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 Müller; Natasja Wulff Pedersen; Sine Reker Hadrup; Özcan Met; Barbara Seliger; Bjarne Kromann-Andersen; Thomas Hasselager; Marco Donia; Inge Marie Svane

doi:10.1158/2326-6066.cir-17-0467

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 Müller, Natasja Wulff Pedersen, Sine Reker Hadrup, Özcan Met, Barbara Seliger, Bjarne Kromann-Andersen, Thomas Hasselager, Marco Donia, Inge Marie Svane

Department of Clinical Medicine

31 Citations (Scopus)

Abstract

In vitro expansion of large numbers of highly potent tumorreactive 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.

Original language	English
Journal	Cancer Immunology Research
Volume	6
Issue number	2
Pages (from-to)	222-235
Number of pages	14
ISSN	2326-6066
DOIs	https://doi.org/10.1158/2326-6066.cir-17-0467
Publication status	Published - Feb 2018

Keywords

CD8-Positive T-Lymphocytes/immunology
Carcinoma, Renal Cell/immunology
Cell Line, Tumor
Humans
Immunotherapy, Adoptive/methods
Kidney Neoplasms/immunology
Lymphocyte Activation
Lymphocytes, Tumor-Infiltrating/immunology
Tumor Microenvironment/immunology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Andersen, R., Westergaard, M. C. W., Kjeldsen, J. W., Müller, A., Pedersen, N. W., Hadrup, S. R., Met, Ö., Seliger, B., Kromann-Andersen, B., Hasselager, T., Donia, M., & Svane, I. M. (2018). T-cell Responses in the Microenvironment of Primary Renal Cell Carcinoma-Implications for Adoptive Cell Therapy. Cancer Immunology Research, 6(2), 222-235. https://doi.org/10.1158/2326-6066.cir-17-0467

Andersen, R, Westergaard, MCW, Kjeldsen, JW, Müller, A, Pedersen, NW, Hadrup, SR, Met, Ö, 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

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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 tumorreactive 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.",

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author = "Rikke Andersen and Westergaard, {Marie Christine Wulff} and Kjeldsen, {Julie Westerlin} and Anja M{\"u}ller and Pedersen, {Natasja Wulff} and Hadrup, {Sine Reker} and {\"O}zcan Met and Barbara Seliger and Bjarne Kromann-Andersen and Thomas Hasselager and Marco Donia and Svane, {Inge Marie}",

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doi = "10.1158/2326-6066.cir-17-0467",

language = "English",

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journal = "Cancer Immunology Research",

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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 - Müller, Anja

AU - Pedersen, Natasja Wulff

AU - Hadrup, Sine Reker

AU - Met, Özcan

AU - Seliger, Barbara

AU - Kromann-Andersen, Bjarne

AU - Hasselager, Thomas

AU - Donia, Marco

AU - Svane, Inge Marie

PY - 2018/2

Y1 - 2018/2

N2 - In vitro expansion of large numbers of highly potent tumorreactive 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.

AB - In vitro expansion of large numbers of highly potent tumorreactive 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.

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KW - Carcinoma, Renal Cell/immunology

KW - Cell Line, Tumor

KW - Humans

KW - Immunotherapy, Adoptive/methods

KW - Kidney Neoplasms/immunology

KW - Lymphocyte Activation

KW - Lymphocytes, Tumor-Infiltrating/immunology

KW - Tumor Microenvironment/immunology

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

M3 - Journal article

C2 - 29301752

SN - 2326-6066

VL - 6

SP - 222

EP - 235

JO - Cancer Immunology Research

JF - Cancer Immunology Research

IS - 2

ER -

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

Abstract

Keywords

UN SDGs

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