title: Tc1 and Tc2 effector cell therapy elicit long-term tumor immunity by contrasting mechanisms that result in complementary endogenous type 1 antitumor responses.
abstract: Cytolytic CD8(+) effector cells fall into two subpopulations based on cytokine secretion. Type 1 CD8(+) T cells (Tc1) secrete IFN-gamma, whereas type 2 CD8(+) T cells (Tc2) secrete IL-4 and IL-5. Both effector cell subpopulations display predominantly perforin-dependent cytolysis in vitro. Using an OVA-transfected B16 lung metastases model, we show that adoptively transferred OVA-specific Tc1 and Tc2 cells induce considerable suppression, but not cure, of pulmonary metastases. However, long-term tumor immunity prolonged survival times indefinitely and was evident by resistance to lethal tumor rechallenge. At early stages after therapy, protection by Tc2 and Tc1 effector cells were dependent in part on effector cell-derived IL-4, IL-5, and IFN-gamma, respectively. Whereas effector cell-derived perforin was not necessary. Over time the numbers of both donor cells diminished to low, yet still detectable, levels. Concomitantly, Tc1 and Tc2 effector cell therapies potentiated endogenous recipient-derived antitumor responses by inducing 1) local T cell-derived chemokines associated with type 1-like immune responses; 2) elevated levels of recipient-derived OVA tetramer-positive CD8 memory T cells that were CD44(high), CD122(+), and Ly6C(high) that predominantly produced IFN-gamma and TNF-alpha; and 3) heightened numbers of activated recipient-derived Th1 and Tc1 T cell subpopulations expressing CD25(+), CD69(+), and CD95(+) cell surface activation markers. Moreover, both Tc2 and Tc1 effector cell therapies were dependent in part on recipient-derived IFN-gamma and TNF-alpha for long-term survival and protection. Collectively, Tc1 and Tc2 effector cell immunotherapy mediate long-term tumor immunity by different mechanisms that subsequently potentiate endogenous recipient-derived type 1 antitumor responses.
authors.affiliation: Trudeau Institute, Saranac Lake, NY 12983, USA. mdobrzanski@trudeauinstitute.org
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Dobrzanski
authors.forename: Joyce B
authors.initials: JB
authors.lastname: Reome
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Hollenbaugh
authors.forename: Richard W
authors.initials: RW
authors.lastname: Dutton
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018925:Chemokines / Q000096:biosynthesis / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D018984:Epitopes, T-Lymphocyte / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D005260:Female; D007111:Immunity, Cellular / Q000235:genetics; D016130:Immunophenotyping; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D008168:Lung / Q000276:immunology / Q000378:metabolism; D008175:Lung Neoplasms / Q000276:immunology / Q000401:mortality / Q000556:secondary / Q000628:therapy; D008213:Lymphocyte Activation / Q000235:genetics; D008546:Melanoma, Experimental / Q000276:immunology* / Q000401:mortality / Q000517:prevention & control*; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D010047:Ovalbumin / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D016019:Survival Analysis; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation*; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
chemical_list: D018925:Chemokines; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D014409:Tumor Necrosis Factor-alpha; D054353:Perforin; D007371:Interferon-gamma; D010047:Ovalbumin