Expansion of mucin-reactive T-helper lymphocytes from patients with colorectal cancer.
The ability to identify and expand effector cells with reactivity against tumor-associated antigens (TAA) is critical for effective adoptive cellular therapy. The purpose of this study was to assess lymph node lymphocytes sensitized in vivo to the shed TAA TAG-72 as a potential source of cells for adoptive cellular therapy. Lymph nodes containing microscopic tumor and/or shed TAG-72+ mucin were localized using radiolabeled CC49 monoclonal antibody and a gamma detector at the time of exploratory colorectal surgery. Lymph nodes containing microscopic tumor and shed mucin exhibited approximately 40-fold expansion in short-term (< 21 days) cultures with either IL-2 or IL-1 plus IL-2; the combination of IL-2/anti-CD3 monoclonal antibody (mAb) resulted in significantly higher expansion. Cultures generated with IL-2 alone favored the expansion of CD8+ and CD56+ cells, whereas addition of IL-1 or anti-CD3 mAb to IL-2 promoted outgrowth of CD4+ T-cells. The IL-2/anti-CD3 expanded cells exhibited low levels of cytolytic activity in vitro against autologous and allogeneic colon tumor targets. However, CD4+ cells expanded in IL-2/anti-CD3 retained the ability to proliferate in response to TAG-72 mucin-expressing autologous tumor as well as bovine submaxillary mucin (BSM) a soluble TAG-72+ mucin. In addition, CD4+ cells expressed mRNA for IL-2, IL-4, tumor necrosis factor-beta and IFNg, and retained the ability to secrete IL-2 after expansion. Thus, noncytolytic, cytokine-secreting, mucin-reactive T- cells can be expanded from lymph nodes of patients with colorectal cancer.(ABSTRACT TRUNCATED AT 250 WORDS)
Kim
J A
JA
Department of Surgery, Ohio State University Comprehensive Cancer Center, Columbus, USA.
Martin
E W
EW
Morgan
C J
CJ
Aldrich
W
W
Triozzi
P L
PL
D000951:Antigens, Neoplasm / Q000032:analysis*; D016516:CD4-CD8 Ratio; D015179:Colorectal Neoplasms / Q000276:immunology* / Q000628:therapy; D003602:Cytotoxicity, Immunologic; D006023:Glycoproteins / Q000032:analysis*; D006801:Humans; D016219:Immunotherapy, Adoptive; D007376:Interleukin-2 / Q000096:biosynthesis; D008198:Lymph Nodes / Q000276:immunology*; D009077:Mucins / Q000032:analysis*; D010641:Phenotype; D012333:RNA, Messenger / Q000032:analysis; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D014407:Tumor Cells, Cultured
D000951:Antigens, Neoplasm; D006023:Glycoproteins; D007376:Interleukin-2; D009077:Mucins; D012333:RNA, Messenger; C047052:tumor-associated antigen 72