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-γ, 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-γ, 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 CD44high, CD122+, and Ly6Chigh that predominantly produced IFN-γ and TNF-α; 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-γ and TNF-α 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.

Engineered CD8+ cytotoxic T cells with fiber-modified adenovirus-mediated TNF-α gene transfection counteract immunosuppressive interleukin-10-secreting lung metastasis and solid tumors

“…Recently, it has been reported that membrane TNF-a can delay T-cell activation-induced cell death by activation of AKT and NF-kB, 64 which leads to elongated T-cell survival. Our results are thus consistent with a previous report by Dobrazanski, et al, 65 demonstrating that CD8 þ T-cell therapeutic effect was significantly less efficient in TNF-a À/À KO mice. These long-lived memory T cells possess the unique ability to respond rapidly and specifically to the antigen.…”

“…Interestingly, our data also demonstrated that transfer of the engineered CD8 þ T TNF cells further leads to a stronger longterm antitumor immunity against the IL-10-secreting B16 OVA/ILÀ10 tumor cell challenge. Dobrazanski et al 65 previously reported the induction of the host antigen-specific CD8 þ Tm cells in lung tissues after adoptive transfer of the donor antigen-specific CD8 þ effector T cells. However, the mechanism involved in this interesting finding was not elucidated.…”

CD8+ Cytotoxic T-APC Stimulate Central Memory CD8+ T Cell Responses via Acquired Peptide-MHC Class I Complexes and CD80 Costimulation, and IL-2 Secretion

“…ϩ Tc-derived Tm cells (46,47). However, the corresponding immune mechanism behind this finding has not been disclosed.…”

Tumors Suppress In Situ Proliferation of Cytotoxic T Cells by Promoting Differentiation of Gr-1+ Conventional Dendritic Cells through IL-6

“…For some studies, we used B16 tumors that express the model tumor Ag OVA [B16-OVA; kindly provided by R.W. Dutton, Trudeau Institute (16)]. To establish tumors in mice, 0.5 3 10 6 to 1 3 10 6 tumor cells in 50 ml PBS were injected s.c. into the flank or i.v.…”