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IL-12 triggers a programmatic change in dysfunctional myeloid-derived cells within mouse tumors.

ABSTRACT: Solid tumors are complex masses with a local microenvironment, or stroma, that supports tumor growth and progression. Among the diverse tumor-supporting stromal cells is a heterogeneous population of myeloid-derived cells. These cells are alternatively activated and contribute to the immunosuppressive environment of the tumor; overcoming their immunosuppressive effects may improve the efficacy of cancer immunotherapies. We recently found that engineering tumor-specific CD8(+) T cells to secrete the inflammatory cytokine IL-12 improved their therapeutic efficacy in the B16 mouse model of established melanoma. Here, we report the mechanism underlying this finding. Surprisingly, direct binding of IL-12 to receptors on lymphocytes or NK cells was not required. Instead, IL-12 sensitized bone marrow-derived tumor stromal cells, including CD11b(+)F4/80(hi) macrophages, CD11b(+)MHCII(hi)CD11c(hi) dendritic cells, and CD11b(+)Gr-1(hi) myeloid-derived suppressor cells, causing them to enhance the effects of adoptively transferred CD8(+) T cells. This reprogramming of myeloid-derived cells occurred partly through IFN-?. Surprisingly, direct presentation of antigen to the transferred CD8(+) T cells by tumor was not necessary; however, MHCI expression on host cells was essential for IL-12-mediated antitumor enhancements. These results are consistent with a model in which IL-12 enhances the ability of CD8(+) T cells to collapse large vascularized tumors by triggering programmatic changes in otherwise suppressive antigen-presenting cells within tumors and support the use of IL-12 as part of immunotherapy for the treatment of solid tumors.

SUBMITTER: Kerkar SP

PROVIDER: S-EPMC3226001 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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IL-12 triggers a programmatic change in dysfunctional myeloid-derived cells within mouse tumors.

Kerkar Sid P SP Goldszmid Romina S RS Muranski Pawel P Chinnasamy Dhanalakshmi D Yu Zhiya Z Reger Robert N RN Leonardi Anthony J AJ Morgan Richard A RA Wang Ena E Marincola Francesco M FM Trinchieri Giorgio G Rosenberg Steven A SA Restifo Nicholas P NP

The Journal of clinical investigation 20111107 12

Solid tumors are complex masses with a local microenvironment, or stroma, that supports tumor growth and progression. Among the diverse tumor-supporting stromal cells is a heterogeneous population of myeloid-derived cells. These cells are alternatively activated and contribute to the immunosuppressive environment of the tumor; overcoming their immunosuppressive effects may improve the efficacy of cancer immunotherapies. We recently found that engineering tumor-specific CD8(+) T cells to secrete ...[more]

PMID: 22056381

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Project description:ObjectivesProgrammatic assessment attempts to facilitate learning through individual assessments designed to be of low-stakes and used only for high-stake decisions when aggregated. In practice, low-stake assessments have yet to reach their potential as catalysts for learning. We explored how teachers conceptualise assessments within programmatic assessment and how they engage with learners in assessment relationships.MethodsWe used a constructivist grounded theory approach to explore teachers' assessment conceptualisations and assessment relationships in the context of programmatic assessment. We conducted 23 semi-structured interviews at two different graduate-entry medical training programmes following a purposeful sampling approach. Data collection and analysis were conducted iteratively until we reached theoretical sufficiency. We identified themes using a process of constant comparison.ResultsResults showed that teachers conceptualise low-stake assessments in three different ways: to stimulate and facilitate learning; to prepare learners for the next step, and to use as feedback to gauge the teacher's own effectiveness. Teachers intended to engage in and preserve safe, yet professional and productive working relationships with learners to enable assessment for learning when securing high-quality performance and achievement of standards. When teachers' assessment conceptualisations were more focused on accounting conceptions, this risked creating tension in the teacher-learner assessment relationship. Teachers struggled between taking control and allowing learners' independence.ConclusionsTeachers believe programmatic assessment can have a positive impact on both teaching and student learning. However, teachers' conceptualisations of low-stake assessments are not focused solely on learning and also involve stakes for teachers. Sampling across different assessments and the introduction of progress committees were identified as important design features to support teachers and preserve the benefits of prolonged engagement in assessment relationships. These insights contribute to the design of effective implementations of programmatic assessment within the medical education context.

Dataset Information

IL-12 triggers a programmatic change in dysfunctional myeloid-derived cells within mouse tumors.

Publications

IL-12 triggers a programmatic change in dysfunctional myeloid-derived cells within mouse tumors.

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