Tumor-infiltrating lymphocytes, particularly the balance between CD8+ T cells and CCR4+ regulatory T cells, affect the survival of patients with oral squamous cell carcinoma
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CCR4
Regulatory T cell
T regulatory cells (Treg) avert autoimmunity, but their increased levels in melanoma confer a poor prognosis. To explore the basis for Treg accumulation in melanoma, we evaluated chemokine expression in patients. A 5-fold increase was documented in the Treg chemoattractants CCL22 and CCL1 in melanoma-affected skin versus unaffected skin, as accompanied by infiltrating FoxP3+ T cells. In parallel, there was an approximately two-fold enhancement in expression of CCR4 in circulating Treg but not T effector cells. We hypothesized that redirecting Treg away from tumors might suppress autoimmune side effects caused by immune checkpoint therapeutics now used widely in the clinic. In assessing this hypothesis, we observed a marked increase in skin Treg in mice vaccinated with Ccl22, with repetitive vaccination sufficient to limit Treg accumulation and melanoma growth in the lungs of animals challenged by tumor cell injection, whether using a prevention or treatment protocol design. The observed change in Treg accumulation in this setting could not be explained by Treg conversion. Overall, our findings offered a preclinical proof of concept for the potential use of CCL22 delivered by local injection as a strategy to enhance the efficacious response to immune checkpoint therapy while suppressing its autoimmune side effects. Cancer Res; 76(21); 6230-40. ©2016 AACR.
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In a mixed leukocyte culture (MLC) reaction of allogenic mouse spleen cells differing for H-2K or H-2D, only a weak cytotoxic response is generated. This cytotoxic response is augmented significantly if bacterial lipopolysaccharide (LPS), 5 microgram/ml, or polyadenylic acid (poly A):polyuridylic acid (poly U), 20 microgram/ml, is present in the culture. The cytotoxic cells generated in the presence of these two agents are specific for sensitizing H-2K or H-2D antigen. Two lines of evidence suggest that these two agents exert their effect at different steps in the development of cytotoxic lymphocytes: (a) the effect of poly A:U depends on the presence of adherent cells, whereas the effect of LPS is independent of the presence of adherent cells and (b) LPS promotes the development of cytotoxic cells when ultraviolet light-treated stimulating cells are used in the MLC whereas poly A:U does not.
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Abstract The main conclusion from these experiments is that the antigen‐specific suppressor T cell of mice which inhibits the induction of cytotoxic T lymphocytes is not itself a cytotoxic T cell. This conclusion is supported by two main observations: first, a certain cell number from first‐step cultures which was suppressive in the presence of a high dose of antigen actually helped the cytotoxic response at a lower antigen dose. This observation is difficult to reconcile with the hypothesis that suppression is due to the killing of the stimulator or the responder cells in the second‐step culture by cytotoxic T cells. Second, cells from first‐step cultures of cortisone‐treated mice displayed cytotoxic activity but had no suppressive effect on the generation of killer cells. It was further demonstrated that these cells failed to influence in any way the suppressive effect, however weak, of cells from first‐step cultures of normal spleen. We therefore favor the view that the suppression observed in this system is due to a regulatory signal which occurs as a result of the ability of both inhibitory cells and responder cells to recognize and respond to allogeneic determinants expressed on the surface of stimulator cells. The suppressor T cells described here act by linked associative recognition of antigen. That is, suppressor T cells only inhibit the induction of a precursor cytotoxic T cell in the presence of an antigen to which both the precursor cell and the suppressor cell can bind. In this sense, suppressors act in a manner analogous to helper T cells in T‐B cell cooperation; carrier‐specific helper T cells only enhance an anti‐hapten B cell response in the presence of hapten‐carrier conjugates. Similarly, alloantigen a (carrier)‐specific suppressor T cells only inhibit alloantigen b (hapten)‐specific cytotoxic responses in the presence of (a × b)F 1 stimulator cells (hapten‐carrier conjugate), not in the presence of a mixture of parental stimulator cells (a + b).
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Sir: A number of investigators have recently reported that cell membranes, or solubilized proteins derived from them, are capable of inducing cytotoxic responses in secondary cultures (1–6). They have implied thereby that they are gaining insight into the specificity of the structures recognized by cytotoxic T cells. An alternative interpretation seems equally plausible: that the membrane preparations act not directly on cytotoxic memory cells, but rather on helper T cells, which, by secreting soluble mediators, “trigger” cytotoxic cell differentiation. This interpretation is supported by several recent reports. Thus, Ryser et al. (7), Wagner and Rollinghoff (8), and this laboratory (Okada et al. , in press) have shown that cell mediators secreted by primed Lyt I+ T cells can cause the direct differentiation of cytotoxic T cells in secondary (memory) cultures. Moreover, the specificity of the cytotoxic cells induced by these mediators is that of the antigen initially used for priming.
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CCR4
CCL17
CCL22
Asymptomatic carrier
CC chemokine receptors
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Abstract New treatments are needed for patients with cutaneous T‐cell lymphoma (CTCL), particularly for advanced mycosis fungoides (MF) and Sezary syndrome (SS). The immunopathology of MF and SS is complex, but recent advances in tumor microenvironment understanding have identified CCR4 as a promising therapeutic target. CCR4 is widely expressed on malignant T cells and Tregs in the skin and peripheral blood of patients with MF and SS. The interaction of CCR4 with its dominant ligands CCL17 and CCL22 plays a critical role in the development and progression of CTCL, facilitating the movement into, and accumulation of, CCR4‐expressing T cells in the skin, and recruiting CCR4‐expressing Tregs into the tumor microenvironment. Expression of CCR4 is upregulated at all stages of MF and in SS, increasing with advancing disease. Several CCR4‐targeted therapies are being evaluated, including “chemotoxins” targeting CCR4 via CCL17, CCR4‐directed chimeric antigen receptor‐modified T‐cell therapies, small‐molecule CCR4 antagonists, and anti‐CCR4 monoclonal antibodies. Only one is currently approved: mogamulizumab, a defucosylated, fully humanized, anti‐CCR4, monoclonal antibody for the treatment of relapsed/refractory MF and SS. Clinical trial da1ta confirm that mogamulizumab is an effective and well‐tolerated treatment for relapsed/refractory MF or SS, demonstrating the clinical value of targeting CCR4.
CCR4
Cutaneous T-cell lymphoma
CCL17
CC chemokine receptors
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Abstract Sir: A number of investigators have recently reported that cell membranes, or solubilized proteins derived from them, are capable of inducing cytotoxic responses in secondary cultures (1–6). They have implied thereby that they are gaining insight into the specificity of the structures recognized by cytotoxic T cells. An alternative interpretation seems equally plausible: that the membrane preparations act not directly on cytotoxic memory cells, but rather on helper T cells, which, by secreting soluble mediators, “trigger” cytotoxic cell differentiation. This interpretation is supported by several recent reports. Thus, Ryser et al. (7), Wagner and Rollinghoff (8), and this laboratory (Okada et al., in press) have shown that cell mediators secreted by primed Lyt I+ T cells can cause the direct differentiation of cytotoxic T cells in secondary (memory) cultures. Moreover, the specificity of the cytotoxic cells induced by these mediators is that of the antigen initially used for priming.
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Homing (biology)
CXCR3
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