Potent effector function of tumor-sensitized L-selectin(low) T cells against subcutaneous tumors requires LFA-1 co-stimulation.

Abstract

OBJECTIVE:

Animal tumor models have demonstrated that adoptive transfer of tumor-draining lymph node (TDLN) T lymphocytes can cure established tumors in many anatomic sites. However, subcutaneous tumors are relatively refractory and have required maximally tolerated doses of cells. The goals of this study were to determine whether a subset of TDLN T lymphocytes varying in expression of the cell adhesion molecule L-selectin (CD62L) had augmented therapeutic efficacy and to determine the co-stimulatory requirements for trafficking and anti-tumor effector function.

STUDY DESIGN:

TDLNs were recovered from mice bearing progressive MCA 205 fibrosarcomas, and the T lymphocytes were segregated into CD62L(low) and CD62L(high) subsets and activated ex vivo with anti-CD3 mAb and IL-2. Mice bearing established subcutaneous MCA 205 tumors were treated with activated T cell subsets and in some experiments with additional mAb against cell adhesion molecules.

RESULTS:

Adoptive transfer of as few as 5 x 10(6) activated cells cured mice bearing 3-day subcutaneous MCA 205 tumors initiated with 6 x 10(6) cells, and the tumors demonstrated a dense infiltrate of CD62L(low) cells. In marked contrast, adoptive transfer of 10 times as many T cells derived from the reciprocal CD62L(high) compartment had no effect on tumor growth. The effector function of the CD62L(low) T cells was clearly dependent on co-stimulation through the cell adhesion molecule LFA-1, because anti-LFA-1 mAb completely abrogated the anti-tumor reactivity of the transferred cells against subcutaneous tumors and inhibited tumor infiltration. In contrast, blockade of ICAM-1, VLA-4, or VCAM-1 had no inhibitory effect on the anti-tumor function.

CONCLUSION:

These studies demonstrate the high therapeutic activity of the CD62L(low) subset of tumor-draining LN T cells against subcutaneous tumors, a relatively refractory site, and confirm the essential role of LFA-1 for effector T cell function.

SIGNIFICANCE:

Identification of the phenotype and requirements for effector function of T lymphocytes sensitized to tumor antigens has implications for clinical trials of adoptive immunotherapy for head and neck carcinoma using a similar approach.

• Authors: B M Seeley, S W Barthel, W C To, J Kjaergaard, S Shu, G E Plautz
• Journal: Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery (Otolaryngol Head Neck Surg) Vol. 124 Issue 4 Pg. 436-41 (Apr 2001) ISSN: 0194-5998 [Print] England
• PMID: 11283503 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antigens, Neoplasm
• Interleukin-2
• Leukocyte L1 Antigen Complex
• Lymphocyte Function-Associated Antigen-1
• Membrane Glycoproteins
• Neural Cell Adhesion Molecules
• L-Selectin

Topics

• Adoptive Transfer (methods)
• Animals
• Antigens, Neoplasm (immunology)
• Carcinoma (immunology)
• Cell Separation
• Disease Models, Animal
• Female
• Fibrosarcoma (immunology)
• Immunotherapy
• Interleukin-2 (immunology)
• L-Selectin (immunology)
• Leukocyte L1 Antigen Complex
• Lymphocyte Activation (physiology)
• Lymphocyte Function-Associated Antigen-1 (immunology)
• Lymphocyte Subsets (immunology)
• Lymphocytes, Tumor-Infiltrating (immunology)
• Membrane Glycoproteins (immunology)
• Mice
• Mice, Inbred C57BL
• Neoplasms, Adipose Tissue (immunology)
• Neural Cell Adhesion Molecules (immunology)
• Tumor Cells, Cultured