Limits...
Cyclophosphamide chemotherapy sensitizes tumor cells to TRAIL-dependent CD8 T cell-mediated immune attack resulting in suppression of tumor growth.

van der Most RG, Currie AJ, Cleaver AL, Salmons J, Nowak AK, Mahendran S, Larma I, Prosser A, Robinson BW, Smyth MJ, Scalzo AA, Degli-Esposti MA, Lake RA - PLoS ONE (2009)

Bottom Line: This treatment was associated with an IFN-alpha/beta response and a profound negative impact on the anti-tumor and total CD8 T cell responses.Despite this negative effect, CD8 T cells were essential for curative responses.The important effector molecules used by the anti-tumor immune response included IFN-gamma and TRAIL.

View Article: PubMed Central - PubMed

Affiliation: National Research Centre for Asbestos Related Diseases, University of Western Australia, Perth, Australia. robbertvdm@gmail.com

ABSTRACT

Background: Anti-cancer chemotherapy can be simultaneously lymphodepleting and immunostimulatory. Pre-clinical models clearly demonstrate that chemotherapy can synergize with immunotherapy, raising the question how the immune system can be mobilized to generate anti-tumor immune responses in the context of chemotherapy.

Methods and findings: We used a mouse model of malignant mesothelioma, AB1-HA, to investigate T cell-dependent tumor resolution after chemotherapy. Established AB1-HA tumors were cured by a single dose of cyclophosphamide in a CD8 T cell- and NK cell-dependent manner. This treatment was associated with an IFN-alpha/beta response and a profound negative impact on the anti-tumor and total CD8 T cell responses. Despite this negative effect, CD8 T cells were essential for curative responses. The important effector molecules used by the anti-tumor immune response included IFN-gamma and TRAIL. The importance of TRAIL was supported by experiments in nude mice where the lack of functional T cells could be compensated by agonistic anti-TRAIL-receptor (DR5) antibodies.

Conclusion: The data support a model in which chemotherapy sensitizes tumor cells for T cell-, and possibly NK cell-, mediated apoptosis. A key role of tumor cell sensitization to immune attack is supported by the role of TRAIL in tumor resolution and explains the paradox of successful CD8 T cell-dependent anti-tumor responses in the absence of CD8 T cell expansion.

Show MeSH

Related in: MedlinePlus

CD8 T cell effector mechanisms.(A) Tumor growth and Kaplan-Meier survival curves in CY-treated IFN-γ-deficient mice and control mice. Data shown are mean±SEM (n = 5) from one experiment (growth curve, left panel) or total data from two experiments (survival curve, right panel). Tumor cells were inoculated at day 0, treated with CY at day 9. * P<0.05 when CY in immunocompetent mice and IFN-γ deficient mice is compared. (B) Tumor growth curves and Kaplan-Meier survival curves in CY-treated perforin-deficient and normal control mice. ns = not significant when CY in immuno-competent and perforin-deficient mice are compared. Tumor cells were inoculated at day 0 and treated with CY at day 8. ns, not significant. (C) Tumor growth and Kaplan-Meier survival curves after CY treatment in perforin/IFN-γ double-deficient mice, compared to immunocompetent mice. Data shown are mean±SEM (n = 5) from one experiment (growth curve, left panel) or total data from two experiments (survival curve, right panel). Tumor cells were inoculated at day 0 and treated with CY at day 9. * P<0.05, *** P<0.001 when BALB/c + CY is compared with IFN-γ/pfp-ko + CY.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2734989&req=5

pone-0006982-g005: CD8 T cell effector mechanisms.(A) Tumor growth and Kaplan-Meier survival curves in CY-treated IFN-γ-deficient mice and control mice. Data shown are mean±SEM (n = 5) from one experiment (growth curve, left panel) or total data from two experiments (survival curve, right panel). Tumor cells were inoculated at day 0, treated with CY at day 9. * P<0.05 when CY in immunocompetent mice and IFN-γ deficient mice is compared. (B) Tumor growth curves and Kaplan-Meier survival curves in CY-treated perforin-deficient and normal control mice. ns = not significant when CY in immuno-competent and perforin-deficient mice are compared. Tumor cells were inoculated at day 0 and treated with CY at day 8. ns, not significant. (C) Tumor growth and Kaplan-Meier survival curves after CY treatment in perforin/IFN-γ double-deficient mice, compared to immunocompetent mice. Data shown are mean±SEM (n = 5) from one experiment (growth curve, left panel) or total data from two experiments (survival curve, right panel). Tumor cells were inoculated at day 0 and treated with CY at day 9. * P<0.05, *** P<0.001 when BALB/c + CY is compared with IFN-γ/pfp-ko + CY.

Mentions: To address the question how CD8 T cells can be the key mediators for tumor resolution under conditions that limit T cell proliferation, we set out to delineate the effector mechanisms responsible for the CY-induced anti-tumor immune responses. We evaluated the roles of different CD8 T cell effector mechanisms using gene-targeted mice lacking specific CD8 T cell effector functions, i.e., IFN-γ and/or perforin. To define the role of IFN-γ, we analyzed tumor growth in IFN-γ knock-out mice and found that IFN-γ deficiency prevented the anti-tumor response in 7/10 mice (total for two experiments) (Figure 5A) (P<0.05 in the growth curve and P<0.05 in the survival curve). To determine whether direct CD8 T cell cytotoxicity was required for the CY-induced anti-tumor response, we assessed the efficacy of CY in perforin (pfp)-deficient mice. Perforin-deficiency did not abolish the anti-tumor efficacy of CY (Figure 5B), and there was no significant difference in survival (Figure 5B). It is important to note that slightly larger tumors were treated in these experiments (4–6 mm2 instead of 1 mm2 in other experiments), which has a negative impact on the efficacy of CY. This explains why CY is less efficacious in these experiments. Finally, we evaluated the efficacy of CY in IFN-γ/perforin double knock-out mice and found that combined deficiency of IFN-γ and perforin completely abrogated the CY-induced anti-tumor effects (9/9 mice, two experiments), consistent with the results from the IFN-γ-knock-out mice and highlighting the key role of this effector molecule (Figure 5C). In fact, these tumors grew with similar kinetics as in T-cell deficient nude mice (Figure 6B), consistent with our previous data [18].


Cyclophosphamide chemotherapy sensitizes tumor cells to TRAIL-dependent CD8 T cell-mediated immune attack resulting in suppression of tumor growth.

van der Most RG, Currie AJ, Cleaver AL, Salmons J, Nowak AK, Mahendran S, Larma I, Prosser A, Robinson BW, Smyth MJ, Scalzo AA, Degli-Esposti MA, Lake RA - PLoS ONE (2009)

CD8 T cell effector mechanisms.(A) Tumor growth and Kaplan-Meier survival curves in CY-treated IFN-γ-deficient mice and control mice. Data shown are mean±SEM (n = 5) from one experiment (growth curve, left panel) or total data from two experiments (survival curve, right panel). Tumor cells were inoculated at day 0, treated with CY at day 9. * P<0.05 when CY in immunocompetent mice and IFN-γ deficient mice is compared. (B) Tumor growth curves and Kaplan-Meier survival curves in CY-treated perforin-deficient and normal control mice. ns = not significant when CY in immuno-competent and perforin-deficient mice are compared. Tumor cells were inoculated at day 0 and treated with CY at day 8. ns, not significant. (C) Tumor growth and Kaplan-Meier survival curves after CY treatment in perforin/IFN-γ double-deficient mice, compared to immunocompetent mice. Data shown are mean±SEM (n = 5) from one experiment (growth curve, left panel) or total data from two experiments (survival curve, right panel). Tumor cells were inoculated at day 0 and treated with CY at day 9. * P<0.05, *** P<0.001 when BALB/c + CY is compared with IFN-γ/pfp-ko + CY.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2734989&req=5

pone-0006982-g005: CD8 T cell effector mechanisms.(A) Tumor growth and Kaplan-Meier survival curves in CY-treated IFN-γ-deficient mice and control mice. Data shown are mean±SEM (n = 5) from one experiment (growth curve, left panel) or total data from two experiments (survival curve, right panel). Tumor cells were inoculated at day 0, treated with CY at day 9. * P<0.05 when CY in immunocompetent mice and IFN-γ deficient mice is compared. (B) Tumor growth curves and Kaplan-Meier survival curves in CY-treated perforin-deficient and normal control mice. ns = not significant when CY in immuno-competent and perforin-deficient mice are compared. Tumor cells were inoculated at day 0 and treated with CY at day 8. ns, not significant. (C) Tumor growth and Kaplan-Meier survival curves after CY treatment in perforin/IFN-γ double-deficient mice, compared to immunocompetent mice. Data shown are mean±SEM (n = 5) from one experiment (growth curve, left panel) or total data from two experiments (survival curve, right panel). Tumor cells were inoculated at day 0 and treated with CY at day 9. * P<0.05, *** P<0.001 when BALB/c + CY is compared with IFN-γ/pfp-ko + CY.
Mentions: To address the question how CD8 T cells can be the key mediators for tumor resolution under conditions that limit T cell proliferation, we set out to delineate the effector mechanisms responsible for the CY-induced anti-tumor immune responses. We evaluated the roles of different CD8 T cell effector mechanisms using gene-targeted mice lacking specific CD8 T cell effector functions, i.e., IFN-γ and/or perforin. To define the role of IFN-γ, we analyzed tumor growth in IFN-γ knock-out mice and found that IFN-γ deficiency prevented the anti-tumor response in 7/10 mice (total for two experiments) (Figure 5A) (P<0.05 in the growth curve and P<0.05 in the survival curve). To determine whether direct CD8 T cell cytotoxicity was required for the CY-induced anti-tumor response, we assessed the efficacy of CY in perforin (pfp)-deficient mice. Perforin-deficiency did not abolish the anti-tumor efficacy of CY (Figure 5B), and there was no significant difference in survival (Figure 5B). It is important to note that slightly larger tumors were treated in these experiments (4–6 mm2 instead of 1 mm2 in other experiments), which has a negative impact on the efficacy of CY. This explains why CY is less efficacious in these experiments. Finally, we evaluated the efficacy of CY in IFN-γ/perforin double knock-out mice and found that combined deficiency of IFN-γ and perforin completely abrogated the CY-induced anti-tumor effects (9/9 mice, two experiments), consistent with the results from the IFN-γ-knock-out mice and highlighting the key role of this effector molecule (Figure 5C). In fact, these tumors grew with similar kinetics as in T-cell deficient nude mice (Figure 6B), consistent with our previous data [18].

Bottom Line: This treatment was associated with an IFN-alpha/beta response and a profound negative impact on the anti-tumor and total CD8 T cell responses.Despite this negative effect, CD8 T cells were essential for curative responses.The important effector molecules used by the anti-tumor immune response included IFN-gamma and TRAIL.

View Article: PubMed Central - PubMed

Affiliation: National Research Centre for Asbestos Related Diseases, University of Western Australia, Perth, Australia. robbertvdm@gmail.com

ABSTRACT

Background: Anti-cancer chemotherapy can be simultaneously lymphodepleting and immunostimulatory. Pre-clinical models clearly demonstrate that chemotherapy can synergize with immunotherapy, raising the question how the immune system can be mobilized to generate anti-tumor immune responses in the context of chemotherapy.

Methods and findings: We used a mouse model of malignant mesothelioma, AB1-HA, to investigate T cell-dependent tumor resolution after chemotherapy. Established AB1-HA tumors were cured by a single dose of cyclophosphamide in a CD8 T cell- and NK cell-dependent manner. This treatment was associated with an IFN-alpha/beta response and a profound negative impact on the anti-tumor and total CD8 T cell responses. Despite this negative effect, CD8 T cells were essential for curative responses. The important effector molecules used by the anti-tumor immune response included IFN-gamma and TRAIL. The importance of TRAIL was supported by experiments in nude mice where the lack of functional T cells could be compensated by agonistic anti-TRAIL-receptor (DR5) antibodies.

Conclusion: The data support a model in which chemotherapy sensitizes tumor cells for T cell-, and possibly NK cell-, mediated apoptosis. A key role of tumor cell sensitization to immune attack is supported by the role of TRAIL in tumor resolution and explains the paradox of successful CD8 T cell-dependent anti-tumor responses in the absence of CD8 T cell expansion.

Show MeSH
Related in: MedlinePlus