In vivo MAb anti-mouse CD8α (2023)

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Balogh, K.N., et al. (2018). "Macrophage migration inhibitory factor protects cancer cells from immunogenic cell death and alters antitumor immune responses" PLoS One 13(6): e0197702.PubMed

Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine that is overexpressed in several types of cancer, and increased MIF expression is often correlated with tumor aggressiveness and poor health. In this study, we sought to better understand the relationship between MIF expression in the primary tumor and increased tumor growth. Using the MMTV-PyMT mouse model of breast cancer, we observed that increased MIF expression promoted tumor appearance and growth. Favorably, we confirm our earlier observation that increased MIF expression supported tumor growth in the 4T1 mouse model of breast cancer. We subsequently found that loss of MIF expression in 4T1 cells resulted in decreased cell number and increased vitrounder reduced serum culture conditions. Our hypothesis is that this increase in cell death would promote recognition by the host's immune, which could explain the observed deterioration in tumor growth. Favorably, we showed that loss of MIF expression in the primary tumor resulted in an increased frequency of intratumoral IFNgamma-producing CD4+ and CD8+ T cells, and that depletion of T cells from MIF-deficient tumor-bearing mice restored tumor growth. tumor expressing MIF. Furthermore, we found that MIF depletion of tumor cells resulted in an increased number of activated intratumoral dendritic cells (DCs). Finally, we show that loss of MIF expression resulted in the robust induction of a specialized form of cell death, immunogenic cell death (IDC).in vitro. Taken together, our data suggest a model in which MIF expression in the primary tumor suppresses the antitumor immune response and promotes tumor growth.

liveCD8+ T-Zell depletion
Li, J., et al. (2018). "B7 superfamily member 1 co-inhibitory molecule expressed by tumor-infiltrating myeloid cells induces antitumor CD8(+) T-cell dysfunction" Immunity 48(4): 773-786 e775.PubMed

The molecular mechanisms by which CD8(+) T cells are "depleted" in the tumor microenvironment remain unclear. Programmed death ligand 1 (PD-L1) is up-regulated in tumor cells, and blocking PD-1-PD-L1 has significant efficacy in human tumors; However, most patients do not respond, suggesting additional mechanisms underlying T cell depletion. Member 1 of the B7 superfamily (B7S1), also called B7-H4, B7x, or VTCN1, regulates T cell activation of T cells. Here we show increased expression of B7S1 in myeloid cells of human hepatocellular carcinoma correlated with CD8(+) T cell dysfunction. Inhibition of B7S1 suppressed murine tumor development. The putative B7S1 receptor was co-expressed with PD-1 but not with T cell immunoglobulin and mucin-containing domain 3 (Tim-3) in an activated state of early tumor infiltrating CD8(+) T cells and T cell depletion promoted by B7S1, possibly due to overexpression of Eomes. Combinatorial blocking of antitumor immune responses synergistically enhanced by B7S1 and PD-1. Overall, B7S1 initiates tumor-infiltrating CD8(+) T cell dysfunction and may be the target of cancer immunotherapy.

(Video) humanized antibody

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Moynihan, K.D., et al. (2016). "Eradication of large established tumors in mice by combined immunotherapy using innate and adaptive immune responses" Nat Med. doi: 10.1038/nm.4200.PubMed

Blocking checkpoints with antibodies specific for cytotoxic T lymphocyte-associated protein (CTLA)-4 or programmed cell death 1 (PDCD1; also known as PD-1) causes permanent tumor regression in metastatic cancer, but these dramatic responses are limited to a The suboptimal result is likely due in part to the complex network of immunosuppressive signaling pathways present in advanced tumors that are unlikely to be overcome by intervention at a single signaling checkpoint. Here we describe a combination immunotherapy that recruits a variety of innate and adaptive immune cells to eliminate large tumor burdens in syngenic tumor models and a genetically modified mouse model of melanoma; As far as we know, tumors of this size are not curable by treatments based on endogenous immunity. Four components were required for maximum antitumor efficacy: an antibody directed at the tumor antigen, a long half-life recombinant interleukin-2, anti-PD-1, and an effective T-cell vaccine. Featuring dendritic cells and several other cell subsets innate immune cells were required for tumor regression. Effective treatment induced immune cell infiltration and tumor inflammatory cytokine production, increased antibody-mediated tumor antigen uptake, and promoted antigen secretion. These results demonstrate the ability of an endogenously generated immune response to destroy large established tumors and elucidate the essential features of combination immunotherapies capable of curing most tumors in experimental settings that are normally considered untreatable.

liveCD8+ T-Zell depletion
Voron, T., et al. (2015). "VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors" J Exp Med 212(2): 139-148.PubMed

Immune flight is a prerequisite for tumor development. To escape the immune system, tumors develop several mechanisms, including T cell depletion characterized by the expression of inhibitory immune receptors such as PD-1, CTLA-4, Tim-3 and a progressive loss of function. The recent development of therapies targeting PD-1 and CTLA-4 has attracted great interest as it has elicited long-lasting objective responses in patients with advanced metastatic tumors. However, the regulation of PD-1 expression and therefore depletion is unclear. VEGF-A, a pro-angiogenic molecule produced by tumors, plays a key role in the development of an immunosuppressive microenvironment. In the present work, we report that VEGF-A produced in the tumor microenvironment increases the expression of PD-1 and other inhibitory checkpoints involved in the depletion of CD8(+) T cells, which is associated with VEGF-targeted antiangiogenic agents that can reverse -VEGFR . Given these results, the association of antiangiogenic molecules with checkpoint inhibitory immunomodulators in VEGF-A producing tumors may be of particular interest.

liveCD8+ T-Zell depletion
Vanpouille-Box, C., et al. (2015). "TGFbeta is an important regulator of radiotherapy-induced antitumor immunity" Cancer Res 75(11): 2232-2242.PubMed

T cells that target endogenous tumor antigens are potent mediators of tumor regression. Recent advances in immunotherapy have identified effective interventions to induce tumor-specific T cell activity in patients who naturally develop it. Obtaining T-cell responses for a patient's individual tumor remains a major challenge. Radiotherapy can induce immune responses to model antigens expressed by tumors, but it is still unclear whether it can effectively prime T cells specific for endogenous antigens expressed by poorly immunogenic tumors. We hypothesize that TGFbeta activity is a major hurdle hampering radiation's ability to generate a tumor vaccine in situ. Here we show that antibody-mediated neutralization of TGFbeta during radiotherapy efficiently induces CD8(+) T cell responses to various endogenous tumor antigens in poorly immunogenic mouse carcinomas. The generated T cells effectively regressed irradiated tumors and non-irradiated lung metastases or synchronous tumors (abscopal effect). Genetic signatures associated with IFNgamma and immune-mediated rejection have been demonstrated in tumors treated with radiotherapy and TGFbeta blockade in combination, but not as individual agents. Upregulation of programmed death (PD) ligands 1 and 2 in neoplastic and myeloid cells and PD-1 in intratumoral T cells limited tumor rejection, resulting in rapid recurrence. Addition of anti-PD-1 antibodies prolonged survival achieved with radiation and TGFbeta blockade. Thus, TGFbeta is a critical regulator of radiotherapy's ability to generate an in situ tumor vaccine. Combining local radiotherapy with TGFbeta neutralization offers a new, individualized approach to vaccinating patients against their tumours.

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Yamada, D.H., et al. (2015). "Fcgamma Receptor-Mediated Suppression of Antibody Effector Function During Prolonged Viral Infection" Immunity 42(2): 379-390.PubMed

Understanding how viruses subvert host immunity and persist is critical to developing strategies to eradicate infection. T-cell depletion during chronic viral infection is well described, but the implications for antibody-mediated effector activity are unclear. Here, we show that increasing the amount of immune complexes generated in mice persistently infected with lymphocytic choriomeningitis virus (LCMV) disrupts several functions of the Fcgamma receptor (FcgammaR). High levels of immune complexes suppressed antibody-mediated cellular depletion, therapeutic clearance of antibodies from LCMV-infected cells and human tumors expressing CD20, and reduction of immune complex-mediated cross-presentation on FcgammaR T cells was not due to inhibitory FcgammaR or high levels of free FcgammaR antibodies and proper FcgammaR functions were restored when persistently infected mice lacked specific immune complexes. Thus, we identified a mechanism of immunosuppression during the persistence of the virus with implications for understanding the effective activity of antibodies directed at controlling the pathogen.

(Video) Kinetic study of B cell depletion with a novel mAb anti-mouse CD20, clone SA271G2
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Twyman-Saint Victor, C., et al. (2015). "Radiation and double checkpoint blockade activate non-redundant immune mechanisms in cancer" Nature 520(7547): 373-377.PubMed

Immune checkpoint inhibitors produce impressive clinical responses, but optimal results require a combination with each other and with other therapies. This raises fundamental questions about redundancy and resiliency mechanisms. Here we report large tumor regressions in a subset of patients with metastatic melanoma treated with an anti-CTLA4 antibody (anti-CTLA4) and radiation, and reproduce this effect in mouse models. Although the combination treatment improved responses in both irradiated and non-irradiated tumors, resistance frequently emerged. Unbiased analysis of mice showed that resistance was due to upregulation of PD-L1 in melanoma cells and was associated with T cell depletion. Consequently, optimal response in melanoma and other cancers requires radiation, anti- CTLA4 and anti-PD-L1/PD-1. Anti-CTLA4 predominantly inhibits regulatory T cells (Treg cells) and therefore increases the ratio of CD8 T cells to Tregs (CD8/Tregs). Irradiation increases the diversity of the T cell receptor (TCR) repertoire of intratumoral T cells. Together, anti-CTLA4 promotes T cell expansion while radiation shapes the TCR repertoire of expanded peripheral clones. The addition of PD-L1 blockade reverses T cell depletion to mitigate the depression in the CD8/Treg ratio and further promotes expansion of oligoclonal T cells. Similar to the mouse results, patients in our clinical study with melanoma who had elevated PD-L1 did not respond to more anti-CTLA4 radiation, showed sustained T-cell depletion, and progressed rapidly. Thus, in melanoma cells, PD-L1 allows tumors to escape anti-CTLA4-based therapy, and the combination of radiation, anti-CTLA4, and anti-PD-L1 promotes response and immunity through distinct mechanisms. .

liveCD8+ T-Zell depletion
Coffelt, S.B., et al. (2015). "IL-17-producing gamma delta T cells and neutrophils conspire to promote breast cancer metastasis" Nature 522 (7556): 345-348.PubMed

Metastases remain the leading cause of death in patients with breast cancer. The various steps of the metastatic cascade are based on mutual interactions between cancer cells and their microenvironment. In this local microenvironment and in distant organs, immune cells and their mediators are known to facilitate metastasis. However, the precise contribution of tumor-induced systemic inflammation to metastasis and the mechanisms that regulate systemic inflammation are poorly understood. Here, we show that tumors maximize their chances of metastasis by inducing a systemic inflammatory cascade in mouse models of spontaneous breast cancer metastasis. We mechanically show that interleukin (IL)-1beta induces IL-17 expression of gamma-delta T cells (gamma-delta), resulting in granulocyte colony-stimulating factor (G-CSF)-dependent neutrophil expansion and polarization. ) systemically in mice with mammary tumors. Tumor-induced neutrophils acquire the ability to suppress cytotoxic T lymphocytes carrying the CD8 antigen, thus limiting the formation of metastases. Neutralization of IL-17 or G-CSF and absence of gamma-delta T cells prevent neutrophil accumulation and down-regulate the T cell suppressor phenotype of neutrophils. Furthermore, the absence of gamma delta T cells or neutrophils significantly reduces lung and lymph node metastases without affecting primary tumor progression. Our data indicate that counteracting this novel domino effect initiated by cancer cells in the immune system (the gamma delta axis of T cells/IL-17/neutrophils) represents a novel strategy to inhibit metastatic disease.

liveCD8+ T-Zell depletion
Evans, E.E., et al. (2015). "Semaphorin 4D blocking antibodies promote tumor immune infiltration and enhance response to other immunomodulatory therapies" Cancer Immunol Res 3(6): 689-701.PubMed

Semaphorin 4D (SEMA4D, CD100) and its receptor plexin-B1 (PLXNB1) are highly expressed in murine and human tumors and their expression has been shown to correlate with invasive disease in several human tumors. SEMA4D normally serves to regulate the motility and differentiation of many cell types, including those of the immune, vascular, and nervous systems. In the cancer context, SEMA4D-PLXNB1 interactions have been reported to affect vascular stabilization and ERBB2 transactivation, but the effects on immune cell trafficking in the tumor microenvironment (TME) have not been studied. We describe a new immunomodulatory role of SEMA4D, whereby the high expression of SEMA4D in the invasive edges of actively growing tumors affects the infiltration and distribution of leukocytes in the TME. Neutralizing the SEMA4D antibody interrupts this expression gradient, increases tumor recruitment of activated monocytes and lymphocytes, and shifts the balance of cells and cytokines to a pro-inflammatory and anti-tumor environment within the TME. This orchestrated change in tumor architecture was associated with durable tumor rejection in Colon26 and ERBB2(+) mouse breast cancer models. The immunomodulatory activity of the anti-SEMA4D antibody can be increased when combined with other immunotherapies, including immune checkpoint inhibition and chemotherapy. Surprisingly, the combination of anti-SEMA4D antibodies with antibodies against CTLA-4 acts synergistically to promote complete tumor rejection and survival. SEMA4D inhibition represents a new mechanism and therapeutic strategy to promote functional immune infiltration into the TME and inhibit tumor progression.

(Video) Webinar: Introduction to In Vivo Platforms for Cancer Immunotherapy

liveCD8+ T-Zell depletion
Van der Jught, K., et al. (2014). "Intratumoral administration of mRNA encoding a Fusocin composed of IFN-beta and the TGF-beta II receptor ectodomain potentiates antitumor immunity" Oncotarget 5(20): 10100-10113.PubMed

It is generally accepted that the success of immunotherapy depends on the presence of tumor-specific cytotoxic CD8(+) T cells and modulation of the tumor environment. In this study, we validated soluble factors encoding mRNA as a tool to modulate the tumor microenvironment to enhance tumor-specific T cell infiltration. Intratumoral administration of mRNA encoding a fusion protein composed of interferon-beta and transforming growth factor II receptor ectodomain-beta, called Fbeta(2), showed therapeutic potential. Treatment efficacy was dependent on CD8(+) T cells and could be increased by blocking PD-1/PD-L1 interactions. In vitro studies showed that administration of Fbeta(2) to tumor cells resulted in decreased proliferation and increased expression of MHC I, but also PD-L1. Importantly, Fbeta(2) increased the antigen-presenting capacity of dendritic cells, while at the same time reducing the suppressive activity of myeloid suppressor cells. Taken together, these data suggest that intratumoral administration of mRNA encoding soluble proteins such as Fbeta(2) can modulate the tumor microenvironment, resulting in potent antitumor T cell responses that are further enhanced by combination therapy.

liveCD8+ T-Zell depletion
Deng, L., et al. (2014). "Radiation and anti-PD-L1 treatment synergistically promote anti-tumor immunity in mice" J Clin Invest 124(2): 687-695.PubMed

High-dose ionizing (IR) radiation leads to direct killing of tumor cells and enhances tumor-specific immunity, improving tumor control locally and remotely. Unfortunately, local recurrences often occur after IR treatment, indicating that IR-induced responses are insufficient to maintain antitumor immunity. Therapeutic blockade of T cell negative regulator Programmed Death Ligand 1 (PD-L1, also called B7-H1) may enhance T cell effector function when PD-L1 is expressed in chronically inflamed tissues and tumors. Here we show that PD-L1 was upregulated in the tumor microenvironment after IR. Administration of anti-PD-L1 increased IR efficacy through a cytotoxic T cell-dependent mechanism. Concurrent with IR-mediated tumor regression, we observed that IR and anti-PD-L1 synergistically reduced the local accumulation of tumor-infiltrating myeloid suppressor cells (MDSCs), which suppress T cells and alter the tumor immune microenvironment. Furthermore, activation of cytotoxic T cells with the combination therapy mediated the reduction of MDSCs in tumors through the cytotoxic effects of TNF. Our data demonstrate a close interaction between IR, T cells and the PD-L1/PD-1 axis and provide a basis for rational design of combined therapy with immunomodulators and radiotherapy.

liveCD8+ T-Zell depletion
DeBerge, MP, et al. (2014). "Soluble but not transmembrane TNF-alpha is required during influenza infection to limit the magnitude of immune responses and the magnitude of immunopathology" J Immunol 192(12): 5839-5851.PubMed

TNF-alpha is a pleotropic cytokine that has pro-inflammatory and anti-inflammatory functions during influenza infection. TNF-alpha is first expressed as a transmembrane protein that is proteolytically processed to release a soluble form. Transmembrane TNF-alpha (memTNF-alpha) and soluble TNF-alpha (solTNF-alpha) have demonstrated differential pathological or tissue protective effects in different disease models. However, the relative contributions of memTNF-alpha or solTNF-alpha to the regulation of pulmonary immunopathology following influenza infection are unclear. Therefore, we performed intranasal influenza infection in mice expressing only non-cleavable memTNF-alpha or completely lacking TNF-alpha and examined the results. We found that solTNF-alpha, but not memTNF-alpha, was required to limit the strength of the immune response and the extent of injury. In the absence of solTNF-alpha, there was a significant increase in CD8(+) T cell response, including virus-specific CD8(+) T cells, due in part to increased resistance to activation-induced cell death. We found that solTNF-alpha mediates these immunoregulatory effects primarily through TNFR1, as mice lacking TNFR1 but not TNFR2 exhibited dysregulated immune responses and aggravated lesions similar to those seen in mice lacking solTNF-alpha. We also found that solTNF-alpha expression was required early in infection to regulate the magnitude of the CD8(+) T cell response, indicating that early inflammatory events are critical for effector phase regulation. Taken together, these results suggest that the processing of memTNF-alpha to release solTNF-alpha is a critical event regulating the immune response during influenza infection.

liveCD8+ T-Zell depletion
Vegan, F., et al. (2014). "The transcription factor IRF1 determines the IL-21-dependent anticancer functions of TH9 cells" Nat Immunol 15(8): 758-766.PubMed

Initially, the TH9 subset of helper T cells was shown to contribute to the induction of autoimmune and allergic diseases, but later evidence suggested that these cells also exert antitumor activities. However, the molecular events that explain its effector properties are undefined. Here we found that the transcription factor IRF1 increased the effector function of TH9 cells and dictated their anticancer properties. Under TH9-biased conditions, interleukin 1beta (IL-1beta)-induced phosphorylation of the STAT1 transcription factor and subsequent expression of IRF1, which binds to the IL9 and IL21 promoters and secretes the cytokines IL-9 and IL-21 from TH9 cells strengthened . Furthermore, IL-1beta-induced TH9 cells exerted potent anticancer functions in an IRF1 and IL-21 dependent manner. Our results identify IRF1 as a target to control TH9 cell function.

(Video) Monoclonal Antibodies and its Production
liveCD8+ T-Zell depletion
Sandoval, F., et al. (2013). "Mucosal imprinting of vaccine-induced CD8(+) T cells is critical for inhibition of mucosal tumor growth" Sci Transl Med 5(172):172ra120.PubMed

Although many human cancers are located in the mucosa, most cancer vaccines are tested in preclinical models against subcutaneous tumors. Therefore, we wondered whether mucosal-specific targeting instructions to the immune system could affect mucosal tumor growth. We showed that the growth of orthotopic head and neck or lung cancer was inhibited when a cancer vaccine was administered intranasally into the mucosa but not intramuscularly. This antitumor effect was dependent on CD8(+) T cells. In fact, only intranasal vaccination induced mucosal-specific CD8(+) T cells expressing the mucosal integrin CD49a. CD49a blockade decreased the intratumoral infiltration of CD8(+) T cells and the effectiveness of the anticancer vaccine in the tumoral mucosa. We therefore showed that after intranasal vaccination, dendritic cells from the lung parenchyma, but not those from the spleen, induced CD49a expression in specific co-cultured CD8(+) T cells. Human mucosal lung cancer tumor infiltrating lymphocytes also expressed CD49a, supporting the relevance and possible extrapolation of these results to humans. Thus, we identified an association between the route of vaccination and the induction of a mucosal homing program in induced CD8(+) T cells by controlling their traffic. The route of immunization directly affected the effectiveness of the cancer vaccine in fighting mucosal tumors.

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Kearl, T.J., et al. (2013). "Programmed Death Receptor-1/Programmed Death Receptor Ligand-1 Blockade After Transient Lymphocyte Depletion for the Treatment of Myeloma" J Immunol 190(11): 5620-5628.PubMed

Early-stage clinical trials targeting the programmed death receptor-1/ligand-1 (PD-1/PD-L1) pathway to overcome tumor-mediated immunosuppression have reported promising results in a variety of cancer types. This pathway appears to play an important role in the failure of immune reactivity to malignant plasma cells in patients with multiple myeloma, since tumor cells express relatively high levels of PD-L1 and T cells show increased PD-1 expression. In the current study, we show that blocking PD-1/PD-L1 with a PD-L1-specific Ab causes murine myeloma rejection when combined with lymphocyte-depleting radiation. This particular combined approach alone has not been shown to be effective in other tumor models. The antitumor effect of anti-PD-L1/lymphocyte depletion therapy was strongest when T cells challenged with tumor Ag were present, either by cell transfer or survival after non-myeloablative radiation. In vivo depletion of CD4 or CD8 T cells completely abrogated the antitumor efficacy of anti-PD-L1/lymphocyte depletion therapy, suggesting that both T cell subsets are responsible for tumor rejection. Clearance of myeloma by T cells is relatively rapid, as tumor cells were almost undetectable in the bone marrow 5 days after the first anti-PD-L1 treatment, suggesting that anti-myeloma reactivity is mediated primarily by pre-T cells. activated and not mediated by newly formed myeloma. reactive T cells. Anti-PD-L1 plus lymphatic depletion failed to improve survival in two solid tumor models, but showed significant efficacy in two hematologic malignancy models. Taken together, our results support clinical trials of lymphatic depletion and PD-1/PD-L1 blockade as a new approach to improve survival in patients with multiple myeloma.

liveCD8+ T-Zell depletion
Pasche, N., et al. (2012). "Antibody-based delivery of interleukin-12 to tumor neovasculature eliminates mouse cancer models in combination with paclitaxel" Clin Cancer Res 18(15): 4092-4103.PubMed

OBJECTIVE: Interleukin-12 (IL12) is a potent pro-inflammatory cytokine with antitumor activity. Due to its heterodimeric nature, it is compatible with a variety of different immunocytokine formats. Here we report the design, production and characterization of a novel immunocytokine based on the fusion of the F8 antibody (specific for the alternatively spliced ​​EDA domain of fibronectin, a marker for tumor neovasculature) with IL12 (named IL12-F8-F8). EXPERIMENTAL DESIGN: We developed a novel immunocytokine based on the sequential fusion of interleukin-12 as a single polypeptide with two F8 ​​antibodies in the single-chain Fv (scFv) format. The fusion protein was characterizedin vitro, and its segmentation performance was evaluatedlive. The antitumor activity of immunocytokines was investigated in three different models of murine tumors, both in monotherapy and in combination therapies. Furthermore, depletion experiments and tumor analyzes have shown a dominant role for natural killer cells in the mechanism of action. RESULTS: IL12-F8-F8 can be produced in mammalian cells, resulting in a product of good pharmaceutical quality capable of selective localization in tumor, judging by quantitative biodistribution analysis using radioiodinated protein preparations. The protein potently inhibited tumor growth in three different models of immunocompetent syngeneic cancer. Treatment was generally well tolerated. Furthermore, the IL12-F8-F8 fusion protein can be produced with murine IL12 (mIL12) and human IL12 (hIL12). CONCLUSIONS: The potent antitumor activity of mIL12-F8-F8, studied alone or in combination with paclitaxel in different tumor models, paves the way for the clinical development of fully human immunocytokine.

(Video) Utilization of an In Vivo PBMC Humanized Mouse Model for Determining Bispecific Antibody Related...

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Quezada, S.A., et al. (2010). "Tumor-reactive CD4(+) T cells develop cytotoxic activity and clear established large melanomas after transmission to lymphopenic hosts" J Exp Med 207(3): 637-650.PubMed

Adoptive transfer of large numbers of CD8(+) cytotoxic T lymphocytes (CTL) reactive with expanded and differentiated tumorsin vitroshowed promising clinical activity against cancer. However, these protocols are complicated by extensive ex vivo manipulations of reactive tumor cells and focus largely on CD8(+) CTLs, with much less emphasis on the role and contribution of CD4(+) T cells. Using a mouse model of advanced melanoma, we found that the transfer of small numbers of virgin tumor-reactive CD4 (+) T cells to lymphopenic receptors induces substantial expansion, differentiation and regression of T cells from large established tumors, without this being necessaryin vitroHandling. Surprisingly, CD4(+) T cells developed cytotoxic activity and tumor rejection was dependent on impaired recognition of class II tumors by tumor-reactive CD4(+) T cells. Furthermore, blockade of CTL-associated co-inhibitory antigen 4 (CTLA-4) on transferred CD4(+) T cells resulted in increased expansion of effector T cells, decreased accumulation of tumor-reactive regulatory T cells, and increased activity capable of inducing the regression of spontaneous mouse melanoma. These results suggest a new potential therapeutic role for cytotoxic CD4(+) T cells and CTLA-4 blockade in cancer immunotherapy and demonstrate the potential benefits of differentiating tumor-reactive CD4(+) cells.liveabout the current protocols that favorin vitroextension and differentiation.


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