Killing of laminin receptor-positive human lung cancers by tumor infiltrating lymphocytes bearing gammadelta(+) t-cell receptors.
BACKGROUND
The monomeric laminin receptor, a 67-kd high-affinity laminin-binding protein, is expressed by a variety of normal cell types. Overexpression and abnormal surface distribution of this receptor have been demonstrated in tumor cells where it appears to promote tumor invasion and metastasis. Previously, we reported the existence of an association between laminin receptor overexpression by lung cancer cells and the presence of tumor-infiltrating lymphocytes (TILs) bearing gammadelta T-cell receptors. Gammadelta(+) lymphocytes represents a sizable fraction of the TILs in approximately one fourth of lung cancers analyzed thus far.


OBJECTIVE
The aim of this study was to determine whether gammadelta(+) TILs might participate in the immune response against lung cancer through recognition of monomeric laminin receptors expressed by tumor cells.


METHODS
Tumor cells from 11 lung cancer specimens exhibiting sizable gammadelta(+) T-cell infiltrates and from 11 other specimens infiltrated predominantly by lymphocytes bearing alphabeta(+) T-cell receptors were analyzed for expression of the monomeric laminin receptor by use of the monoclonal antibody (MAb) MLuC5. Gammadalta TILs and chibeta+ TILs derived from four tumors were each examined for cytotoxic activity toward lung cancer target cells by use of a standard 51Cr-release assay and lung tumor cell lines expressing different levels of surface monomeric laminin receptor. The ability of MAbs directed against the laminin receptor (i.e., MLuC5) or against gammadelta T-cell receptors (i.e., TigammaA and A13) as well as laminin peptides known to bind to the laminin receptor to inhibit TIL-mediated target cells lysis was also determined.


RESULTS
We confirmed that the association between overexpression of the monomeric laminin receptor by lung tumor cells and the presence of gammadeltadelta+ TILs is statistically significant (two sided P = .003; Fisher's exact test). We also observed a relationship between the levels of laminin receptor expression on cultured lung cancer cells and their susceptibility to specific lysis by gammadelta(+), but not alphabeta+, TILs. This specific cell killing was not T-cell receptor mediated, but it was inhibited by addition of the anti-monomeric laminin receptor MAb MLuC5 and by a synthetic peptide corresponding to amino acids 2091-2108 of the laminin A chain.


CONCLUSIONS
Our results indicate gammadelta(+) TILs localized at human lung cancer sites can kill tumor cells in a process that involves interaction with the monomeric laminin receptor. The infiltration of gammadelta(+) TILs at lung tumor sites may represent a first line of defense against cells undergoing malignant transformation.
Ferrarini
M
M
Laboratori Immunoterapia Adottiva, Istituto Scientifico H.S. Raffaele.
Heltai
S
S
Pupa
S M
SM
Mernard
S
S
Zocchi
R
R
D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002051:Burkitt Lymphoma; D018288:Carcinoma, Small Cell / Q000276:immunology* / Q000473:pathology; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D006801:Humans; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology; D008175:Lung Neoplasms / Q000276:immunology* / Q000473:pathology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000473:pathology; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000276:immunology / Q000494:pharmacology; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000032:analysis*; D017474:Receptors, Laminin / Q000032:analysis* / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D010446:Peptide Fragments; D016692:Receptors, Antigen, T-Cell, gamma-delta; D017474:Receptors, Laminin