New strategies for melanoma immunotherapy (original) (raw)
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Cancer Research, 2008
We previously reported that bone marrows of breast cancer patients contained tumor antigen-specific CD8 + T cells with central or effector memory phenotype. Using a recently developed ret transgenic mouse melanoma model, we now show that bone marrows and tumors of transgenic mice contain high frequencies of CD8 + T cells specific for the melanoma antigen tyrosinase-related protein 2 and showing mostly effector memory phenotype. Moreover, increased numbers of bone marrow tyrosinase-related protein-2-specific effector memory CD8 + T cells are also detected in transgenic animals older than 20 weeks with disseminated melanoma cells in the bone marrow and lymph nodes but showing no visible skin tumors and no further melanoma progression. After a short-term coincubation with dendritic cells generated from the bone marrow and pulsed with melanoma lysates, bone marrow memory T cells from mice without macroscopic melanomas produced IFN-; in vitro and exerted antitumor activity in vivo after adoptive transfer into melanoma-bearing mice. Our data indicate that functionally active bone marrowderived melanoma-specific memory T cells are detectable at the phase of microscopic tumor load, suggesting that thereby they could control disseminated melanoma cells. [Cancer Res 2008;68(22):9451-8]
Molecular Therapy, 2015
Clinical therapy with T cells shows promise for cancer patients, but is currently challenged by incomplete responses and tumor relapse. The exact mechanisms that contribute to tumor relapse remain largely unclear. Here, we treated mouse melanomas with T cell receptor-engineered T cells directed against a human peptide-major histocompatibility complex antigen in immune-competent mice. T cells resulted in significant tumor regression, which was followed by relapse in about 80-90% of mice. Molecular analysis revealed that relapsed tumors harbored nonmutated antigen genes, not silenced by promoter methylation, and functionally expressed surface antigen at levels equal to nontreated tumors. Relapsed tumors resisted a second in vivo T cell treatment, but regained sensitivity to T cell treatment upon retransplantation in mice. Notably, relapsed tumors demonstrated decreased levels of CD8 T cells and monocytes, which were substantiated by downregulated expression of chemoattractants and adhesion molecules. These observations were confirmed when using T cells specific for a less immunogenic, endogenous mouse melanoma antigen. We conclude that tumors, when exposed to T cell treatment, can relapse without loss of antigen and develop a milieu that evades recruitment of effector CD8 T cells. Our findings support the concept to target the tumor milieu to aid T cell therapy in limiting tumor relapse
Strategies to overcome obstacles to successful immunotherapy of melanoma
International journal of immunopathology and pharmacology
The immunogenicity of malignant melanomas has been recognized by the observed recruitment of tumor-specific cytotoxic T-cells (CTL), leading to the identification of several melanoma associated antigen (MAA). However, numerous strategies to treat melanoma with immunotherapy have resulted in only partial success. In this editorial, we discuss recent data related to the ability of tumors to elude immune responses. We therefore discuss different strategies to induce a clinically effective immune response. These approaches include 1) immunostimulation: including peptide/protein based vaccines, dendritic cell vaccines, and adoptive cell transfer; and 2) overcoming immunosuppression, including targeting of checkpoint molecules such as CTLA-4, circumventing the activity of Tregs, and assuring antigen expression by tumor cells (thwarting antigen silencing). Finally, we discuss recent advances in gene therapy, including adoptive therapy with engineered T cell receptors (TCRs). These issues l...
Melanoma Immunomodulation: A War of Attrition
Treatment of Metastatic Melanoma, 2011
At the cellular level, melanoma tumors differentially express cytokines, chemokines, and soluble molecules responsible for immunosuppression and tumor proliferation which will be discussed further in this chapter, particularly those with potential for targeting or with therapeutic benefits (Lazar-Molnar et al., 2000). Melanoma cells are also less efficient in antigen (Ag) presentation to CD4+ T cells, reducing immune detection of melanoma tumors and the effectiveness of some immunotherapy strategies (Norton & Haque, 2009). Multiple defects along the HLA class II pathway are present in melanoma cells, the alteration of which could prove useful in novel tumor targeting and immunotherapeutic vaccination strategies. These defects and the potential to overcome them will be further explained in this chapter. Costimulatory molecules are also altered in melanoma cells, reducing positive cellular interaction with T cells and professional antigen presenting cells (APCs), while promoting immunosuppressive interactions through CD28, CTLA-4, and the B7 family of immune inhibitors (Pardee et al., 2009; Wolchok & Saenger, 2008). Study focused on enhancing these secondary stimulation signals would promote complete T cell stimulation and activation of anti-tumor CD8+ T cells, a current goal of most immunotherapy strategies. Melanoma cells are also capable of modulating the surrounding immune cells including: suppression of tumor infiltrating lymphocytes (TILs), enhancement of CD4+CD25+FoxP3+ T regulatory cells (Tregs), increased immature myeloid suppressor cells, increased protumorigenic m2 macrophages, and generation of melanoma-associated fibroblasts (Oble et al.
The Journal of Immunology, 2012
Therapeutic treatment of large established tumors using immunotherapy has yielded few promising results. We investigated whether adoptive transfer of tumor-specific CD8 + T cells, together with tumor-specific CD4 + T cells, would mediate regression of large established B16BL6-D5 melanomas in lymphopenic Rag1 2/2 recipients devoid of regulatory T cells. The combined adoptive transfer of subtherapeutic doses of both TRP1-specific TCR transgenic Rag1 2/2 CD4 + T cells and gp100-specific TCR transgenic Rag1 2/2 CD8 + T cells into lymphopenic recipients, who received vaccination, led to regression of large (100-400 mm 2 ) melanomas. The same treatment strategy was ineffective in lymphoreplete wild-type mice. Twenty-five percent of mice (15/59) had tumors recur (15-180 d postregression). Recurrent tumors were depigmented and had decreased expression of gp100, the epitope targeted by the CD8 + T cells. Mice with recurrent melanoma had increased CD4 + Foxp3 + TRP1-specific T cells compared with mice that did not show evidence of disease. Importantly, splenocytes from mice with recurrent tumor were able to suppress the in vivo therapeutic efficacy of splenocytes from tumor-free mice. These data demonstrate that large established tumors can be treated by a combination of tumor-specific CD8 + and CD4 + T cells. Additionally, recurrent tumors exhibited decreased Ag expression, which was accompanied by conversion of the therapeutic tumor-specific CD4 + T cell population to a Foxp3 + CD4 + regulatory T cell population.
mRNA based dendritic cell immunization improves survival inrettransgenic mouse melanoma model
OncoImmunology, 2016
Malignant melanoma is characterized by a rapid progression, metastasis to distant organs and resistance to chemo and radiotherapy. Although melanoma is capable of eliciting an immune response, the disease progresses and the overall results of immunotherapeutic clinical studies are not satisfactory. Recently, we have developed a novel genetic platform for improving an induction of peptide-specific CD8 C T cells by dendritic cell (DC) based on membrane-anchored b2-microglobulin (b2m) linked to a selected antigenic peptide at the N-terminus and to the cytosolic domain of TLR4 at the C-terminus. In vitro transcribed mRNA transfection of antigen-presenting cells (APCs) resulted in an efficient coupling of peptide presentation and cell activation. In this research, we utilize the chimeric platform to induce an immune response in ret transgenic mice that spontaneously develop malignant skin melanoma and to examine its effect on the overall survival of tumor-bearing mice. Following immunization with chimeric construct system, we observe a significantly prolonged survival of tumor-bearing mice as compared to the control group. Moreover, we see elevations in the frequency of CD62L hi CD44 hi central and CD62L lo CD44 hi effector memory CD8 C T-cell subsets. Importantly, we do not observe any changes in frequencies of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) in the vaccinated groups. Our data suggest that this novel vaccination approach could be efficiently applied for the immunotherapy of malignant melanoma.
Ret transgenic mouse model of spontaneous skin melanoma: focus on regulatory T cells
Pigment cell & melanoma research, 2013
Ret transgenic mouse model of skin malignant melanoma is characterized by the overexpression of the human ret transgene in melanin-containing cells. Transgenic mice spontaneously develop skin tumors with metastases in lymph nodes, lungs, liver, brain, and the bone marrow. Tumor lesions show typical melanoma morphology and express melanoma-associated antigens. Although transgenic mice demonstrate an accumulation of melanoma antigen-specific memory and effector T cells, their anti-tumor effects could be blocked by highly immunosuppressive leukocytes enriched in the tumor microenvironment and in the periphery. Here, we discuss the role of one of the most potent immunosuppressive subset, regulatory T cells, in the melanoma progression in this model.
Concomitant Tumor Immunity to a Poorly Immunogenic Melanoma Is Prevented by Regulatory T Cells
Concomitant tumor immunity describes immune responses in a host with a progressive tumor that rejects the same tumor at a remote site. In this work, concomitant tumor immunity was investigated in mice bearing poorly immunogenic B16 melanoma. Progression of B16 tumors did not spontaneously elicit concomitant immunity. However, depletion of CD4 ϩ T cells in tumor-bearing mice resulted in CD8 ϩ T cell-mediated rejection of challenge tumors given on day 6. Concomitant immunity was also elicited by treatment with cyclophosphamide or DTA-1 monoclonal antibody against the glucocorticoid-induced tumor necrosis factor receptor. Immunity elicited by B16 melanoma cross-reacted with a distinct syngeneic melanoma, but not with nonmelanoma tumors. Furthermore, CD8 ϩ T cells from mice with concomitant immunity specifically responded to major histocompatibility complex class I-restricted epitopes of two melanocyte differentiation antigens. RAG1 ϪրϪ mice adoptively transferred with CD8 ϩ and CD4 ϩ T cells lacking the CD4 ϩ CD25 ϩ compartment mounted robust concomitant immunity, which was suppressed by readdition of CD4 ϩ CD25 ϩ cells. Naturally occurring CD4 ϩ CD25 ϩ T cells efficiently suppressed concomitant immunity mediated by previously activated CD8 ϩ T cells, demonstrating that precursor regulatory T cells in naive hosts give rise to effective suppressors. These results show that regulatory T cells are the major regulators of concomitant tumor immunity against this weakly immunogenic tumor.