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CD16^low/negative Tumor-Infiltrating Lymphocyte: Lymphoid or Myeloid in Origin?

Consiglio Nazionale delle Ricerche Institute for Organ Transplantation and Immunocytology, Rome, Italy

Domenico Del Principe

Department of Pediatrics, School of Medicine, University of Tor Vergata, Rome, Italy

A. John Barrett

Allogeneic Stem Cell Transplantation, Hematology Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland

To the Editors: Although tumor-infiltrating lymphocytes (TIL) are predominantly composed of T lymphocytes, other immune cells also occur within the tumor and may be important in tumor control. We therefore read with interest the study of Schleypen et al. (1) who identified a proportion of TIL in renal cell carcinomas as natural killer (NK) cells. In some tumors, the proportion of such NK-TIL exceeded 20% (high NK-TIL), whereas others had fewer than 20% (low NK-TIL). High NK-TIL were mostly CD16^positive. In contrast, low NK-TIL were CD16^{low or negative}. These NK cell populations were not cytolytic to the HLA class I antigen–negative cell line K562; they showed a diversity of CD16 expression and variable ability to become cytotoxic after stimulation. Interestingly, low NK-TIL were cytotoxin^negative and perforin^dim/negative. Our own in vitro studies on human NK cell development shed further light on the nature of these NK TIL cells.

We stimulated granulocyte-colony stimulating factor mobilized CD34^positive cells from healthy donors with stem cell factor and interleukin-2. After 3 weeks, the cultures generated a heterogeneous CD56^positiveCD16^{positive/negative} cell population, which phenotypically and functionally resembled the low NK-TIL described in Schleypen et al. article. These cultured cells included two populations: a CD56^brightCD16^negative and a CD56^lowCD16^low/negative population. They had few or no cytotoxic granules and showed negligible cytotoxicity against K562 and P815 cell lines. Interestingly, the CD56^low population expressed the myeloid marker CD33 (2, 3). To further investigate the myeloid origin of CD56^lowCD33^positive cells, these cells were electronically sorted (Fig. 1A ) and cultured in the presence of stem cell factor, interleukin-2, interleukin-4, and granulocyte macrophage colony-stimulating factor. After a 10-day culture, these cells underwent a profound morphologic change, rounding up, losing adherence, and acquiring numerous digitations, closely resembling immature dendritic cells (Fig. 1B). Because of technical limitations, we could not analyze their phenotype, but we showed that both lymphoid (CD33^negative; ref. 4) and myeloid (CD33^positive) populations (2, 3) had a strong antiproliferative effect on the myeloid cell lines K562 and P815.

View larger version (27K): [in this window] [in a new window]   Fig. 1. CD56+ myeloid cells acquired dendritic cell characteristics on interleukin-4 and GM-CSF stimulation.

References

1. Schleypen JS, Baur N, Kammerer R, et al. Cytotoxic markers and frequency predict functional capacity of natural killer cells infiltrating renal cell carcinoma. Clin Cancer Res 2006;12:718–25.[Abstract/Free Full Text]
2. Sconocchia G, Fujiwara H, Rezvani K, et al. G-CSF-mobilized CD34⁺ cells cultured in interleukin-2 and stem cell factor generate a phenotypically novel monocyte. J Leukoc Biol 2004;76:1214–9.[Abstract/Free Full Text]
3. Sconocchia G, Keyvanfar K, El OF, et al. Phenotype and function of a CD56⁺ peripheral blood monocyte. Leukemia 2005;19:69–76.[Medline]
4. Sconocchia G, Provenzano M, Rezvani K, et al. CD34⁺ cells cultured in stem cell factor and interleukin-2 generate CD56⁺ cells with antiproliferative effects on tumor cell lines. J Transl Med 2005;3:15.[CrossRef][Medline]
5. Coca S, Perez-Piqueras J, Martinez D, et al. The prognostic significance of intratumoral natural killer cells in patients with colorectal carcinoma. Cancer 1997;79:2320–8.[CrossRef][Medline]
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7. Ishigami S, Natsugoe S, Tokuda K, et al. Prognostic value of intratumoral natural killer cells in gastric carcinoma. Cancer 2000;88:577–83.[CrossRef][Medline]

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