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Nitroaspirin corrects immune dysfunction in tumor-bearing hosts and promotes tumor eradication by cancer vaccination.

ABSTRACT: Active suppression of tumor-specific T lymphocytes can limit the immune-mediated destruction of cancer cells. Of the various strategies used by tumors to counteract immune attacks, myeloid suppressors recruited by growing cancers are particularly efficient, often resulting in the induction of systemic T lymphocyte dysfunction. We have previously shown that the mechanism by which myeloid cells from tumor-bearing hosts block immune defense strategies involves two enzymes that metabolize L-arginine: arginase and nitric oxide (NO) synthase. NO-releasing aspirin is a classic aspirin molecule covalently linked to a NO donor group. NO aspirin does not possess direct antitumor activity. However, by interfering with the inhibitory enzymatic activities of myeloid cells, orally administered NO aspirin normalized the immune status of tumor-bearing hosts, increased the number and function of tumor-antigen-specific T lymphocytes, and enhanced the preventive and therapeutic effectiveness of the antitumor immunity elicited by cancer vaccination. Because cancer vaccines and NO aspirin are currently being investigated in independent phase I/II clinical trials, these findings offer a rationale to combine these treatments in subjects with advanced neoplastic diseases.

SUBMITTER: De Santo C

PROVIDER: S-EPMC554823 | biostudies-other | 2005 Mar

REPOSITORIES: biostudies-other

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Nitroaspirin corrects immune dysfunction in tumor-bearing hosts and promotes tumor eradication by cancer vaccination.

De Santo Carmela C Serafini Paolo P Marigo Ilaria I Dolcetti Luigi L Bolla Manlio M Del Soldato Piero P Melani Cecilia C Guiducci Cristiana C Colombo Mario P MP Iezzi Manuela M Musiani Piero P Zanovello Paola P Bronte Vincenzo V

Proceedings of the National Academy of Sciences of the United States of America 20050307 11

Active suppression of tumor-specific T lymphocytes can limit the immune-mediated destruction of cancer cells. Of the various strategies used by tumors to counteract immune attacks, myeloid suppressors recruited by growing cancers are particularly efficient, often resulting in the induction of systemic T lymphocyte dysfunction. We have previously shown that the mechanism by which myeloid cells from tumor-bearing hosts block immune defense strategies involves two enzymes that metabolize L-arginine ...[more]

PMID: 15753302

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Project description:Abstract INTRODUCTION We recently demonstrated that hematopoietic stem and progenitor cell (HSC) transfer during adoptive T cell immunotherapy (ACT) for malignant brain tumors facilitates extended survival and long-term cures. HSCs migrated to tumors and used T cell-released IFN-g to differentiate into dendritic cells (DCs). In those studies, we transferred syngeneic HSCs from naïve hosts that were not endemic to the tumor-bearing hosts, unlike the clinical paradigm of autologous transfers. In peripheral cancers, HSCs of tumor-bearing hosts (TB HSCs) possess considerable immunosuppressive potential. OBJECTIVE We therefore evaluated the immunologic function of HSCs from naïve and tumor-bearing hosts to determine if malignant gliomas affect the immune-potentiating function of HSCs. METHODS We used treatment-resistant intracranial gliomas KR158B and GL261 to generate TB HSCs that were isolated from the bone marrow. We then performed in vitro HSC culture experiments alone and with activated T cell supernatants to study HSC differentiation by flow cytometry. Intravenous transfers were used to study HSC differentiation in brain tumors as well as survival benefit during ACT. RESULTS Culturing naïve or TB HSCs led to differentiation into 30% or 60% myeloid-derived suppressor cells (MDSCs; CD11b+Ly-6G/6C+), respectively. However, when cultured in activated T cell supernatants containing IFN-g, both HSC types differentiated into 30% MDSCs and 80% MHCII+ antigen-presenting cells. We then determined that TB HSCs express more IFN-gR than naïve HSCs including 40% more IFN-gR1 and 90% more IFN-gR2 on DC progenitors. In vivo, ACT rescued intratumoral TB HSC differentiation, prolonged median survival, and led to long-term cures. CONCLUSIONS While gliomas exert an immunosuppressive pressure on TB HSCs, ACT can reprogram TB HSC differentiation into functional antigen-presenting cells. A phase I trial evaluating the impact of HSC transfer on adoptive immunotherapy in pediatric high-grade gliomas is underway at our center (ACTION; clinicaltrials.gov NCT03334305).

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Nitroaspirin corrects immune dysfunction in tumor-bearing hosts and promotes tumor eradication by cancer vaccination.

Publications

Nitroaspirin corrects immune dysfunction in tumor-bearing hosts and promotes tumor eradication by cancer vaccination.

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