negative regulator of T cell-mediated immune response is well established, whereas much less is known about the immunoregulatory role of its soluble isoform (sCTLA-4). No data are available on CTLA-4 expression and prognostic impact in malignant pleural mesothelioma (MPM). We investigated, by immunohistochemistry, CTLA-4 expression in tumor tissues and, by ELISA, sCTLA-4 levels in sera and matched pleural effusions from 45 MPM patients. Prognostic effect of CTLA-4 expression on overall survival (OS) was assessed through Cox regression and prognostic significance expressed as death rate ratio (HR). We found that 56.0 % of MPM tissues expressed CTLA-4 with variable intensity and percentage of positive cells estimated by the immunoreactive score. sCTLA-4 levels were significantly higher in sera (S-sCTLA-4) than in pleural effusions (PE-sCTLA-4) (geometric mean ratio = 2.70, P value = 0.020). CTLA-4 expression at the tissue level was higher in the epithelioid histological subtype than in the sarcomatoid, whereas at the serum level, it was higher in the sarcomatoid subtype. A homogeneous favorable prognostic effect was found for CTLA-4 overexpression in tissue, serum and pleural effusion. Interestingly, only the PE-sCTLA-4 was found to be a statistically significant positive prognostic factor (HR = 0.37, 95 % CI = 0.18-0.77, P value = 0.007). Indeed, PE-sCTLA-4 correlated with CTLA-4 expression in tissues, whereas this latter expression showed a weak association with OS. To confirm our findings, further experimental evidences obtained from a larger cohort of MPM patients are required. However, our results would indicate a positive correlation of PE-sCTLA-4 levels and OS in MPM patients.

• CTLA4 blockade in mesothelioma: finally a competing strategy over cytotoxic/target therapy?. L. Calabrò, G.L. Ceresoli, A. di Pietro, et al. 2015;64(1):105-12. Review PubMed · Publisher · Free full text

  Abstract

  No second-line treatment significantly prolongs the survival of malignant mesothelioma patients who have a high unmet medical need. Here, we comment on the therapeutic potential of cytotoxic T-lymphocyte-associated protein (CTLA)4-blockade by the anti-CTLA4 monoclonal antibody (mAb) tremelimumab of refractory malignant mesothelioma patients. We also focus on the critical role of an accurate tumor assessment in the course of treatment with immunomodulating mAb. Finally, treatment with potentially effective, second-generation checkpoint(s) inhibiting mAb, as well future combination strategies in this deadly disease, will be discussed.

• Immunomodulatory activity of SGI-110, a 5-aza-2'-deoxycytidine-containing demethylating dinucleotide. S. Coral, G. Parisi, H.J. Nicolay, et al. 2013;62(3):605-14. PubMed · Publisher · Free full text

  Abstract

  Purpose: Pharmacologic DNA hypomethylation holds strong promises in cancer immunotherapy due to its immunomodulatory activity on neoplastic cells. Searching for more efficient DNA hypomethylating agents to be utilized to design novel immunotherapeutic strategies in cancer, we investigated the immunomodulatory properties of the new DNA hypomethylating agent SGI-110, that is resistant to in vivo inactivation by cytidine deaminase.

  Experimental Design: Cutaneous melanoma, mesothelioma, renal cell carcinoma, and sarcoma cells were treated in vitro with SGI-110. RT-PCR, quantitative RT-PCR, quantitative methylation-specific PCR, and flow cytometric analyses were performed to investigate changes induced by SGI-110 in the constitutive immune profile of cancer cells. The recognition by gp100-specific CTL of gp100-positive melanoma cells, treated or not with SGI-110, was tested by LDH release assays.

  Results: SGI-110 induced/up-regulated the expression of investigated cancer/testis antigens (CTA) (i.e., MAGE-A1, MAGE-A2, MAGE-A3, MAGE-A4, MAGE-A10, GAGE 1-2, GAGE 1-6, NY-ESO-1, and SSX 1-5) in all cancer cell lines studied, both at mRNA and at protein levels. Quantitative methylation-specific PCR analyses identified a hypomethylation of MAGE-A1 and NY-ESO-1 promoters in SGI-110-treated neoplastic cells, demonstrating a direct role of pharmacologic DNA demethylation in CTA induction. SGI-110 also up-regulated the expression of HLA class I antigens and of ICAM-1, resulting in an improved recognition of cancer cells by gp100-specific CTL.

  Conclusions: Our findings show that SGI-110 is a highly attractive therapeutic agent to comprehensively increase immunogenicity and immune recognition of neoplastic cells, and provide the scientific rationale for its clinical development to design novel chemo-immunotherapeutic approaches in cancer patients.

• Peripheral CD8(+) T cell proliferation is prognostic for patients with advanced thoracic malignancies. M.J. McCoy, A.K. Nowak, R.G. van der Most, et al. 2013;62(3):529-39. PubMed · Publisher · Free full text

  Abstract

  There is a complex interplay between the immune system and a developing tumor that is manifest in the way that the balance of T cell subsets in the local tumor environment reflects clinical outcome. Tumor infiltration by CD8(+) T cells and regulatory T cells (Treg) is associated with improved and reduced survival, respectively, in many cancer types. However, little is known of the prognostic value of immunological parameters measured in peripheral blood. In this study, peripheral CD8(+) T cells and Treg from 43 patients with malignant mesothelioma or advanced non-small-cell lung cancer scheduled to commence palliative chemotherapy were assessed by flow cytometry and evaluated for association with patient survival. Patients had a higher proportion of peripheral Treg, proliferating CD8(+) T cells and CD8(+) T cells with an activated effector phenotype compared with age-matched healthy controls. Higher proportions of Treg and proliferating CD8(+) T cells were both associated with poor survival in univariate analyses (hazard ratio [HR] 3.81, 95 % CI 1.69-8.57; p < 0.01 and HR 2.86, 95 % CI 1.26-6.50; p < 0.05, respectively). CD8(+) T cell proliferation was independently predictive of reduced survival in multivariate analysis (HR 2.58, 95 % CI 1.01-6.61; p < 0.05). These findings suggest that peripheral CD8(+) T cell proliferation can be a useful prognostic marker in patients with thoracic malignancies planned for palliative chemotherapy.

• Chronic inflammation in tumor stroma is an independent predictor of prolonged survival in epithelioid malignant pleural mesothelioma patients. K. Suzuki, K. Kadota, C.S. Sima, et al. 2011;60(12):1721-8. PubMed · Publisher · Free full text

  Abstract

  This study aims to determine whether a semi-quantitative assessment of inflammatory response in tumor and stroma on routine hematoxylin and eosin-stained (H&E) slides can predict survival in patients with epithelioid malignant pleural mesothelioma (MPM). H&E sections of 175 epithelioid MPM specimens from a single institution (1989-2009) were reviewed. Patients who received neoadjuvant chemotherapy were excluded from analysis. Each tumor was histologically assessed for acute and chronic inflammatory response both within the tumor and the stromal component. Inflammatory response was graded: low (none to mild infiltrate) or high (moderate to severe infiltrate). Log-rank test and Cox proportional hazards regression were used to investigate the association between the degree of inflammation (acute/tumor, acute/stroma, chronic/tumor, and chronic/stroma) and overall survival (OS). Patients with high chronic inflammatory response in stroma (n = 59) had improved survival compared to low (n = 116) (median OS = 19.4 vs. 15.0 months, P = 0.01). This prognostic stratification remained significant in stage III patients (median OS = 16.0 vs. 9.3 months, P = 0.03). In multivariate analysis, chronic inflammation in stroma was an independent predictor of survival (HR = 0.659, 95% CI 0.464-0.937, P = 0.02). While high degree of chronic inflammatory cell infiltration in the stromal component was associated with improved overall survival, degree of other inflammatory responses did not show significant correlation with OS. Our study for the first time investigates inflammatory response in tumor and stroma and not only suggests the prognostic value of inflammatory response in epithelioid MPM but also provides rationale for investigation of immunotherapy to benefit epithelioid MPM patients.

• Immune responses and immunotherapeutic interventions in malignant pleural mesothelioma. A.J. Bograd, K. Suzuki, E. Vertes, et al. 2011;60(11):1509-27. Review PubMed · Publisher · Free full text

  Abstract

  Malignant pleural mesothelioma (MPM) is an aggressive, primary pleural malignancy with poor prognosis, hypothesized to originate from a chronic inflammatory state within the pleura. Similar to what has been observed in other solid tumors (melanoma, ovarian and colorectal cancer), clinical and pre-clinical MPM investigations have correlated anti-tumor immune responses with improved survival. As such, a better understanding of the complex MPM tumor microenvironment is imperative in strategizing successful immunotherapies. Herein, we review the immune responses vital to the development and progression of MPM, as well as assess the role of immunomodulatory therapies, highlighting recent pre-clinical and clinical immunotherapy investigations.

• CD8+ tumor-infiltrating lymphocytes predict favorable prognosis in malignant pleural mesothelioma after resection. N. Yamada, S. Oizumi, E. Kikuchi, et al. 2010;59(10):1543-9. PubMed · Publisher · Free full text

  Abstract

  Defects in human leukocyte antigen (HLA) class I expression may allow tumor cells to escape immune recognition. T cell infiltration is associated with a good prognosis in many cancers. However, the role of HLA class I expression and tumor-infiltrating lymphocytes (TILs) in malignant pleural mesothelioma (MPM) has not been fully analyzed. In the present study, we investigated the immune profiles and conducted outcome analyses of MPM patients. HLA class I expression and TILs (CD4(+), CD8(+), and NK cells) were detected by immunohistochemistry in a series of 44 MPM cases. To detect HLA class I expression, specimens were stained with the anti-pan HLA class I monoclonal antibody EMR8-5. The expression of HLA class I was positive in all patients. There was no case that showed negative HLA class I expression. The density of CD4(+) and CD8(+) TILs were strongly correlated (R = 0.76, p < 0.001). A high density of CD8(+) TILs was a significantly better prognostic factor for the survival of patients with extrapleural pneumonectomy (p < 0.05). Multivariate analysis revealed that a high density of CD8(+) TILs is an independent prognostic factor for patients who underwent extrapleural pneumonectomy. The presence of intratumoral CD8(+) T cells was correlated with an improved clinical outcome, raising the possibility that CD8(+) T cells might play a pivotal role in the antitumor immune response against MPMs. Thus, the stimulation of CD8(+) lymphocytes might be an efficacious immunotherapy for MPM patients.

• WT1 peptide vaccinations induce CD4 and CD8 T cell immune responses in patients with mesothelioma and non-small cell lung cancer. L.M. Krug, T. Dao, A.B. Brown, et al. 2010;59(10):1467-79. PubMed · Publisher · Free full text

  Abstract

  Background: The transcription factor, WT1, is highly overexpressed in malignant pleural mesothelioma (MPM) and immunohistochemical stains for WT1 are used routinely to aid in its diagnosis. Using computer prediction analysis we designed analog peptides derived from WT1 sequences by substituting amino acids at key HLA-A0201 binding positions. We tested the safety and immunogenicity of a WT1 vaccine comprised of four class I and class II peptides in patients with thoracic neoplasms expressing WT1.

  Methods: Therapy consisted of six subcutaneous vaccinations administered with Montanide adjuvant on weeks 0, 4, 6, 8, 10, and 12, with 6 additional monthly injections for responding patients. Injection sites were pre-stimulated with GM-CSF (70 mcg). Immune responses were evaluated by DTH, CD4 T-cell proliferation, CD8 T-cell interferon gamma release, intracellular cytokine staining, WT1 peptide MHC-tetramer staining, and cytotoxicity against WT1 positive tumor cells.

  Results: Nine patients with MPM and 3 with NSCLC were vaccinated, with 8 patients receiving at least 6 vaccinations; in total, 10 patients were evaluable for immune response. Six out of nine patients tested demonstrated CD4 T-cell proliferation to WT1 specific peptides, and five of the six HLA-A0201 patients tested mounted a CD8 T-cell response. Stimulated T cells were capable of cytotoxicity against WT-1 positive cells. Vaccination also induced polyfunctional CD8 T cell responses.

  Conclusions: This multivalent WT1 peptide analog vaccine induces immune responses in a high proportion of patients with thoracic malignancies with minimal toxicity. A randomized trial testing this vaccine as adjuvant therapy in MPM is planned.

2000s

• Tumor eradication after cyclophosphamide depends on concurrent depletion of regulatory T cells: a role for cycling TNFR2-expressing effector-suppressor T cells in limiting effective chemotherapy. R.G. van der Most, A.J. Currie, S. Mahendran, et al. 2009;58(8):1219-28. PubMed · Publisher · Free full text

  Abstract

  Tumor cell death potentially engages with the immune system. However, the efficacy of anti-tumor chemotherapy may be limited by tumor-driven immunosuppression, e.g., through CD25+ regulatory T cells. We addressed this question in a mouse model of mesothelioma by depleting or reconstituting CD25+ regulatory T cells in combination with two different chemotherapeutic drugs. We found that the efficacy of cyclophosphamide to eradicate established tumors, which has been linked to regulatory T cell depletion, was negated by adoptive transfer of CD25+ regulatory T cells. Analysis of post-chemotherapy regulatory T cell populations revealed that cyclophosphamide depleted cycling (Ki-67(hi)) T cells, including foxp3+ regulatory CD4+ T cells. Ki-67(hi) CD4+ T cells expressed increased levels of two markers, TNFR2 and ICOS, that have been associated with a maximally suppressive phenotype according to recently published studies. This suggest that cyclophosphamide depletes a population of maximally suppressive regulatory T cells, which may explain its superior anti-tumor efficacy in our model. Our data suggest that regulatory T cell depletion could be used to improve the efficacy of anti-cancer chemotherapy regimens. Indeed, we observed that the drug gemcitabine, which does not deplete cycling regulatory T cells, eradicates established tumors in mice only when CD25+ CD4+ T cells are concurrently depleted. Cyclophosphamide could be used to achieve regulatory T cell depletion in combination with chemotherapy.

1990s

• Interleukin-6 involvement in mesothelioma pathobiology: inhibition by interferon alpha immunotherapy. H. Bielefeldt-Ohmann, A.L. Marzo, R.P. Himbeck, et al. 1995;40(4):241-50. PubMed · Publisher · Free full text

  Abstract

  A role for interleukin-6 (IL-6) in malignant mesothelioma has been suggested by the clinically presenting symptoms of mesothelioma patients, which include fever, weight loss and thrombocytosis. A murine model of malignant mesothelioma was therefore used to examine the potential role of IL-6 in this cancer type and whether the effect of interferon alpha (IFN alpha) therapy on mesothelioma might be mediated, in part, by regulating IL-6 levels and/or IL-6-induced pathobiology. A panel of human and murine mesothelioma cell lines was assayed for endogenous IL-6 production in a bioassay, and for IL-6-mRNA expression. Four out of 5 human and 5 out of 15 murine mesothelioma cell lines produced moderate to high levels of bioactive IL-6 in vitro. This result was corroborated by mRNA detection. One of the representative murine cell lines, AB22, was chosen for further in vivo studies in the murine mesothelioma model. In AB22-inoculated mice detectable serum IL-6 levels were found to precede macroscopically detectable tumour growth, clinical signs (cachexia, abdominal distension, diarrhoea) and changes in the peripheral lymphoid organs (cell depletion and functional depression). Treatment with anti-IL-6 antibody curtailed the clinical symptoms (P < 0.001), as did treatment with recombinant human (rhu) IFN alpha (P < 0.001). Neither anti-IL-6 antibody nor rhuIFN alpha had a direct growth-inhibitory effect on the AB22 mesothelioma cell line in vitro, however, in vivo rhuIFN alpha treatment of mice inoculated with AB22 cells attenuated both IL-6 mRNA expression in the tumours and serum IL-6 levels, ameliorated the depression of lymphocyte activities, and enhanced the number of tumour-infiltrating lymphocytes and macrophages. On the basis of these results it is suggested that IL-6 mediates some of these effects, directly or indirectly, and that a combination therapy of rhuIFN alpha and anti-IL-6 antibody may be an improved palliative treatment for patients with malignant mesothelioma.

• Patho- and immunobiology of malignant mesothelioma: characterisation of tumour infiltrating leucocytes and cytokine production in a murine model. H. Bielefeldt-Ohmann, D.R. Fitzpatrick, A.L. Marzo, et al. 1994;39(6):347-59. PubMed · Publisher · Free full text

  Abstract

  Malignant mesothelioma (MM) is an aggressive, uniformly fatal serosal tumour, usually associated with asbestos exposure, for which there currently is no effective treatment. In order to gain insight into the mechanism(s) whereby MM might escape immune surveillance, a murine model for MM was used (a) to characterise the tumour-infiltrating lymphocytes (TIL) and macrophages (TIM) phenotypically, (b) to examine systemic immune recognition of MM, and (c) to examine the possible influence of tumour-derived cytokines on systemic and local pathobiological manifestations of MM. A profound down-regulation of lymphocyte surface markers, known to be involved in T cell activation, was found in TIL. Likewise, although TIM were present in large numbers, their expression of MHC class II antigen and integrins was weak or absent, suggestive of altered functional activity. Significant amounts of cytokines, in particular transforming growth factor beta, interleukin-6 (IL-6), IL-1 and tumour necrosis factor were produced during the course of MM tumour development-directly by the MM cells and/or indirectly in response to tumour growth. These factors may contribute both to derangement of antitumour effector mechanisms and to the clinical and pathological manifestations of the disease.

• Effects of natural interferon alpha, natural tumor necrosis factor alpha and their combination on human mesothelioma xenografts in nude mice. T. Ohnuma, L. Szrajer, J.F. Holland, et al. 1993;36(1):31-6. PubMed · Publisher · Free full text

  Abstract

  Effects of human natural interferon alpha (nIFN) alone, human natural tumor necrosis factor alpha (nTNF) alone and their combination (OH-1) were tested on three human mesothelioma lines implanted in nude mice. Tumors were transplanted subcutaneously by trocar on treatment day -12. nIFN was given intraperitoneally (i.p.) at a dose of 2 x 10(7) or 2 x 10(8) IU kg-1 day-1, 5 days a week for 3 weeks. nTNF was given i.p. at a dose of 2 x 10(7) or 2 x 10(8) U kg-1 day-1 in the same schedule as that of nIFN. Tumor diameters were serially measured and tumor volumes were calculated. Antitumor effects were assessed by two methods: comparison of final tumor volumes in treated and control groups (T/C), and changes in median average total tumor volume. The treatment produced no clinically discernible toxicities. nIFN had strong inhibitory activity against all three human mesothelioma lines. nTNF alone had modest activity only at the high dose used. The combination of the two produced activity essentially similar to that produced by nIFN alone. High-dose nIFN may have a role as an active agent in the treatment of patients with mesothelioma.

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