T-cell Responses in the Microenvironment of Primary Renal Cell Carcinoma-Implications for Adoptive Cell Therapy

Rikke Andersen, Marie Christine Wulff Westergaard, Julie Westerlin Kjeldsen, Anja Mueller, Natasja Wulff Pedersen, Sine Reker Hadrup, Ozcan Met, Barbara Seliger, Bjarne Kromann-Andersen, Thomas Hasselager, Marco Donia, Inge Marie Svane*

*Corresponding author for this work

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    Abstract

    In vitro expansion of large numbers of highly potent tumor-reactive T cells appears a prerequisite for effective adoptive cell therapy (ACT) with autologous tumor-infiltrating lymphocytes (TIL) as shown in metastatic melanoma (MM). We therefore sought to determine whether renal cell carcinomas (RCC) are infiltrated with tumor-reactive T cells that could be efficiently employed for adoptive transfer immunotherapy. TILs and autologous tumor cell lines (TCL) were successfully generated from 22 (92%) and 17 (77%) of 24 consecutive primary RCC specimens and compared with those generated from metastatic melanoma. Immune recognition of autologous TCLs or fresh tumor digests was observed in CD8(+) TILs from 82% of patients (18/22). Cytotoxicity assays confirmed the tumoricidal capacity of RCC-TILs. The overall expansion capacity of RCC-TILs was similar to MM-TILs. However, the magnitude, polyfunctionality, and ability to expand in classical expansion protocols of CD8(+) T-cell responses was lower compared with MM-TILs. The RCC-TILs that did react to the tumor were functional, and antigen presentation and processing of RCC tumors was similar to MM-TILs. Direct recognition of tumors with cytokine-induced overexpression of human leukocyte antigen class II was observed from CD4(+) T cells (6/12; 50%). Thus, TILs from primary RCC specimens could be isolated, expanded, and could recognize tumors. However, immune responses of expanded CD8(+) RCC-TILs were typically weaker than MM-TILs and displayed a mono-/oligofunctional pattern. The ability to select, enrich, and expand tumor-reactive polyfunctional T cells may be critical in developing effective ACT with TILs for RCC. In summary, TILs isolated from primary RCC specimens could recognize tumors. However, their immune responses were weaker than MM-TILs and displayed a mono-/oligofunctional pattern. The ability to select and expand polyfunctional T cells may improve cell therapy for RCC. (C) 2018 AACR.
    Original languageEnglish
    JournalCancer Immunology Research
    Volume6
    Issue number2
    Pages (from-to)222-235
    ISSN2326-6066
    DOIs
    Publication statusPublished - 2018

    Cite this

    Andersen, Rikke ; Westergaard, Marie Christine Wulff ; Kjeldsen, Julie Westerlin ; Mueller, Anja ; Pedersen, Natasja Wulff ; Hadrup, Sine Reker ; Met, Ozcan ; Seliger, Barbara ; Kromann-Andersen, Bjarne ; Hasselager, Thomas ; Donia, Marco ; Svane, Inge Marie. / T-cell Responses in the Microenvironment of Primary Renal Cell Carcinoma-Implications for Adoptive Cell Therapy. In: Cancer Immunology Research. 2018 ; Vol. 6, No. 2. pp. 222-235.
    @article{dc9ad723bc944d748138bc3dbace0441,
    title = "T-cell Responses in the Microenvironment of Primary Renal Cell Carcinoma-Implications for Adoptive Cell Therapy",
    abstract = "In vitro expansion of large numbers of highly potent tumor-reactive T cells appears a prerequisite for effective adoptive cell therapy (ACT) with autologous tumor-infiltrating lymphocytes (TIL) as shown in metastatic melanoma (MM). We therefore sought to determine whether renal cell carcinomas (RCC) are infiltrated with tumor-reactive T cells that could be efficiently employed for adoptive transfer immunotherapy. TILs and autologous tumor cell lines (TCL) were successfully generated from 22 (92{\%}) and 17 (77{\%}) of 24 consecutive primary RCC specimens and compared with those generated from metastatic melanoma. Immune recognition of autologous TCLs or fresh tumor digests was observed in CD8(+) TILs from 82{\%} of patients (18/22). Cytotoxicity assays confirmed the tumoricidal capacity of RCC-TILs. The overall expansion capacity of RCC-TILs was similar to MM-TILs. However, the magnitude, polyfunctionality, and ability to expand in classical expansion protocols of CD8(+) T-cell responses was lower compared with MM-TILs. The RCC-TILs that did react to the tumor were functional, and antigen presentation and processing of RCC tumors was similar to MM-TILs. Direct recognition of tumors with cytokine-induced overexpression of human leukocyte antigen class II was observed from CD4(+) T cells (6/12; 50{\%}). Thus, TILs from primary RCC specimens could be isolated, expanded, and could recognize tumors. However, immune responses of expanded CD8(+) RCC-TILs were typically weaker than MM-TILs and displayed a mono-/oligofunctional pattern. The ability to select, enrich, and expand tumor-reactive polyfunctional T cells may be critical in developing effective ACT with TILs for RCC. In summary, TILs isolated from primary RCC specimens could recognize tumors. However, their immune responses were weaker than MM-TILs and displayed a mono-/oligofunctional pattern. The ability to select and expand polyfunctional T cells may improve cell therapy for RCC. (C) 2018 AACR.",
    author = "Rikke Andersen and Westergaard, {Marie Christine Wulff} and Kjeldsen, {Julie Westerlin} and Anja Mueller and Pedersen, {Natasja Wulff} and Hadrup, {Sine Reker} and Ozcan Met and Barbara Seliger and Bjarne Kromann-Andersen and Thomas Hasselager and Marco Donia and Svane, {Inge Marie}",
    year = "2018",
    doi = "10.1158/2326-6066.CIR-17-0467",
    language = "English",
    volume = "6",
    pages = "222--235",
    journal = "Cancer Immunology Research",
    issn = "2326-6066",
    publisher = "American Association for Cancer Research",
    number = "2",

    }

    Andersen, R, Westergaard, MCW, Kjeldsen, JW, Mueller, A, Pedersen, NW, Hadrup, SR, Met, O, Seliger, B, Kromann-Andersen, B, Hasselager, T, Donia, M & Svane, IM 2018, 'T-cell Responses in the Microenvironment of Primary Renal Cell Carcinoma-Implications for Adoptive Cell Therapy', Cancer Immunology Research, vol. 6, no. 2, pp. 222-235. https://doi.org/10.1158/2326-6066.CIR-17-0467

    T-cell Responses in the Microenvironment of Primary Renal Cell Carcinoma-Implications for Adoptive Cell Therapy. / Andersen, Rikke; Westergaard, Marie Christine Wulff; Kjeldsen, Julie Westerlin; Mueller, Anja; Pedersen, Natasja Wulff; Hadrup, Sine Reker; Met, Ozcan; Seliger, Barbara; Kromann-Andersen, Bjarne; Hasselager, Thomas; Donia, Marco; Svane, Inge Marie.

    In: Cancer Immunology Research, Vol. 6, No. 2, 2018, p. 222-235.

    Research output: Contribution to journalJournal articleResearchpeer-review

    TY - JOUR

    T1 - T-cell Responses in the Microenvironment of Primary Renal Cell Carcinoma-Implications for Adoptive Cell Therapy

    AU - Andersen, Rikke

    AU - Westergaard, Marie Christine Wulff

    AU - Kjeldsen, Julie Westerlin

    AU - Mueller, Anja

    AU - Pedersen, Natasja Wulff

    AU - Hadrup, Sine Reker

    AU - Met, Ozcan

    AU - Seliger, Barbara

    AU - Kromann-Andersen, Bjarne

    AU - Hasselager, Thomas

    AU - Donia, Marco

    AU - Svane, Inge Marie

    PY - 2018

    Y1 - 2018

    N2 - In vitro expansion of large numbers of highly potent tumor-reactive T cells appears a prerequisite for effective adoptive cell therapy (ACT) with autologous tumor-infiltrating lymphocytes (TIL) as shown in metastatic melanoma (MM). We therefore sought to determine whether renal cell carcinomas (RCC) are infiltrated with tumor-reactive T cells that could be efficiently employed for adoptive transfer immunotherapy. TILs and autologous tumor cell lines (TCL) were successfully generated from 22 (92%) and 17 (77%) of 24 consecutive primary RCC specimens and compared with those generated from metastatic melanoma. Immune recognition of autologous TCLs or fresh tumor digests was observed in CD8(+) TILs from 82% of patients (18/22). Cytotoxicity assays confirmed the tumoricidal capacity of RCC-TILs. The overall expansion capacity of RCC-TILs was similar to MM-TILs. However, the magnitude, polyfunctionality, and ability to expand in classical expansion protocols of CD8(+) T-cell responses was lower compared with MM-TILs. The RCC-TILs that did react to the tumor were functional, and antigen presentation and processing of RCC tumors was similar to MM-TILs. Direct recognition of tumors with cytokine-induced overexpression of human leukocyte antigen class II was observed from CD4(+) T cells (6/12; 50%). Thus, TILs from primary RCC specimens could be isolated, expanded, and could recognize tumors. However, immune responses of expanded CD8(+) RCC-TILs were typically weaker than MM-TILs and displayed a mono-/oligofunctional pattern. The ability to select, enrich, and expand tumor-reactive polyfunctional T cells may be critical in developing effective ACT with TILs for RCC. In summary, TILs isolated from primary RCC specimens could recognize tumors. However, their immune responses were weaker than MM-TILs and displayed a mono-/oligofunctional pattern. The ability to select and expand polyfunctional T cells may improve cell therapy for RCC. (C) 2018 AACR.

    AB - In vitro expansion of large numbers of highly potent tumor-reactive T cells appears a prerequisite for effective adoptive cell therapy (ACT) with autologous tumor-infiltrating lymphocytes (TIL) as shown in metastatic melanoma (MM). We therefore sought to determine whether renal cell carcinomas (RCC) are infiltrated with tumor-reactive T cells that could be efficiently employed for adoptive transfer immunotherapy. TILs and autologous tumor cell lines (TCL) were successfully generated from 22 (92%) and 17 (77%) of 24 consecutive primary RCC specimens and compared with those generated from metastatic melanoma. Immune recognition of autologous TCLs or fresh tumor digests was observed in CD8(+) TILs from 82% of patients (18/22). Cytotoxicity assays confirmed the tumoricidal capacity of RCC-TILs. The overall expansion capacity of RCC-TILs was similar to MM-TILs. However, the magnitude, polyfunctionality, and ability to expand in classical expansion protocols of CD8(+) T-cell responses was lower compared with MM-TILs. The RCC-TILs that did react to the tumor were functional, and antigen presentation and processing of RCC tumors was similar to MM-TILs. Direct recognition of tumors with cytokine-induced overexpression of human leukocyte antigen class II was observed from CD4(+) T cells (6/12; 50%). Thus, TILs from primary RCC specimens could be isolated, expanded, and could recognize tumors. However, immune responses of expanded CD8(+) RCC-TILs were typically weaker than MM-TILs and displayed a mono-/oligofunctional pattern. The ability to select, enrich, and expand tumor-reactive polyfunctional T cells may be critical in developing effective ACT with TILs for RCC. In summary, TILs isolated from primary RCC specimens could recognize tumors. However, their immune responses were weaker than MM-TILs and displayed a mono-/oligofunctional pattern. The ability to select and expand polyfunctional T cells may improve cell therapy for RCC. (C) 2018 AACR.

    U2 - 10.1158/2326-6066.CIR-17-0467

    DO - 10.1158/2326-6066.CIR-17-0467

    M3 - Journal article

    C2 - 29301752

    VL - 6

    SP - 222

    EP - 235

    JO - Cancer Immunology Research

    JF - Cancer Immunology Research

    SN - 2326-6066

    IS - 2

    ER -