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Tumor necrosis factor is dispensable for the success of immunogenic anticancer chemotherapy.

Ma Y, Yamazaki T, Yang H, Kepp O, Galluzzi L, Zitvogel L, Smyth MJ, Kroemer G - Oncoimmunology (2013)

Bottom Line: The antineoplastic effects of anthracyclines have been shown to rely, at least in part, on a local immune response that involves dendritic cells (DCs) and several distinct subsets of T lymphocytes.In particular, TNFα-blocking strategies did not influence the antineoplastic effects of doxorubicin (a prototypic anthracycline) against MCA205 fibrosarcomas growing in C57BL/6 mice, F244 sarcomas developing in 129/Sv hosts and H2N100 mammary carcinomas arising in BALB/c mice.These findings imply that, in contrast to other cytokines (such as interleukin-1β, interleukin-17 and interferon γ), TNFα is not required for anthracyclines to elicit therapeutic anticancer immune responses.

View Article: PubMed Central - PubMed

Affiliation: INSERM, U848; Villejuif, France ; Institut Gustave Roussy, Villejuif, France ; Université Paris Sud/Paris XI; Le Kremlin Bicêtre; Paris, France.

ABSTRACT
The antineoplastic effects of anthracyclines have been shown to rely, at least in part, on a local immune response that involves dendritic cells (DCs) and several distinct subsets of T lymphocytes. Here, we show that the administration of anthracyclines to mice bearing established neoplasms stimulates the intratumoral secretion of tumor necrosis factor α (TNFα). However, blocking the TNFα/TNF receptor (TNFR) system by three different strategies-namely, (1) neutralizing antibodies, (2) etanercept, a recombinant protein in which TNFR is fused to the constant domain of an IgG1 molecule, and (3) gene knockout-failed to negatively affect the therapeutic efficacy of anthracyclines in three distinct tumor models. In particular, TNFα-blocking strategies did not influence the antineoplastic effects of doxorubicin (a prototypic anthracycline) against MCA205 fibrosarcomas growing in C57BL/6 mice, F244 sarcomas developing in 129/Sv hosts and H2N100 mammary carcinomas arising in BALB/c mice. These findings imply that, in contrast to other cytokines (such as interleukin-1β, interleukin-17 and interferon γ), TNFα is not required for anthracyclines to elicit therapeutic anticancer immune responses.

No MeSH data available.


Related in: MedlinePlus

Figure 3. Influence of TNFα on the therapeutic effects of anthracyclines. (A–D) Tnf−/−(A) or wild type (WT) (A and B) C57BL/6 mice carrying MCA205 fibrosarcomas (tumor surface 25–45 mm2) were treated with doxorubicin (DX) or an equivalent volume of PBS, as a single intratumoral injection (day 8). On the same day, some of the mice were initiated on a course of intraperitoneal etanercept (ETA), for 4 consecutive days. Alternatively, WT 129/Sv mice bearing established F244 sarcomas (C) or BALB/c mice harboring H2N100 mammary carcinomas (D) received DX or an equivalent volume of PBS, as a single intratumoral injection, on day 10 or 8 after the inoculation of tumor cells, respectively. One day prior to chemotherapy, a fraction of mice was initiated on a course of TNFα-neutralizing antibodies (or isotype-matched control antibodies), which were given i.v. on days 9, 10, 14, 17 and 21 (C) or on day 7, 8, 12, 15, 19 and 22 (D). Tumor area was then monitored routinely by means of a common caliper. Results are expresses as means ± SEM (n = 5 mice/group). These experiments were repeated independently twice, yielding comparable results. ns, nonsignificant; (Mann–Whitney U test), as compared with DX-treated WT mice.
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Figure 3: Figure 3. Influence of TNFα on the therapeutic effects of anthracyclines. (A–D) Tnf−/−(A) or wild type (WT) (A and B) C57BL/6 mice carrying MCA205 fibrosarcomas (tumor surface 25–45 mm2) were treated with doxorubicin (DX) or an equivalent volume of PBS, as a single intratumoral injection (day 8). On the same day, some of the mice were initiated on a course of intraperitoneal etanercept (ETA), for 4 consecutive days. Alternatively, WT 129/Sv mice bearing established F244 sarcomas (C) or BALB/c mice harboring H2N100 mammary carcinomas (D) received DX or an equivalent volume of PBS, as a single intratumoral injection, on day 10 or 8 after the inoculation of tumor cells, respectively. One day prior to chemotherapy, a fraction of mice was initiated on a course of TNFα-neutralizing antibodies (or isotype-matched control antibodies), which were given i.v. on days 9, 10, 14, 17 and 21 (C) or on day 7, 8, 12, 15, 19 and 22 (D). Tumor area was then monitored routinely by means of a common caliper. Results are expresses as means ± SEM (n = 5 mice/group). These experiments were repeated independently twice, yielding comparable results. ns, nonsignificant; (Mann–Whitney U test), as compared with DX-treated WT mice.

Mentions: MCA205 fibrosarcomas grew in wild-type and Tnf−/− C57BL/6 mice with virtually overlapping kinetics, and anthracycline-based chemotherapy completely retained its efficacy in the absence of host-derived TNFα (Fig. 3A). Along similar lines, the neutralization of TNFα with etanercept shortly before and continuously after chemotherapy failed to significantly alter the therapeutic efficacy of doxorubicin against MCA205 fibrosarcomas growing in C57BL/6 mice (Fig. 3B). Similar results were obtained when the TNFα system was blocked by the administration of a TNFα-neutralizing antibody. In particular, F244 sarcomas developing in 129/Sv mice as well as H2N100 mammary carcinomas growing in BALB/c mice responded to doxorubicin irrespective of the co-administration of the TNFα-targeting antibody TN3–19.12 (Fig. 3C and D). These findings indicate that TNFα does not influence the responsiveness of tumor-bearing mice to immunogenic chemotherapy.


Tumor necrosis factor is dispensable for the success of immunogenic anticancer chemotherapy.

Ma Y, Yamazaki T, Yang H, Kepp O, Galluzzi L, Zitvogel L, Smyth MJ, Kroemer G - Oncoimmunology (2013)

Figure 3. Influence of TNFα on the therapeutic effects of anthracyclines. (A–D) Tnf−/−(A) or wild type (WT) (A and B) C57BL/6 mice carrying MCA205 fibrosarcomas (tumor surface 25–45 mm2) were treated with doxorubicin (DX) or an equivalent volume of PBS, as a single intratumoral injection (day 8). On the same day, some of the mice were initiated on a course of intraperitoneal etanercept (ETA), for 4 consecutive days. Alternatively, WT 129/Sv mice bearing established F244 sarcomas (C) or BALB/c mice harboring H2N100 mammary carcinomas (D) received DX or an equivalent volume of PBS, as a single intratumoral injection, on day 10 or 8 after the inoculation of tumor cells, respectively. One day prior to chemotherapy, a fraction of mice was initiated on a course of TNFα-neutralizing antibodies (or isotype-matched control antibodies), which were given i.v. on days 9, 10, 14, 17 and 21 (C) or on day 7, 8, 12, 15, 19 and 22 (D). Tumor area was then monitored routinely by means of a common caliper. Results are expresses as means ± SEM (n = 5 mice/group). These experiments were repeated independently twice, yielding comparable results. ns, nonsignificant; (Mann–Whitney U test), as compared with DX-treated WT mice.
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Figure 3: Figure 3. Influence of TNFα on the therapeutic effects of anthracyclines. (A–D) Tnf−/−(A) or wild type (WT) (A and B) C57BL/6 mice carrying MCA205 fibrosarcomas (tumor surface 25–45 mm2) were treated with doxorubicin (DX) or an equivalent volume of PBS, as a single intratumoral injection (day 8). On the same day, some of the mice were initiated on a course of intraperitoneal etanercept (ETA), for 4 consecutive days. Alternatively, WT 129/Sv mice bearing established F244 sarcomas (C) or BALB/c mice harboring H2N100 mammary carcinomas (D) received DX or an equivalent volume of PBS, as a single intratumoral injection, on day 10 or 8 after the inoculation of tumor cells, respectively. One day prior to chemotherapy, a fraction of mice was initiated on a course of TNFα-neutralizing antibodies (or isotype-matched control antibodies), which were given i.v. on days 9, 10, 14, 17 and 21 (C) or on day 7, 8, 12, 15, 19 and 22 (D). Tumor area was then monitored routinely by means of a common caliper. Results are expresses as means ± SEM (n = 5 mice/group). These experiments were repeated independently twice, yielding comparable results. ns, nonsignificant; (Mann–Whitney U test), as compared with DX-treated WT mice.
Mentions: MCA205 fibrosarcomas grew in wild-type and Tnf−/− C57BL/6 mice with virtually overlapping kinetics, and anthracycline-based chemotherapy completely retained its efficacy in the absence of host-derived TNFα (Fig. 3A). Along similar lines, the neutralization of TNFα with etanercept shortly before and continuously after chemotherapy failed to significantly alter the therapeutic efficacy of doxorubicin against MCA205 fibrosarcomas growing in C57BL/6 mice (Fig. 3B). Similar results were obtained when the TNFα system was blocked by the administration of a TNFα-neutralizing antibody. In particular, F244 sarcomas developing in 129/Sv mice as well as H2N100 mammary carcinomas growing in BALB/c mice responded to doxorubicin irrespective of the co-administration of the TNFα-targeting antibody TN3–19.12 (Fig. 3C and D). These findings indicate that TNFα does not influence the responsiveness of tumor-bearing mice to immunogenic chemotherapy.

Bottom Line: The antineoplastic effects of anthracyclines have been shown to rely, at least in part, on a local immune response that involves dendritic cells (DCs) and several distinct subsets of T lymphocytes.In particular, TNFα-blocking strategies did not influence the antineoplastic effects of doxorubicin (a prototypic anthracycline) against MCA205 fibrosarcomas growing in C57BL/6 mice, F244 sarcomas developing in 129/Sv hosts and H2N100 mammary carcinomas arising in BALB/c mice.These findings imply that, in contrast to other cytokines (such as interleukin-1β, interleukin-17 and interferon γ), TNFα is not required for anthracyclines to elicit therapeutic anticancer immune responses.

View Article: PubMed Central - PubMed

Affiliation: INSERM, U848; Villejuif, France ; Institut Gustave Roussy, Villejuif, France ; Université Paris Sud/Paris XI; Le Kremlin Bicêtre; Paris, France.

ABSTRACT
The antineoplastic effects of anthracyclines have been shown to rely, at least in part, on a local immune response that involves dendritic cells (DCs) and several distinct subsets of T lymphocytes. Here, we show that the administration of anthracyclines to mice bearing established neoplasms stimulates the intratumoral secretion of tumor necrosis factor α (TNFα). However, blocking the TNFα/TNF receptor (TNFR) system by three different strategies-namely, (1) neutralizing antibodies, (2) etanercept, a recombinant protein in which TNFR is fused to the constant domain of an IgG1 molecule, and (3) gene knockout-failed to negatively affect the therapeutic efficacy of anthracyclines in three distinct tumor models. In particular, TNFα-blocking strategies did not influence the antineoplastic effects of doxorubicin (a prototypic anthracycline) against MCA205 fibrosarcomas growing in C57BL/6 mice, F244 sarcomas developing in 129/Sv hosts and H2N100 mammary carcinomas arising in BALB/c mice. These findings imply that, in contrast to other cytokines (such as interleukin-1β, interleukin-17 and interferon γ), TNFα is not required for anthracyclines to elicit therapeutic anticancer immune responses.

No MeSH data available.


Related in: MedlinePlus