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J Immunother Cancer. 2014 Nov 18;2(1):38. doi: 10.1186/s40425-014-0038-9. eCollection 2014.

Detailed characterization of tumor infiltrating lymphocytes in two distinct human solid malignancies show phenotypic similarities.

Author information

1
Earle A. Chiles Research Institute, Providence Cancer Center, Portland Providence Medical Center, 4805 NE Glisan St, Portland, Oregon 97213 USA.
2
Earle A. Chiles Research Institute, Providence Cancer Center, Portland Providence Medical Center, 4805 NE Glisan St, Portland, Oregon 97213 USA ; Agonox Inc, 4805 NE Glisan St, Portland, Oregon 97213 USA.
3
Agonox Inc, 4805 NE Glisan St, Portland, Oregon 97213 USA.
4
Providence Gynecologic Oncology, Providence Cancer Center, Portland Providence Medical Center, 4805 NE Glisan St, Portland, Oregon 97213 USA.
5
Providence Surgical Oncology, Providence Cancer Center, Portland Providence Medical Center, 4805 NE Glisan St, Portland, Oregon 97213 USA.
6
OHSU, division of oncological surgery and OHSU Knight Cancer Center, 3303 SW Bond Ave, Portland, OR 97239 USA.

Abstract

BACKGROUND:

We examined the phenotype and function of lymphocytes collected from the peripheral blood (PBL) and tumor (TIL) of patients with two different solid malignancies: colorectal cancer liver metastases (CRLM) and ovarian cancer (OVC).

METHODS:

Tumor and corresponding peripheral blood were collected from 16 CRLM and 22 OVC patients; immediately following resection they were processed and analyzed using a multi-color flow cytometry panel. Cytokine mRNA from purified PBL and TIL CD4(+) T cells were also analyzed by qPCR.

RESULTS:

Overall, we found similar changes in the phenotypic and cytokine profiles when the TIL were compared to PBL from patients with two different malignancies. The percentage of Treg (CD4(+)/CD25(+)/FoxP3(+)) in PBL and TIL was similar: 8.1% versus 10.2%, respectively in CRLM patients. However, the frequency of Treg in primary OVC TIL was higher than PBL: 19.2% versus 4.5% (p <0.0001). A subpopulation of Treg expressing HLA-DR was markedly increased in TIL compared to PBL in both tumor types, CRLM: 69.0% versus 31.7% (p = 0.0002) and OVC 74.6% versus 37.0% (p <0.0001), which suggested preferential Treg activation within the tumor. The cytokine mRNA profile showed that IL-6, a cytokine known for its immunosuppressive properties through STAT3 upregulation, was increased in TIL samples in patients with OVC and CRLM. Both TIL populations also contained a significantly higher proportion of activated CD8(+) T cells (HLA-DR(+)/CD38(+)) compared to PBL (CRLM: 30.2% vs 7.7%, (p = 0.0012), OVC: 57.1% vs 12.0%, (p <0.0001)).

CONCLUSION:

This study demonstrates that multi-color flow cytometry of freshly digested tumor samples reveals phenotypic differences in TIL vs PBL T cell sub-populations. The TIL composition in primary and metastatic tumors from two distinct histologies were remarkably similar, showing a greater proportion of activated/suppressive Treg (HLA-DR(+), CD39(+), CTLA-4(+) and Helios(+)) and activated cytotoxic T cells (CD8(+)/HLA-DR(+)/CD38(+)) when compared to PBL and an increase in IL-6 mRNA from CD4 TIL.

KEYWORDS:

Regulatory T cells; Tumor infiltrating lymphocytes

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