Adoptive immunotherapy of established tumors. Acquisition of radioresistance by tumor-specific T cells after passive transfer into tumor-bearing recipients

1994 ◽  
Vol 57 (4) ◽  
pp. 592-597 ◽  
Author(s):  
Pamela L. Dunn ◽  
Robert J. North
Keyword(s):  
T Cells ◽  
Adoptive Immunotherapy ◽  
Passive Transfer ◽  
Tumor Bearing

scholarly journals Expression of passively transferred immunity against an established tumor depends on generation of cytolytic T cells in recipient. Inhibition by suppressor T cells.

1983 ◽  
Vol 157 (5) ◽  
pp. 1448-1460 ◽  
Author(s):  
C D Mills ◽  
R J North
Keyword(s):  
T Cells ◽  
Lymph Node ◽  
T Cell ◽  
Cell Response ◽  
Passive Transfer ◽  
T Cell Response ◽  
Suppressor T Cells ◽  
Tumor Bearing ◽  
Draining Lymph Node ◽  
Adoptive Immunity

The results of this study with the P815 mastocytoma confirm the results of previous studies that showed that the passive transfer of tumor-sensitized T cells from immunized donors can cause the regression of tumors growing in T cell-deficient (TXB) recipients, but not in normal recipients. The key additional finding was that the expression of adoptive immunity against tumors growing in TXB recipients is immediately preceded by a substantial production of cytolytic T cells in the recipients' draining lymph node. On the other hand, failure of adoptive immunity to be expressed against tumors growing in normal recipients was associated with a cytolytic T cell response of much lower magnitude, and a similar low magnitude response was generated in TXB recipients infused with normal spleen cells and in tumor-bearing control mice. Because the passively transferred sensitized T cells possessed no cytolytic activity of their own, the results indicate that the 6-8-d delay before adoptive immunity is expressed represents the time needed for passively transferred helper or memory T cells to give rise to a cytolytic T cell response of sufficient magnitude to destroy the recipient's tumor. In support of this interpretation was the additional finding that inhibition of the expression of adoptive immunity by the passive transfer of suppressor T cells from tumor-bearing donors was associated with a substantially reduced cytolytic T cell response in the recipient's draining lymph node. The results serve to illustrate that interpretation of the results of adoptive immunization experiments requires a knowledge of the events that take place in the adoptively immunized recipient. They support the interpretation that suppressor T cells function in this model to "down-regulate" the production of cytolytic effector T cells.

scholarly journals T cell-mediated immunosuppression as an obstacle to adoptive immunotherapy of the P815 mastocytoma and its metastases.

1981 ◽  
Vol 154 (4) ◽  
pp. 1033-1042 ◽  
Author(s):  
E S Dye ◽  
R J North
Keyword(s):  
T Cells ◽  
T Cell ◽  
Adoptive Immunotherapy ◽  
Immune Cells ◽  
Suppressor Cells ◽  
Tumor Bearing ◽  
Chemically Induced ◽  
Progressive Growth ◽  
P815 Mastocytoma

Progressive growth of the P815 mastocytoma in semisyngeneic mice evokes the generation of a T cell-mediated mechanism of immunosuppression that inhibits the capacity of passively transferred, tumor-sensitized T cells from regressing this tumor in recipient mice. This conclusion is based on two findings: (a) that it is possible to demonstrate adoptive T cell-mediated regression of established tumors, but only if the tumors are growing in T cell-deficient recipients, and (b) that adoptive T cell-mediated regression of tumors in these recipients can be inhibited by the infusion of splenic T cells from T cell-intact, tumor-bearing donors. The results of additional experiments designed to measure the effect of decreasing the number of suppressor cells and the time that they are infused, relative immune cells, indicate that the function of suppressor cells in this model is to inhibit the replication of passively transferred immune T cells. The results obtained with the P815 mastocytoma are similar to those obtained previously with a chemically induced fibrosarcoma. They show, in addition, that passively transferred immune cells are capable of destroying already seeded metastases in T cell-deficient recipients.

scholarly journals 678 Addition of a single bacteria facilitates anti-tumor immunity and long-term survival in colorectal cancer

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A717-A717
Author(s):  
Abigail Overacre-Delgoffe ◽  
Anthony Cillo ◽  
Hannah Bumgarner ◽  
Ansen Burr ◽  
Justin Tometich ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
Tumor Immunity ◽  
Tumor Burden ◽  
Intestinal Microbiome ◽  
Tumor Control ◽  
Mesenteric Lymph Nodes ◽  
Term Survival ◽  
16S Sequencing ◽  
Tumor Bearing

BackgroundColorectal cancer remains one of the most common and deadliest cancers worldwide and effective therapies are lacking. While immunotherapy has revolutionized treatment for many cancers, the overwhelming majority of colorectal cancer patients are non-responsive and the 5-year survival rate for advanced disease is <20%. Immunotherapeutic response has been associated with select members of the microbiome in melanoma; however, the potential benefit in colorectal cancer and the underlying mechanisms remain unclear. We sought to determine how specific members of the intestinal microbiome affect anti-tumor immunity in colorectal cancer (CRC) in hopes of discovering novel treatments and revealing potential hurdles to current therapeutic response in CRC patients.MethodsWe utilized a carcinogen-induced mouse model of CRC and colonized half of the tumor-bearing mice with Helicobacter hepaticus (Hhep) 7 weeks post AOM. Tumor number was assessed 12 weeks post AOM. We isolated lymphocytes from the lamina propria, colonic epithelium, mesenteric lymph nodes, and tumor(s) to track the spatial and transcriptional Hhep-specific and endogenous immune responses during tumor progression through 5’ single cell RNAseq, flow cytometry, and immunofluorescence. In addition, we utilized 16S sequencing and FISH to track Hhep colonization, location within the colon, and its impact on the surrounding microbiome.ResultsWe have found that rational modification of the microbiome of colon tumor-bearing mice through addition of a single bacteria, Hhep, led to tumor control or clearance and a significant survival advantage. Colonization led to the expansion of the lymphatic network and development of numerous peri- or intra-tumoral tertiary lymphoid structures (TLS) composed of Hhep-specific CD4 T follicular helper cells (TFH) as well as the bacteria itself. This led to an overall ‘heating’ of the tumor, wherein we saw an increase of CD4 T cell infiltration to the tumor core as well as an increase in CD103+ type 1 DC (cDC1) recruitment through increased chemokines such as CCL5 and XCL1. Hhep-specific TFH were both necessary and sufficient to drive TLS formation, increased immune invasion, and anti-tumor immunity.ConclusionsWe have shown that addition of a single bacteria, Hhep, leads to a reduction in CRC tumor burden or clearance through lymphatic expansion, TLS formation, and remodeling of the tumor microenvironment, and that Hhep-specific T cells are required for tumor control. These studies suggest that rational modification of the microbiome and microbiome-specific T cells can positively impact anti-tumor immunity and may represent a unique immunotherapeutic target to turn resistant tumors into responsive tumors.

scholarly journals 49 In situ phenotypic analysis of T cells in the tumor microenvironment of a pre-clinical model of non-small cell lung cancer (NSCLC) by tissue sectioning and whole-mount immunofluorescence imaging

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A52-A52
Author(s):  
Elen Torres ◽  
Stefani Spranger
Keyword(s):  
T Cells ◽  
Spatial Distribution ◽  
T Cell ◽  
Spatial Location ◽  
Cell Infiltration ◽  
Cell Populations ◽  
Tumor Bearing ◽  
T Cell Infiltration ◽  
Volume Imaging ◽  
Whole Mount

BackgroundUnderstanding the interactions between tumor and immune cells is critical for improving current immunotherapies. Pre-clinical and clinical evidence has shown that failed T cell infiltration into lung cancer lesions might be associated with low responsiveness towards checkpoint blockade.1 For this reason, it is necessary to characterize not only the phenotype of T cells in tumor-bearing lungs but also their spatial location in the tumor microenvironment (TME). Multiplex immunofluorescence staining allows the simultaneous use of several cell markers to study the state and the spatial location of cell populations in the tissue of interest. Although this technique is usually applied to thin tissue sections (5 to 12 µm), the analysis of large tissue volumes may provide a better understanding of the spatial distribution of cells in relation to the TME. Here, we analyzed the number and spatial distribution of cytotoxic T cells and other immune cells in the TME of tumor-bearing lungs, using both 12 µm sections and whole-mount preparations imaged by confocal microscopy.MethodsLung tumors were induced in C57BL/6 mice by tail vein injection of a cancer cell line derived from KrasG12D/+ and Tp53-/- mice. Lung tissue with a diverse degree of T cell infiltration was collected after 21 days post tumor induction. Tissue was fixed in 4% PFA, followed by snap-frozen for sectioning. Whole-mount preparations were processed according to Weizhe Li et al. (2019) 2 for tissue clearing and multiplex volume imaging. T cells were labeled with CD8 and FOXP3 antibodies to identify cytotoxic or regulatory T cells, respectively. Tumor cells were labeled with a pan-Keratin antibody. Images were acquired using a Leica SP8 confocal microscope. FIJI3 and IMARIS were used for image processing.ResultsWe identified both cytotoxic and regulatory T cell populations in the TME using thin sections and whole-mount. However, using whole-mount after tissue clearing allowed us to better evaluate the spatial distribution of the T cell populations in relation to the tumor structure. Furthermore, tissue clearance facilitates the imaging of larger volumes using multiplex immunofluorescence.ConclusionsAnalysis of large lung tissue volumes provides a better understanding of the location of immune cell populations in relation to the TME and allows to study heterogeneous immune infiltration on a per-lesion base. This valuable information will improve the characterization of the TME and the definition of cancer-immune phenotypes in NSCLC.ReferencesTeng MW, et al., Classifying cancers based on T-cell infiltration and PD-L1. Cancer Res 2015;75(11): p. 2139–45.Li W, Germain RN, and Gerner MY. High-dimensional cell-level analysis of tissues with Ce3D multiplex volume imaging. Nat Protoc 2019;14(6): p. 1708–1733.Schindelin J, et al, Fiji: an open-source platform for biological-image analysis. Nat Methods 2012;9(7): p. 676–82.

scholarly journals Adoptive Immunotherapy beyond CAR T-Cells

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 743
Author(s):  
Aleksei Titov ◽  
Ekaterina Zmievskaya ◽  
Irina Ganeeva ◽  
Aygul Valiullina ◽  
Alexey Petukhov ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Solid Tumors ◽  
Adoptive Immunotherapy ◽  
Γδ T Cells ◽  
Car T Cells ◽  
Car T Cell ◽  
Cell Immunotherapy ◽  
Car T

Adoptive cell immunotherapy (ACT) is a vibrant field of cancer treatment that began progressive development in the 1980s. One of the most prominent and promising examples is chimeric antigen receptor (CAR) T-cell immunotherapy for the treatment of B-cell hematologic malignancies. Despite success in the treatment of B-cell lymphomas and leukemia, CAR T-cell therapy remains mostly ineffective for solid tumors. This is due to several reasons, such as the heterogeneity of the cellular composition in solid tumors, the need for directed migration and penetration of CAR T-cells against the pressure gradient in the tumor stroma, and the immunosuppressive microenvironment. To substantially improve the clinical efficacy of ACT against solid tumors, researchers might need to look closer into recent developments in the other branches of adoptive immunotherapy, both traditional and innovative. In this review, we describe the variety of adoptive cell therapies beyond CAR T-cell technology, i.e., exploitation of alternative cell sources with a high therapeutic potential against solid tumors (e.g., CAR M-cells) or aiming to be universal allogeneic (e.g., CAR NK-cells, γδ T-cells), tumor-infiltrating lymphocytes (TILs), and transgenic T-cell receptor (TCR) T-cell immunotherapies. In addition, we discuss the strategies for selection and validation of neoantigens to achieve efficiency and safety. We provide an overview of non-conventional TCRs and CARs, and address the problem of mispairing between the cognate and transgenic TCRs. Finally, we summarize existing and emerging approaches for manufacturing of the therapeutic cell products in traditional, semi-automated and fully automated Point-of-Care (PoC) systems.

scholarly journals Genetic engineering of T cells for adoptive immunotherapy

2008 ◽  
Vol 42 (1-3) ◽  
pp. 166-181 ◽  
Author(s):  
Angel Varela-Rohena ◽  
Carmine Carpenito ◽  
Elena E. Perez ◽  
Max Richardson ◽  
Richard V. Parry ◽  
...  
Keyword(s):  
T Cells ◽  
Genetic Engineering ◽  
Adoptive Immunotherapy

scholarly journals Protection against Streptococcus pneumoniae Invasive Pathogenesis by a Protein-Based Vaccine Is Achieved by Suppression of Nasopharyngeal Bacterial Density during Influenza A Virus Coinfection

2016 ◽  
Vol 85 (2) ◽  
Author(s):  
M. Nadeem Khan ◽  
Qingfu Xu ◽  
Michael E. Pichichero
Keyword(s):  
T Cells ◽  
Streptococcus Pneumoniae ◽  
Influenza A Virus ◽  
Influenza A ◽  
Passive Transfer ◽  
Bacterial Density ◽  
Content Type ◽  
Adult Mice ◽  
Significant Difference ◽  
Colonization Density

ABSTRACTAn increase inStreptococcus pneumoniaenasopharynx (NP) colonization density during a viral coinfection initiates pathogenesis. To mimic naturalS. pneumoniaepathogenesis, we commensally colonized the NPs of adult C57BL/6 mice withS. pneumoniaeserotype (ST) 6A or 8 and then coinfected them with mouse-adapted H1N1 influenza A virus (PR/8/34).S. pneumoniaeestablished effective commensal colonization, and influenza virus coinfection causedS. pneumoniaeNP density to increase, resulting in bacteremia and mortality. We then studied histidine triad protein D (PhtD), anS. pneumoniaeadhesin vaccine candidate, for its ability to prevent invasiveS. pneumoniaedisease in adult and infant mice. In adult mice, the efficacy of PhtD vaccination was compared with that of PCV13. Vaccination with PCV13 led to a greater reduction ofS. pneumoniaeNP density (>2.5 log units) than PhtD vaccination (∼1-log-unit reduction). However, no significant difference was observed with regard to the prevention ofS. pneumoniaebacteremia, and there was no difference in mortality. Depletion of CD4+T cells in PhtD-vaccinated adult mice, but not PCV13-vaccinated mice, caused a loss of vaccine-induced protection. In infant mice, passive transfer of antisera or CD4+T cells from PhtD-vaccinated adult mice led to a nonsignificant reduction in NP colonization density, whereas passive transfer of antisera and CD4+T cells was needed to cause a significant reduction in NP colonization density. For the first time, these data show an outcome with regard to prevention of invasiveS. pneumoniaepathogenesis with a protein vaccine similar to that which occurs with a glycoconjugate vaccine despite a less robust reduction in NP bacterial density.

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