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Keywords:

  • anticancer immune response;
  • chemotherapy;
  • immunotherapy;
  • malignant mesothelioma

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. The immune response to mesothelioma – early phase
  5. The immune response to mesothelioma – late phase
  6. Mesothelioma as a target for immunotherapy
  7. Immunotherapy and chemotherapy – friend or foe?
  8. Immunogenic vs non-immunogenic cell death
  9. Chemoimmunotherapy – the way forward?
  10. Concluding remarks
  11. Acknowledgments
  12. References

Whether the immune system can recognize malignant and premalignant cells and eliminate them to prevent the development of cancer is still a matter of open debate, but in our view, the balance of evidence favours this concept. Nonetheless, the International Agency for Research on Cancer has now predicted that cancer will overtake heart disease as the leading cause of death worldwide by 2010, showing that this protective mechanism often fails. Malignant mesothelioma has traditionally been considered a relatively non-immunogenic cancer. However, mesothelioma cells do express a set of well-defined tumour antigens that have been shown to engage with the host immune system. Mesothelioma should therefore be considered a target for immunotherapy. A variety of anticancer immunotherapies have been investigated in mesothelioma and in other malignancies, although these have been largely ineffective when used in isolation. Over recent years, there has been increasing interest in the possibility of combining immunotherapy with chemotherapy in the fight against cancer. Here, we discuss the rationale behind combining these two, long considered antagonistic, treatment options in the context of malignant mesothelioma.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. The immune response to mesothelioma – early phase
  5. The immune response to mesothelioma – late phase
  6. Mesothelioma as a target for immunotherapy
  7. Immunotherapy and chemotherapy – friend or foe?
  8. Immunogenic vs non-immunogenic cell death
  9. Chemoimmunotherapy – the way forward?
  10. Concluding remarks
  11. Acknowledgments
  12. References

Malignant mesothelioma is an aggressive tumour arising from mesothelial cells lining the pleura, peritoneum or pericardium. The major significant cause of mesothelioma is exposure to airborne asbestos. The disease has therefore received much attention worldwide over recent years because of the important issues of asbestos control and financial compensation. The lag-time between asbestos exposure and disease development is around 30–40 years, and while the incidence of mesothelioma may have already peaked in the United States, it is anticipated that the number of cases in Europe, Australia and Japan will continue to rise over the next 10–20 years [reviewed in (1)]. In areas of Asia and India, the mining and import of asbestos continues today and, in line with rapid economic growth, use of the raw material in these continents has risen dramatically in recent years (2). As there is a positive linear relationship between historical asbestos exposure and death from asbestos-related disease (3), the human cost of asbestos can be expected to rise in these parts of the world until at least 2050.

Although surgery is an option for patients with early-stage mesothelioma, most patients present with advanced locally invasive disease, not amenable to surgical resection. For these patients, the current best treatment is palliative combination chemotherapy with cisplatin and pemetrexed. While this treatment regimen relieves symptoms and has been shown to confer a modest survival benefit (4), median survival is still only 9–12 months from diagnosis. There is therefore an urgent need to develop more effective treatments.

The immune response to mesothelioma – early phase

  1. Top of page
  2. Abstract
  3. Introduction
  4. The immune response to mesothelioma – early phase
  5. The immune response to mesothelioma – late phase
  6. Mesothelioma as a target for immunotherapy
  7. Immunotherapy and chemotherapy – friend or foe?
  8. Immunogenic vs non-immunogenic cell death
  9. Chemoimmunotherapy – the way forward?
  10. Concluding remarks
  11. Acknowledgments
  12. References

The anticancer immune response can be thought of as existing in two phases. The first phase involves the recognition and elimination of malignant and premalignant cells by the immune system to prevent the development of cancer. This is often termed ‘immunosurveillance’. When this protective mechanism fails and cancer develops, the aim was to mount an effective response against the established tumour in order to eradicate it. Herein, we will refer to these processes as the early and late phases of the anticancer immune response.

Although Paul Ehrlich first introduced the idea of cancer immunosurveillance in the early 20th century, it was not until 50 years later that the concept was refined and succinctly expressed by Burnet (5). As this theory introduced a grey area in the easily understood notion of ‘self’ and ‘non-self’, it was not readily accepted and has remained a contentious issue ever since. An ideal research tool for testing the immunosurveillance hypothesis became available with the discovery that mice homozygous for the nu mutation lacked a functional thymus. Despite possessing a greatly reduced number of T cells compared with their wild-type counterparts, athymic nude mice were not found to develop spontaneous or chemically induced tumours at a significantly increased rate (6, 7). This lead to widespread rejection of the idea that the immune system plays a role in cancer prevention. It was not until the 1990s that fresh enthusiasm for the concept was generated when mice lacking interferon (IFN)-γ and/or perforin were found to be more susceptible to tumour formation (8, 9). At the beginning of the 21st century, work using recombination-activating gene knockout mice, which completely lack T, B and natural killer T (NKT) cells, showed that lymphocytes can, indeed, protect against tumour development, at least to some extent, and the theory of cancer immunosurveillance was resurrected (10). In recent years, much compelling evidence has come from animal models of cancer to support the original Burnet hypothesis, along with findings of an increased incidence of malignancy in immunosuppressed individuals [reviewed in (11, 12)]. The milestones involved in understanding the anticancer immune response, as described above, are depicted in Figure 1 and have been reviewed in detail (11).

image

Figure 1. The anticancer immune response – 100 years of debate. IFN, interferon; IL, interleukin; NK, natural killer; RAG, recombination activating gene; TRAIL, tumour necrosis factorrelated apoptosis-inducing ligand.

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It is now becoming clear that the generation of an anticancer immune response involves a complex interplay between the innate and the adaptive arms of the immune system. In the early stages of neoplasia, it seems that the components of the innate immune system play a vital role through the recognition of cancerous and precancerous cells by natural killer (NK) cells. NK cells detect both cell stress markers, through receptors such as NK group 2 member D (NKG2D), and reduced major histocompatibility complex (MHC) class I expression, both of which are a common feature of malignant cells [reviewed in (13)]. Secretion of IFN-γ by NK cells, along with infiltration of macrophages, γδ T cells and NKT cells can directly kill tumour cells and lead to chemokine production, which promotes further lymphocyte recruitment. This inflammatory environment enables the maturation of dendritic cells (DC), which then migrate to the local draining lymph node where they can cross-present antigen to tumour-specific CD8+ T cells. Cross-presentation involves the presentation and processing of exogenous antigen through the MHC class I pathway, as depicted in Figure 2, step c. This is thought to be the primary mechanism by which tumour-specific cytotoxic lymphocytes (CTLs) are generated (14, 15). These CTLs can then migrate to the tumour site, along with tumour-specific CD4+ T cells, and destroy tumour cells displaying the relevant antigen.

image

Figure 2. Mechanisms by which chemotherapy may enhance the anti-tumour immune response: physical destruction of the tumour, making it a smaller target for immune attack (a) and potentially increasing the range of available antigens (b); enhancement of cross-presentation and CD8+ T cell priming (c); increasing sensitivity of tumour cells to cytotoxic lymphocyte (CTL) lysis (d); generation of naïve T cells by homeostatic proliferation following lymphodepletion (e) and depletion of regulatory T cells (Tregs) (f). APC, antigen-presenting cell.

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While it is impossible to determine the extent to which immunosurveillance routinely operates within the body, the fact that tumours develop is a testimony to its fallibility. Many mechanisms used by tumours to subvert immunosurveillance have been elucidated in recent years, such as those outlined in Table 1.

Table 1.  Immunosuppressive mechanisms employed by tumours
Mechanism of immunosuppressionEffect on the immune systemReferences
  1. CTL, cytotoxic lymphocyte; IL, interleukin; MHC, major histocompatibility complex; PDL-1, programmed death ligand-1; TGF, transforming growth factor; TRAIL, tumour necrosis factor receptor-associated apoptosis-inducing ligand.

Downregulation of MHC molecules or tumour antigensInhibits CTL-mediated killing(81, 82)
Secretion of soluble factors including IL-10 and TGF-βPrevents dendritic cell recruitment(83, 84)
Inhibits CD8+ T-cell cross-priming
Promotes the generation of Treg
Expression of indoleamine 2,3-dioxygenaseSuppression of T-cell proliferation through tryptophan depletion(85)
Genetic mutations in death receptors including TRAIL and FasRenders tumour less killable by CTL(86, 87)
Expression of inhibitory molecules such as PDL-1 and B7-H1Inhibits T-cell proliferation and cytokine secretion(88, 89)

The ability of the immune system to generate a response against tumour cells could be of particular relevance within the context of malignant mesothelioma because of the inflammatory events that occur during the initial stages of disease development. The presence of asbestos fibres in the lungs triggers the recruitment of macrophages into the pleural space, which attempt to clear the fibres through phagocytosis. This process results in the production of reactive oxygen species (ROS), which activates the Nalp3 inflammasome, leading to secretion of the inflammatory cytokine interleukin (IL)-1β and further immune cell infiltration (16, 17). This could be considered an ideal environment for the detection and elimination of precancerous cells as described above. However, asbestos fibres are often too large to be effectively phagocytosed resulting in what has been termed ‘frustrated phagocytosis’, whereby macrophages continually try to clear the asbestos fibres without success (18) This results in a state of chronic inflammation and prolonged production of ROS and IL-1β. These conditions have been shown to promote the transformation of human immortalized mesothelial cells in vitro (19). It is therefore plausible that, in this context, the inflammatory environment that develops may promote, rather than prevent, the development of mesothelioma.

The immune response to mesothelioma – late phase

  1. Top of page
  2. Abstract
  3. Introduction
  4. The immune response to mesothelioma – early phase
  5. The immune response to mesothelioma – late phase
  6. Mesothelioma as a target for immunotherapy
  7. Immunotherapy and chemotherapy – friend or foe?
  8. Immunogenic vs non-immunogenic cell death
  9. Chemoimmunotherapy – the way forward?
  10. Concluding remarks
  11. Acknowledgments
  12. References

Once cancer is established, the concept of immunosurveillance is no longer relevant. The identification of tumour-antigen-specific antibodies or CTL in the blood of cancer patients, however, shows that the immune system can be aware of the presence of a tumour and continue to mount a response against it, even if this response is not sufficient to prevent growth of a clinically significant tumour.

Different tumours vary greatly in their immunogenicity. Melanoma is considered to be one of the most immunogenic cancers with most patients developing an anti-tumour immune response (20). An array of melanoma-associated antigens recognized by autologous CTL have been identified including cancer–germ line genes such as the melanoma antigen-encoding gene family, melanocyte differentiation antigens, non-tissue-specific antigens overexpressed in melanoma and neo antigens resulting from point mutations [reviewed in (21)]. Intratumoral T-cell infiltration has been associated with improved survival in melanoma patients (22), as has the development of vitiligo-like hypopigmentation (23). The latter is thought to result from the destruction of normal melanocytes by autoantibodies and autoreactive T cells produced in response to the melanoma. In most patients, however, the spontaneous immune response is not powerful enough to eliminate the tumour or is unable to overcome local immunosuppressive mechanisms.

Despite the inflammatory nature of its origin, mesothelioma is considered comparatively non-immunogenic. Tumour-specific antibodies and CTL, for example, are identified less frequently in the blood of mesothelioma patients than that of melanoma patients. Human mesothelioma cells secrete immunosuppressive factors such as transforming growth factor-β (TGF-β) (24). While originally identified as an inducer of oncogenesis (hence its name), TGF-β is a complex cytokine that stimulates growth of some cell types while inhibiting that of others (25). Blocking TGF-β inhibits the proliferation of murine mesothelioma cells in vitro and reduces tumour growth in vivo (26). Secretion of this cytokine, therefore, may have the dual function of stimulating tumour growth while suppressing the anti-tumour immune response.

Nonetheless, mesothelioma cells do have the potential to be immunogenic as several mesothelioma-associated tumour antigens have been identified. Mesothelin, a differentiation antigen expressed at low levels on mesothelial cells of the pleura, peritoneum and pericardium has been found to be highly expressed in the majority of mesotheliomas as well as in ovarian and pancreatic cancer (27). Mesothelin-specific antibodies have been detected in the sera of mesothelioma patients (28), and while the prognostic significance of this is unclear, high tumour mesothelin expression correlates with increased survival in high-grade ovarian cancer following surgery and adjuvant chemotherapy (29). Another antigen expressed on mesothelioma cells is mucin 1 (MUC1), also known as epithelial membrane antigen. MUC1 is a heavily glycosylated protein expressed by epithelial cells of many tissues (30). Mesothelioma cells, however, not only have significantly increased MUC1 expression but also express alternative splice forms of the protein and display alterations in epitope expression compared with normal mesothelial cells (31). The tumour antigens, survivin and telomerase, which are widely expressed by human cancers, are also commonly expressed by mesothelioma (32, 33).

The presence of tumour-infiltrating lymphocytes (TILs) has been associated with better prognosis in a several human malignancies including colorectal and ovarian cancers (34–36). Conversely, infiltration of regulatory T cells (Treg), suppressors of the immune response, has been linked to poor prognosis (37, 38). Treg infiltration was, however, recently found to be associated with improved survival in colorectal cancer (39). An infiltrate of CD4+ and CD8+ T cells and Treg has been found in human mesothelioma biopsies (24), showing that mesothelioma does engage the immune system.

Could it be possible, therefore, that the inability to mount an effective anti-tumour immune response to mesothelioma may be a result of tumour-induced local immunosuppression rather than because of the immune system being ignorant of the tumour’s presence?

Mesothelioma as a target for immunotherapy

  1. Top of page
  2. Abstract
  3. Introduction
  4. The immune response to mesothelioma – early phase
  5. The immune response to mesothelioma – late phase
  6. Mesothelioma as a target for immunotherapy
  7. Immunotherapy and chemotherapy – friend or foe?
  8. Immunogenic vs non-immunogenic cell death
  9. Chemoimmunotherapy – the way forward?
  10. Concluding remarks
  11. Acknowledgments
  12. References

Immunotherapies are either targeted at known tumour antigens, with the aim of generating a de novo anti-tumour immune response, or non-specific, usually with the aim of amplifying an existing response. Antigen-specific immunotherapies can take the form of ‘cancer vaccines’, whereby tumour antigens are administered as peptides or DNA/RNA-containing viral or bacterial vectors, in order to increase antigen availability and therefore stimulate the expansion of tumour-specific T cells. They can also be tumour cell directed, such as monoclonal antibodies that bind and ‘tag’ tumour cells for immune-mediated destruction. Non-specific immunotherapies include, the administration of cytokines, chemokines, activating or blocking antibodies and toll-like receptor ligands. These are often used to stimulate the innate immune response or induce the maturation/activation of antigen-presenting cells (APCs). However, they can also target effector cells directly or, in the case of blocking antibodies, inhibit negative regulators of the immune response, such as Treg. Non-specific immunotherapies can be used as adjuvants in combination with antigen-targeted therapies in order to increase the potency of an induced anti-tumour response.

The fact that mesothelioma can engage, or at least has the potential to engage, the immune system makes it a good candidate for immunotherapy. Several immunotherapies have been investigated to date, and these are listed in Table 2. Those we believe to be of most interest are discussed in more detail below.

Table 2.  Immunotherapies investigated for the treatment of mesothelioma
TherapyMechanisms of actionAnti-tumour effectsReferences
  1. ADCC, antibody-dependent cellular cytotoxicity; APC, antigen-presenting cell; CTL, cytotoxic T lymphocyte; DC, dendritic cell, IFN, interferon; IL, interleukin; MHC, major histocompatibility complex; NK, natural killer; TLR, toll-like receptor.

Type I IFN administrationEnhances NK-cell and macrophage functionsInduction of systemic anti-tumour immunity in murine models of mesothelioma(41, 42)
Stimulates DC maturation
Promotes cross-priming of CD8+ T cellsPhase I clinical trials have shown feasibility and tolerability
Increases MHC class I expression on tumour cells
CD40 ligation using CD40L or an α-CD40-activating antibodyStimulates the generation of tumour-specific CTL by inducing both the upregulation of costimulatory molecules on APC and the IL-12 productionAnti-tumour effects in preclinical studies(46, 47)
Early-phase clinical trial underway in other cancers
Treg depletionRemoval of endogenous immunosuppressionEffective in preclinical studies(48)
TLR agonistsActivate components of the innate immune system by mimicking viral/bacterial infectionInduction of effective anti-tumour responses in preclinical studies(90, 91)
Anti-tumour activity showed in metastatic melanoma
IL-2Stimulates T-cell proliferation and enhances T-cell functionRegression of small tumours showed in a murine model of mesothelioma when administered intratumorally(92)
Damages the tumour vasculature
Mesothelin-targeted immunotherapyTumour-specific T-cell stimulation through increased antigen availabilityAnti-tumour effects showed in phase I clinical trials(93)
Induction of tumour cell death through ADCC/inhibition of protein synthesis

The use of type I IFNs has been one of the most extensively studied immunotherapies for the treatment of mesothelioma. Type I IFNs are known to enhance NK-cell and macrophage functions and have also been shown to stimulate DC maturation, promote the cross-priming of CD8+ T cells and increase MHC class I expression on tumour cells [reviewed in (40)]. Impressive anti-tumour effects have been observed following administration of type I IFNs in murine models of mesothelioma, including the induction of systemic anti-tumour immunity, resulting in the elimination of tumours distal to the treatment site (41). Phase I clinical trials have shown that intrapleural IFN-β gene therapy is feasible and well tolerated in mesothelioma patients (42).

CD40L (also known as CD154) and the activating anti-CD40 antibody FGK45 can be used to stimulate the generation of tumour-specific CTL indirectly through replacing CD4+ T-cell help. CD40 is a costimulatory molecule expressed on APC, while its ligand CD40L is expressed mainly on CD4+ T cells and mast cells (43). The interaction of CD40 with CD40L results in the production of IL-12 and the upregulation of costimulatory molecules of the B7 family on the APC, both of which are required for the priming of CTL (44, 45). Treatment has been found to have anti-tumour effects in several animal models including murine mesothelioma (46). CD40-activating strategies are in early-phase clinical trials but have not yet been tested in mesothelioma (47).

Treg depletion represents one way in which a block on anti-tumour immunity can be removed. The depletion of Treg using the anti-CD25 antibody PC61 has been shown to induce infiltration of IFN-γ-producing T and NK cells into murine mesothelioma, resulting in immune-mediated tumour rejection (48).

While the immunotherapies described above have achieved promising results in preclinical studies, their efficacy as monotherapies in patients has, on the whole, been disappointing. It is unlikely, therefore, that such treatments will convey significant clinical benefit in mesothelioma when used alone. We and others have suggested that immunotherapy should be combined with conventional cancer treatments including chemotherapy, surgery and radiotherapy (49). The most pragmatic option is to combine immunotherapy with cytotoxic chemotherapy as this is the current treatment for patients with unresectable mesothelioma and has proven, albeit modest, efficacy.

Immunotherapy and chemotherapy – friend or foe?

  1. Top of page
  2. Abstract
  3. Introduction
  4. The immune response to mesothelioma – early phase
  5. The immune response to mesothelioma – late phase
  6. Mesothelioma as a target for immunotherapy
  7. Immunotherapy and chemotherapy – friend or foe?
  8. Immunogenic vs non-immunogenic cell death
  9. Chemoimmunotherapy – the way forward?
  10. Concluding remarks
  11. Acknowledgments
  12. References

Chemotherapy and immunotherapy have historically been considered antagonistic treatment options for two reasons. First, most commonly used chemotherapy drugs are not specifically toxic to tumour cells but target all dividing cells, including lymphocytes, so exert an immunosuppressive effect. Second, chemotherapy usually kills tumour cells through apoptosis, which has long been thought of as a non-immunogenic form of cell death, resulting in the tolerization rather than priming of specific CTL (50). However, chemotherapy-induced cell death may actually have the potential to enhance the development of an anti-tumour immune response through altering both the level and the context of antigen presentation. The mechanisms by which this might occur are outlined in Figure 2.

Physical destruction of a tumour by chemotherapy not only makes it a smaller target for immune attack but also potentially increases the range of tumour antigens available to enter the cross-presentation pathway. In a murine model of mesothelioma, the nucleoside analogue gemcitabine has been shown to significantly increase the level of antigen presentation to tumour-specific CD8+ T cells for a given tumour size. These CD8+ T cells were neither tolerized nor deleted, and vaccination of tumour-bearing animals following gemcitabine treatment resulted in a marked decrease in tumour growth and increased survival compared with vaccination without gemcitabine (51). Certain cytotoxic drugs have also been shown to increase the sensitivity of both tumour cells and surrounding stromal cells to immune-mediated attack (52–54). Importantly, this has been shown for the platinum compound cisplatin, which is currently used in the first-line treatment of mesothelioma in combination with pemetrexed (55).

With regard to altering the context of antigen presentation, chemotherapy-induced lymphopenia could, paradoxically, be exploited to enhance anti-tumour immunity. After lymphodepletion, there follows a period of homeostatic T-cell reconstitution driven by immunostimulatory cytokines, including IL-7, IL-15 and IL-21, resulting in a population of newly generated naïve T cells (56). This freshly reconstituted T-cell pool is biased towards self-antigen reactivity and that this could be exploited, through increasing the level of available antigen, to trigger an effective anti-tumour immune response (57). It also appears that while total lymphocyte numbers fall during chemotherapy, B lymphocytes are more profoundly affected leaving T lymphocytes somewhat spared. This has been shown in both animal models and cancer patients (58, 59) and could potentially skew any ensuing immune response towards cell-mediated immunity.

Certain chemotherapy drugs may selectively target Treg. This has been most convincingly shown for the drug cyclophosphamide, which was shown almost 30 years ago to augment delayed-type hypersensitivity reactions in humans (60). Since then, low-dose cyclophosphamide has been shown to selectively deplete Treg in both animal models and cancer patients (61, 62). Selective Treg depletion and restoration of T-cell and NK-cell effector functions have been observed in patients with advanced metastatic cancer receiving 100 mg/day cyclophosphamide. Increasing the dose to 200 mg/day causes the indiscriminate depletion of all lymphocyte subsets.

The mechanism by which cyclophosphamide depletes Treg is yet to be fully understood. However, we have recently shown in murine mesothelioma that cyclophosphamide may not specifically target Treg per se but simply deplete those cells that are most actively proliferating (63). Because the proportion of Treg relative to other T-cell subsets is often increased in the tumour microenvironment (24, 37, 38), could this explain why cyclophosphamide appears to affect Treg more profoundly? We also observed that cycling Treg in this model expressed both inducible costimulatory molecule (ICOS) and tumour necrosis factor receptor type 2 (TNFR2). Both these markers have been associated with maximal suppressive activity (64, 65), pointing perhaps to depletion of a maximally suppressive ‘effector Treg’ population. There has been little research into the effect of other cytotoxic drugs on Treg, although it has been recently suggested that the taxane, paclitaxel, exerts similar effects to cyclophosphamide (66), while gemcitabine does not appear to show a propensity for selective Treg depletion (63).

Few studies to date have investigated the relationship between chemotherapy-induced changes in immunological parameters and clinical response in cancer patients. Recently, however, Anraku et al. reported on a study assessing levels of TILs in patients with malignant pleural mesothelioma, who had received induction chemotherapy with cisplatin/pemetrexed or cisplatin/vinorelbine prior to extrapleural pneumonectomy (67). The presence of high levels of CD8+ TIL following chemotherapy was found to be an independent predictor of delayed recurrence and improved survival. Interestingly, higher levels of CD8+ TIL were observed in patients treated with cisplatin/pemetrexed than in those treated with cisplatin/vinorelbine. Increased tumour infiltration of CD8+ T cells and reduced infiltration of Treg following chemotherapy have also been observed to correlate with improved clinical response in breast cancer (68, 69). Results from studies such as these are encouraging and suggest that immunopotentiating effects of chemotherapy may indeed translate into clinical benefits for the patient. These results also begin to suggest that different drug combinations may engage differently with the human immune response.

Immunogenic vs non-immunogenic cell death

  1. Top of page
  2. Abstract
  3. Introduction
  4. The immune response to mesothelioma – early phase
  5. The immune response to mesothelioma – late phase
  6. Mesothelioma as a target for immunotherapy
  7. Immunotherapy and chemotherapy – friend or foe?
  8. Immunogenic vs non-immunogenic cell death
  9. Chemoimmunotherapy – the way forward?
  10. Concluding remarks
  11. Acknowledgments
  12. References

It is now becoming clear that different cytotoxic agents vary considerably in their capacity to induce immunogenic cell death. Casares et al., reported that while doxorubicin and mitomycin C initiate apoptotic cell death with caspase activation, only doxorubicin-killed tumour cells were able to elicit an effective anti-tumour immune response in a murine colon carcinoma model (70). We have recently assessed the immunogenicity of cell death induced by a variety of chemotherapy drugs in our model of murine mesothelioma by comparing anti-tumour effects in athymic nude and wild-type mice. We found that doxorubicin was less dependent on a fully functional immune system than either pemetrexed or gemcitabine (unpublished data). It may be, therefore, that the immunogenicity of chemotherapy-induced death is tumour type dependent.

Two factors have now been put forward as indicative of immunogenic cell death: the translocation of calreticulin to the cell surface of dying tumour cells and their secretion of the non-histone chromatin-binding nuclear constituent, high-mobility group box 1 (HMGB1) (71, 72). We know that there are many molecular signals and/or cellular events that distinguish immunogenic from non-immunogenic cell death and hypothesize others are yet to be discovered. IL-1α has recently been identified as a key mediator of the neutrophilic inflammatory response to necrotic and UV-irradiated cells in mice through the Myd88 signalling pathway (73). It is not yet known whether the isoforms of IL-1 play a differential role in dictating the immunogenicity of chemotherapy-induced cell death.

So, while chemotherapy clearly has the potential to synergize with immunotherapy, careful drug selection will be of utmost importance.

Chemoimmunotherapy – the way forward?

  1. Top of page
  2. Abstract
  3. Introduction
  4. The immune response to mesothelioma – early phase
  5. The immune response to mesothelioma – late phase
  6. Mesothelioma as a target for immunotherapy
  7. Immunotherapy and chemotherapy – friend or foe?
  8. Immunogenic vs non-immunogenic cell death
  9. Chemoimmunotherapy – the way forward?
  10. Concluding remarks
  11. Acknowledgments
  12. References

Over the past decade, preclinical studies have shown synergy between chemotherapy and immunotherapy in several cancer types (74–77). In murine mesothelioma, combining cytotoxic chemotherapy (gemcitabine) with an APC-directed non-specific immunotherapy (FGK45) has been shown to induce long-term cures in up to 80% of animals, all of which were then resistant to rechallenge (78). This was vastly superior to either chemotherapy or immunotherapy alone, which only delayed tumour growth. Timing, however, proved to be crucial as the combination treatment was only effective when FGK45 therapy followed gemcitabine. Administering FGK45 prior to chemotherapy actually proved less effective than gemcitabine alone, whereas concurrent treatment was excessively toxic. Recently, we have also shown that Treg depletion significantly improves the efficacy of gemcitabine in this model (63).

While there are little data regarding the use of chemoimmunotherapy in patients with malignant mesothelioma, various treatment combinations have been investigated in phase I/II clinical trials in other malignancies. These have generally been encouraging and suggestive of synergistic effects. Probably, the most provocative results to date have been seen in metastatic colon cancer. In a phase II clinical trial of gemcitabine plus FOLFOX (5-fluorouracil ± levofolinic acid + oxaliplatin) chemotherapy, combined with subcutaneous granulocyte–macrophage colony-stimulating factor and IL-2, median time to progression was shown to be significantly greater than previously reported for any other treatment regimen (79). Improved clinical outcome was also shown to correlate with immunological parameters, including increased activation of tumour-specific CTL and depletion of Treg, in these patients (80).

The use of combinations of cytotoxic chemotherapy with immunotherapy has the potential to move the field forward with well-designed clinical trials. When immunotherapy has been considered an alternative, rather than an addition, to chemotherapy, randomized phase II and III clinical trials have been difficult to design and conduct. However, the testing of immunotherapy in the context of chemotherapy may finally be able to bring immunotherapy into the first-line setting using randomized phase II and III clinical trials with standard chemotherapy as a control arm. The sophisticated laboratory models for investigation of immunotherapy also deserve sound scientific design in subsequent clinical testing.

Concluding remarks

  1. Top of page
  2. Abstract
  3. Introduction
  4. The immune response to mesothelioma – early phase
  5. The immune response to mesothelioma – late phase
  6. Mesothelioma as a target for immunotherapy
  7. Immunotherapy and chemotherapy – friend or foe?
  8. Immunogenic vs non-immunogenic cell death
  9. Chemoimmunotherapy – the way forward?
  10. Concluding remarks
  11. Acknowledgments
  12. References

In recent years, it has emerged that chemotherapy and immunotherapy can form a practical partnership in the treatment of cancer. While traditionally considered to be relatively non-immunogenic, it is now evident that malignant mesothelioma does indeed engage the host’s immune system, and chemoimmunotherapy combinations have been shown to be effective in animal models of the disease. With median survival still only 9–12 months from diagnosis, we propose that combining current standard chemotherapy with immunotherapy may be the way forward in the treatment of mesothelioma. We are about to commence a phase I clinical trial, combining standard chemotherapy with cyclophosphamide, with the aim of depleting Treg and are also planning a phase I trial of a humanized αCD40-activating antibody with standard chemotherapy. As different cytotoxic drugs appear to vary considerably in their immune-related effects, it is becoming more and more clear that careful drug selection, dosing and scheduling will be paramount when designing combined chemoimmunotherapy regimens.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. The immune response to mesothelioma – early phase
  5. The immune response to mesothelioma – late phase
  6. Mesothelioma as a target for immunotherapy
  7. Immunotherapy and chemotherapy – friend or foe?
  8. Immunogenic vs non-immunogenic cell death
  9. Chemoimmunotherapy – the way forward?
  10. Concluding remarks
  11. Acknowledgments
  12. References

Work cited in this review was supported by project grants from the National Health (NH) and Medical Research Council (MRC) National Centre for Asbestos Related Disease, Raine Foundation and Cancer Council Western Australia. MJM is funded by an International Postgraduate Research Scholarship.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. The immune response to mesothelioma – early phase
  5. The immune response to mesothelioma – late phase
  6. Mesothelioma as a target for immunotherapy
  7. Immunotherapy and chemotherapy – friend or foe?
  8. Immunogenic vs non-immunogenic cell death
  9. Chemoimmunotherapy – the way forward?
  10. Concluding remarks
  11. Acknowledgments
  12. References