Type 1 and Type 2 CD8+ Effector T Cell Subpopulations Promote Long-Term Tumor Immunity and Protection to Progressively Growing Tumor

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, IL-5, and IL-10. Using an OVA-transfected B16 lung metastases model, we assessed the therapeutic effects of adoptively transferred OVA-specific Tc1 and Tc2 subpopulations in mice bearing established pulmonary malignancy. Effector cell-treated mice exhibiting high (5 × 105) tumor burdens experienced significant (p < 0.05) delays in mortality compared with those of untreated control mice, whereas high proportions (70–90%) of mice receiving therapy with low (1 × 105) tumor burdens survived indefinitely. Long-term tumor immunity was evident by resistance to lethal tumor rechallenge, heightened levels of systemic OVA Ag-specific CTL responses ex vivo, and detection of long-lived TCR transgene-positive donor cells accompanied by an elevation in the total numbers of CD8+ CD44high activated and/or memory T cells at sites of tumor growth. Long-lasting protection by Tc2 and Tc1 effector cells were dependent, in part, on both the level of tumor burden and effector cell-derived IL-4, IL-5, and IFN-γ, respectively. We conclude that Tc1 and Tc2 effector cells provide immunity by different mechanisms that subsequently potentiate host-derived 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

“…At 12 days after tumor cell injection, mice had lung micrometastasis. 5 These mice were then treated with i.v. injection of the engineered CD8 þ T TNF and the control CD8 þ T control or 'T þ rTNF' cells (2 Â 10 6 cells per mouse).…”

“…4 Recently, it has further been reported that adoptive transfer of cytotoxic T type 1 cells can cure 70% palpable tumors. 5 More recently, Becker et al 6 have shown that Tc cells enriched through an interferon (IFN)-g-capture method displayed enhanced tumor-specific cytotoxicity and the adoptive therapy with these T cells cured 3/5 mice bearing 3-day tumors. In most of these animal models, T-cell adoptive therapy is all limited in treatment of earlystage tumors (e.g., 3-day or palpable tumors or 3-10-day early lung metastases), but not large tumors.…”

Spontaneous Vitiligo in an Animal Model for Human Melanoma

“…To assess such a hypothesis, we monitored the tumor-specific IFN-␥ response in MT/ret melanoma mice and compared it with the response in mice with concurrent vitiligo. Many reports have indicated that IFN-␥ plays a critical role in the development of tumor immunity, and recent reports including ours using IFN-␥ knock-out mice demonstrated a crucial role for IFN-␥ in the control of B16 melanoma growth in vivo (15)(16)(17). To evaluate natural tumor-specific response, ex vivo IFN-␥-ELISPOT assays were performed by using PBLs isolated from MT/ret mice as effector cells and a Melan-ret cell line as melanoma antigen-presenting cells.…”

Combined CD4+ Th1 effect and lymphotactin transgene expression enhance CD8+ Tc1 tumor localization and therapy

“…[9][10][11] Dutton et al 12 have originally reported that both tumor-specific Tc1 and Tc2 cells can mediate reduction in lung metastasis of B16 melanoma in vivo. Recently, they have further shown that these tumorspecific Tc1 and Tc2 can also cure intradermally transplanted B16 melanomas, but only in their palpable sizes, 13 but Tc1 cells were more effective than Tc2 in controlling tumor growth and in prolonging the survival times of tumor-bearing mice. 14 …”