Successful elimination of large established tumors and avoidance of antigen‐loss variants by aggressive adoptive T cell immunotherapy

Matsui, Ken; O'Mara, Leigh A.; Allen, Paul M.

doi:10.1093/intimm/dxg078

Cited by 28 publications

(37 citation statements)

References 51 publications

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“…The use of monoclonal CD8 T cells specific for a natural tumor Ag permitted us to address the question of tumor development/escape in the face of a defined effector population. Monoclonal adoptive T cell immunotherapy has previously been shown to result either in restriction of tumor growth (43,44) or in immune escape by Ag loss or drift (22,(45)(46)(47). We describe a model in which monoclonal naive TCRP1A CD8 T cells specific for Ag P815AB can lead to marked reduction of s.c. inoculated mastocytoma P815 even if the T cells are transferred into a host bearing an established tumor.…”

Section: Discussionmentioning

confidence: 99%

CD8 T Cell Help for Innate Antitumor Immunity

Shanker

Verdeil

Buferne

et al. 2007

The Journal of Immunology

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Innate immunity is considered to initiate adaptive antitumor responses. We demonstrate that monoclonal CD8 T lymphocytes reactive to tumor Ag P1A on P815 mastocytoma cells provide essential “help” to NK cells for rejection of P1A-deficient tumors. RAG-deficient mice have normal NK cells but do not reject either tumor. Reconstitution of these mice with P1A-specific T cells conferred resistance to both P1A-expressing and -deficient tumor cells provided they were present at the same site. Elimination of Ag-negative tumor variants required both activated T and NK cells. Gene expression profiling of NK cells infiltrating P1A-positive tumors in mice with specific CD8 T cells demonstrated an activated effector phenotype. However, CD8 T cell help to NK cells appeared ineffective for P1A-negative variants separated from the P1A-positive tumor. Local tumor Ag-specific T cell-NK cell collaboration results in the elimination of tumor cells whether they express or not the T cell tumor Ag epitope, thus containing the emergence of tumor escape variants before metastasis.

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Section: Discussionmentioning

confidence: 99%

CD8 T Cell Help for Innate Antitumor Immunity

Shanker

Verdeil

Buferne

et al. 2007

The Journal of Immunology

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“…Splenocytes from mice expressing the DO11.10 T cell receptor (TCR) transgene (a gift from Dr. Osami Kanagawa) were stimulated as described previously (17,18) to generate activated CD4 ϩ T cells for use in S1 nuclease protection assays. Splenocytes from mice expressing the DUC18 TCR transgene (a gift from Dr. Paul Allen) were stimulated as described previously (19,20) to generate the activated CD8 ϩ T cells used in an S1 nuclease protection assay.…”

Section: Methodsmentioning

confidence: 99%

Characterization of Murine Cathepsin W and Its Role in Cell-mediated Cytotoxicity

Ondr

Pham

2004

Journal of Biological Chemistry

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Cathepsin W is a member of the papain-like family of cysteine proteases. In this report, we have isolated the cDNA for murine CtsW (mCtsW) from a splenocyte library. The deduced 371-amino-acid sequence shares 68% identity with human CtsW and includes the conserved catalytic triad cysteine, histidine, and asparagine found in all members of this family. In addition to the fulllength form of mCtsW, we have isolated an alternatively spliced form of the mRNA that lacks a complete catalytic triad. An S1 nuclease protection assay and a Western blot analysis showed that mCtsW is mainly restricted to the CD8 ؉ T cell and natural killer cell compartments. In addition, we confirmed that, like its human homologue, mCtsW is localized mainly to the endoplasmic reticulum and its expression is up-regulated upon activation. We also characterized the mCtsW locus using bacterial artificial chromosome clones. The gene consists of 10 coding exons and 9 introns spanning 3.2 kb. To elucidate the physiologic role of this protease, we generated mice deficient in mCtsW. Our data establish that mCtsW is not required for cytotoxic lymphocyte-induced target cell death in vitro. In addition, mCtsW deficiency does not alter the susceptibility of cytotoxic lymphocytes to suicide or fratricide after degranulation. Thus, mCtsW does not have a unique role in target cell apoptosis or cytotoxic cell survival in vitro.

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“…CMS5 TIL infiltrate the tumor from the early stages in an unrestricted pattern CMS5 is a methylcholanthrene-induced fibrosarcoma of BALB/c origin (H-2 d ) [19]. Measurable tumors first appeared on day 5 after inoculation with 1Â10 6 CMS5 cells (Fig.…”

Section: Resultsmentioning

confidence: 98%

Clonal dynamics of tumor-infiltrating lymphocytes

Yu¹,

Fujio²,

Tahara³

et al. 2005

Eur. J. Immunol.

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The presence of tumor-infiltrating lymphocytes (TIL) provides important evidence of anti-tumor immunity in vivo. However, TIL are usually not sufficient for inhibiting tumor growth. We explored the spatial and temporal aspects of clonal accumulation of TIL using RT-PCR/single-strand conformation polymorphism analysis. In CMS5 fibrosarcomas in BALB/c mice, accumulated T cell clones were specific in that dominant TIL were identical between distant tumors. Moreover, dominant TIL in the first tumor appeared consistently in the second tumor inoculated after formation of the first tumor. These results suggest that TIL show a certain level of specific tumor surveillance. When we characterized CD4 + and CD8 + TIL separately, CD8 + TIL were highly concentrated and persistently localized at the tumor site, while most CD4 + TIL clones were less concentrated and less persistent. A functional analysis showed that TIL had a certain degree of anti-tumor activity when CD4 + and CD8 + TIL were cotransferred. Co-transfer of CD4 + and CD8 + TIL exhibited equivalent anti-tumor activity, irrespective of tumor stage. However, the numbers of TIL did not increase after the early phase of tumor progression. These data suggest that TIL are specific to the tumor and potentially retain anti-tumor activity, although their accumulation in mice is impaired.

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Successful elimination of large established tumors and avoidance of antigen‐loss variants by aggressive adoptive T cell immunotherapy

Cited by 28 publications

References 51 publications

CD8 T Cell Help for Innate Antitumor Immunity

CD8 T Cell Help for Innate Antitumor Immunity

Characterization of Murine Cathepsin W and Its Role in Cell-mediated Cytotoxicity

Clonal dynamics of tumor-infiltrating lymphocytes

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