Immunotherapy of Cytotoxic T Cell–resistant Tumors by T Helper 2 Cells

Abstract

Currently most attempts at cancer immunotherapy involve the generation of CD8+ cytotoxic T lymphocytes (CTLs) against tumor-associated antigens. Many tumors, however, have been immunoselected to evade recognition by CTLs and thus alternative approaches to cancer immunotherapy are urgently needed. Here we demonstrate that CD4+ T cells that recognize a secreted tumor-specific antigen and exhibit a cytokine secretion profile characteristic of Th2 cells, are capable of clearing established lung and visceral metastases of a CTL-resistant melanoma. Clearance of lung metastases by the Th2 cells was found to be totally dependent on the eosinophil chemokine, eotaxin, and partially dependent on the transcription activator signal transducer and activator of transcription 6 (STAT6), with degranulating eosinophils within the tumors inducing tumor regression. In contrast, tumor-specific CD4+ Th1 cells, that recruited macrophages into the tumors, had no effect on tumor growth. This work provides the basis for a new approach to adoptive T cell immunotherapy of cancer.

CD4+ T‐cell‐mediated anti‐tumor immunity can be uncoupled from autoimmunity via the STAT4/STAT6 signaling axis

“…As discussed above, we did not observe any influence of STAT6 signaling on the differentiation of DCT-specific CD4 1 T cells, suggesting that STAT6 is also required downstream of the effector CD4 1 T cells. Consistent with our observation, Mattes et al [10] demonstrated that tumor regression mediated by transferred Th2 effector cells was dependent on the host expression of STAT6. Furthermore, there is ample evidence that STAT6 plays a critical role in the late phase of allergic asthma, in addition to its requirement in Th2 differentiation [32,33].…”

“…More importantly, this anti-tumor mechanism did not evoke fulminant autoimmune pathology. The utility of Th2 cells or IL-4 as anti-tumor effectors has been reported by others, and in some cases Th2 cells were more effective than Th1 cells in the clearance of cytotoxic T lymphocyte-resistant tumors [10]. Furthermore, a human clinical trial of Canvaxin, a cell-based vaccine, found that the magnitude of vaccine-induced Th2 immunity correlated with overall survival, and anti-tumor Th2 cells can be identified in cancer patients supporting the possibility of generating such populations in humans [30,31].…”

“…Increasing evidence indicates that CD4 1 T cells are able to mediate tumor destruction without direct interaction with tumor cells and that CD4 1 T cells may provide even greater anti-tumor effect than CD8 1 T cells [5][6][7][8]. Furthermore, reports from various groups, including ours, have demonstrated the ability of CD4 1 T cells to reject cytotoxic T lymphocyte-resistant, MHC class II-negative tumors [7,9,10]. Therefore, understanding the potential for CD4 1 T cells as antitumor effectors is of broad value to both MHC class II-positive and -negative tumors.…”

“…With regard to MHC class II-negative tumors, it is believed that APC infiltrating the tumor bed process tumor antigen and present it to CD4 1 T cells. In turn, the tumor antigen-stimulated CD4 1 T cells can produce IFN-g (Th1) or IL-4 (Th2); both of these cytokines display anti-angiogenic properties and are able to recruit other tumoricidal cells such as NK, macrophages or eosinophils into the tumor [5,[10][11][12]. These indirect destructive mechanisms may prove advantageous over the direct effector functions mediated by CD8 1 T cells as the indirect mechanisms should not be affected by MHC expression levels on the tumor cell and consequently may deter the development of tumor escape variants due to antigen loss.…”

Human Eosinophils Exert TNF-α and Granzyme A-Mediated Tumoricidal Activity toward Colon Carcinoma Cells

“…Even though the beneficial effect of TATE remains controversial, the presence of eosinophils appears as an indicator of good prognosis indicator in some cancers, such as head and neck cancers (7)(8)(9) and gastrointestinal cancers (10), particularly in colorectal cancers, in which high eosinophil counts were associated to increased 5-y survival (11). Clinical observations that eosinophil accumulation in intestinal tumors was associated to a better prognosis have been recently supported by experimental data in murine models (12)(13)(14).…”