title: Donor cell cycling, trafficking, and accumulation during adoptive immunotherapy for murine lung metastases.
abstract: Adoptive cellular immunotherapy treats metastatic cancer by infusing cultured T cells derived from resected tumors or primed lymph nodes. The infused cells must accumulate in metastatic lesions to suppress growth; however, this process and the resulting clinical response are dynamic and evolve during the days and weeks following cell infusion. This study used novel experimental techniques to determine the fate of infused, cultured tumor-draining lymph node (TDLN) cells during the treatment of murine pulmonary micrometastases. After infusion, the cultured TDLN cells accumulated in the pulmonary vasculature, systemic lymph nodes, and spleen. Donor cells were initially confined to alveolar capillaries with no movement into metastases. Within 4 h, TDLN cells began migrating across pulmonary postcapillary venules and first appeared within metastases. After 24 h, most donor cells in the lung were associated with tumor nodules. Donor cell proliferation within the lung and lymphoid organs was detected within 24 h of infusion and continued throughout the 5-day period of observation. Furthermore, those proliferating in lymphoid organs trafficked back to the tumor-bearing lungs, accounting for approximately 50% of the donor cells recovered from these sites after 5 days. Finally, donor T cells entering metastases both early (within 1-2 days) and late (after 2 days) suppressed tumor growth, but the early recruits accounted for most of the therapeutic response. Thus, cultured TDLN cells migrate directly into tumor-bearing organs and seed the recirculating pool of lymphocytes after infusion. Small fractions of the later differentiate in lymphoid organs and migrate into the lungs but appear less effective than effector cells in the initial bolus.
authors.affiliation: Department of Pathology, Comprehensive Cancer Center, University of Michigan Medical Center, 1301 Catherine Road, Ann Arbor, MI 48103-0602, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Skitzki
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Craig
authors.forename: Ryugi
authors.initials: R
authors.lastname: Okuyama
authors.forename: Randall N
authors.initials: RN
authors.lastname: Knibbs
authors.forename: Kevin
authors.initials: K
authors.lastname: McDonagh
authors.forename: Alfred E
authors.initials: AE
authors.lastname: Chang
authors.forename: Lloyd M
authors.initials: LM
authors.lastname: Stoolman
mesh_terms: D000818:Animals; D002453:Cell Cycle; D002455:Cell Division; D002465:Cell Movement; D002478:Cells, Cultured; D005260:Female; D005354:Fibrosarcoma / Q000378:metabolism / Q000556:secondary / Q000628:therapy*; D005434:Flow Cytometry; D016219:Immunotherapy, Adoptive; D007376:Interleukin-2 / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary / Q000628:therapy*; D008198:Lymph Nodes / Q000473:pathology; D016246:Lymphocytes, Tumor-Infiltrating / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D037342:Pertussis Toxin; D013154:Spleen / Q000473:pathology; D013601:T-Lymphocytes / Q000473:pathology*; D014407:Tumor Cells, Cultured
chemical_list: D007376:Interleukin-2; D037342:Pertussis Toxin