scholarly journals Tumor MHC Class I Expression Associates with Intralesional Interleukin-2 Response in Melanoma

2022 ◽  
pp. canimm.CIR-21-1083-E.2021
Author(s):  
Maryam Pourmaleki ◽  
Caitlin J Jones ◽  
Charlotte E Ariyan ◽  
Zheng Zeng ◽  
Mono Pirun ◽  
...  
Keyword(s):  
Mhc Class I ◽  
Interleukin 2 ◽  
Class I

Central Role of the Antigen-Presentation and Interferon-γ Pathways in Resistance to Immune Checkpoint Blockade

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Annette Paschen ◽  
Ignacio Melero ◽  
Antoni Ribas
Keyword(s):  
Antigen Presentation ◽  
Tumor Cells ◽  
Mhc Class I ◽  
Cancer Biology ◽  
Interleukin 2 ◽  
Interferon Γ ◽  
Class I ◽  
Annual Review ◽  
Publication Date ◽  
Type I

Resistance to immunotherapy is due in some instances to the acquired stealth mechanisms of tumor cells that lose expression of MHC class I antigen–presenting molecules or downregulate their class I antigen–presentation pathways. Most dramatically, biallelic β2-microglobulin (B2M) loss leads to complete loss of MHC class I expression and to invisibility to CD8+ T cells. MHC class I expression and antigen presentation are potently upregulated by interferon-γ (IFNγ) in a manner that depends on IFNγ receptor (IFNGR) signaling via JAK1 and JAK2. Mutations in these molecules lead to IFNγ unresponsiveness and mediate loss of recognition and killing by cytotoxic T lymphocytes. Loss of MHC class I augments sensitivity of tumor cells to be killed by natural killer (NK) lymphocytes, and this mechanism could be exploited to revert resistance, for instance, with interleukin-2 (IL-2)-based agents. Moreover, in some experimental models, potent local type I interferon responses, such as those following intratumoral injection of Toll-like receptor 9 (TLR9) or TLR3 agonists, revert resistance due to mutations of JAKs. Expected final online publication date for the Annual Review of Cancer Biology, Volume 6 is April 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Immunotherapy of a murine tumor with interleukin 2. Increased sensitivity after MHC class I gene transfection.

1987 ◽  
Vol 166 (6) ◽  
pp. 1716-1733 ◽  
Author(s):  
J S Weber ◽  
G Jay ◽  
K Tanaka ◽  
S A Rosenberg
Keyword(s):  
T Cells ◽  
Mhc Class I ◽  
Interleukin 2 ◽  
Class I ◽  
High Dose ◽  
Class I Mhc ◽  
High Doses ◽  
I Gene

We have shown that two weakly immunogenic MCA sarcomas developed in our laboratory that are sensitive to high-dose IL-2 immunotherapy express class I MHC in vivo and in vitro. Two nonimmunogenic MCA sarcomas are relatively insensitive to IL-2 therapy and express minimal or no class I MHC molecules in vivo and in vitro. To study the role of MHC in the therapy of tumors with IL-2, a class I-deficient murine melanoma, B16BL6, was transfected with the Kb class I gene. Expression of class I MHC rendered B16BL6 advanced pulmonary macrometastases sensitive to IL-2 immunotherapy. 3-d micrometastases of CL8-2, a class I transfected clone of B16BL6, were significantly more sensitive to IL-2 therapy than a control nontransfected line. Expression of Iak, a class II MHC molecule, had no effect on IL-2 therapy of transfectant pulmonary micrometastases in F1 mice. By using lymphocyte subset depletion with mAbs directed against Lyt-2, therapy of class I transfectant macrometastases with high-dose IL-2 was shown to involve an Lyt-2 cell. In contrast, regression of micrometastases treated with low-dose IL-2 involved Lyt-2+ cells, but regression mediated by high doses of IL-2 did not. We hypothesize that both LAK and Lyt-2+ T cells effect IL-2-mediated elimination of micrometastases, but only Lyt-2+ T cells are involved in macrometastatic regression. Low doses of IL-2 stimulate Lyt-2+ cells to eliminate class I-expressing micrometastases, but high doses of IL-2 can recruit LAK cells to mediate regression of micrometastases independent of class I expression. Only high-dose IL-2, mediating its effect predominantly via Lyt-2+ cells, is capable of impacting on MHC class I-expressing macrometastases. Macrometastases devoid of class I MHC antigens appear to be resistant to IL-2 therapy.

scholarly journals Antigen-specific recognition of autologous leukemia cells and allogeneic class-I MHC antigens by IL-2-activated cytotoxic T cells from a patient with acute T-cell leukemia

Blood ◽  
1989 ◽  
Vol 74 (1) ◽  
pp. 343-353 ◽  
Author(s):  
P Fisch ◽  
G Weil-Hillman ◽  
M Uppenkamp ◽  
JA Hank ◽  
BP Chen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class I ◽  
Lymphoblastic Leukemia ◽  
Interleukin 2 ◽  
Class I ◽  
Target Cells ◽  
Class I Mhc ◽  
Blood Lymphocytes ◽  
Mhc Class I Antigens

Abstract Culturing of leukemic blood lymphocytes from a patient with acute T- cell lymphoblastic leukemia (T-ALL) with interleukin-2 (IL-2) yielded T- cell line AK-1 with a remarkable cytotoxic specificity. This line mediated strong lysis of tumor target lines expressing major histocompatibility complex (MHC) class I antigens, such as Raji, CEM, and Molt-4 cells, but no killing of K562 and Daudi cells, which are deficient in MHC class I. In contrast, lymphokine-activated killer (LAK) cells from normal donors destroyed all these tumor targets, without MHC restriction. Line AK-1, originating from residual normal T cells present in the leukemic blood, lysed autologous leukemic blasts and peripheral blood lymphocytes (PBL) from many but not all allogeneic individuals but failed to kill autologous remission lymphocytes. Destruction of the autologous leukemic targets by AK-1 could be inhibited by unlabeled competitor target cells that were lysed by AK-1, but not by target cells that were not lysed. This suggests that AK-1 specifically recognized an alien determinant on the autologous ALL cells, crossreactive with allogeneic MHC class I antigens. This reactivity with some degree of tumor specificity may be a leukemic equivalent to responses reported for populations of tumor infiltrating lymphocytes (TIL) seen in some solid tumors.

Role of CD28 in Acute Graft-Versus-Host Disease

Blood ◽  
1998 ◽  
Vol 92 (8) ◽  
pp. 2963-2970 ◽  
Author(s):  
Xue-Zhong Yu ◽  
Paul J. Martin ◽  
Claudio Anasetti
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Mhc Class I ◽  
Graft Versus Host Disease ◽  
Interleukin 2 ◽  
Class I ◽  
Host Disease ◽  
Cd8 Cells ◽  
Graft Versus Host

Because CD28-mediated T-cell costimulation has a pivotal role in the initiation and maintenance of T-cell responses, we tested the hypothesis that CD28 is critical for the development of graft-versus-host disease (GVHD). We compared the in vivo effects of CD28−/− T cells transplanted from B6 donor with the CD28 gene deleted by homologous recombination with those of CD28+/+ T cells transplanted from wild-type C57BL/6 (B6) donor. Fifty million CD28−/− or CD28+/+ splenocytes from B6 mice were transplanted into unirradiated (B6 × DBA/2)F1 (BDF1) recipients. Unlike CD28+/+, CD28−/− T cells from B6 mice had lower levels of proliferation and interleukin-2 production, had a limited ability to generate cytotoxic T lymphocytes against the recipient, and did not induce immune deficiency, despite survival in the recipient for at least 28 days. The ability to prevent rejection was reduced by the absence of CD28, because as many as 1.0 × 107 CD28−/− CD8+ cells were needed to prevent rejection of major histocompatibility complex (MHC) class-I incompatible marrow in sublethally irradiated (550 cGy) bm1 recipients, whereas 8.0 × 105 CD28+/+CD8+ T cells were sufficient to produce a similar effect, indicating that CD28 on donor CD8+ cells helps to eliminate host immunity. Two million CD4+CD28−/− or CD28+/+ T cells were transplanted into sublethally irradiated (750 cGy), MHC class-II incompatible (B6 × bm12)F1 recipients. With CD28−/−cells, 44% of the recipients died at a median of 20 days compared with 94% at a median of 15 days with CD28+/+ cells (P < .001). Two million CD8+CD28−/− or CD28+/+ T cells were transplanted into sublethally irradiated (750 cGy), MHC class-I incompatible (B6 × bm1) F1 recipients. With CD28−/−cells, 25% of the recipients died at a median of 41 days compared with 100% at a median of 15 days with CD28+/+ cells (P < .001). (B6 × bm12)F1 and (B6 × bm1)F1 mice surviving after transplantation of CD28−/− cells recovered thymocytes, T cells, and B cells in numbers and function comparable with that of irradiation-control F1 mice. We conclude that CD28 contributes to the pathogenesis and the severity of GVHD. Our results suggest that the severity of GVHD could be decreased by the administration of agents that block CD28 function in T lymphocytes. © 1998 by The American Society of Hematology.

scholarly journals Dimerization of soluble major histocompatibility complex-peptide complexes is sufficient for activation of T cell hybridoma and induction of unresponsiveness.

1995 ◽  
Vol 182 (2) ◽  
pp. 439-447 ◽  
Author(s):  
J P Abastado ◽  
Y C Lone ◽  
A Casrouge ◽  
G Boulot ◽  
P Kourilsky
Keyword(s):  
Major Histocompatibility Complex ◽  
T Cell ◽  
Mhc Class I ◽  
Interleukin 2 ◽  
Surface Proteins ◽  
Class I ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Peptide Complexes ◽  
Mhc Class I Molecules

Major histocompatibility complex (MHC) class I molecules are cell-surface proteins that present peptides to CD8+ T cells. These peptides are mostly derived from endogenously synthesized protein. Recombinant, soluble MHC class I molecules were produced, purified, and loaded homogeneously with synthetic peptide. These MHC-peptide complexes were used to activate a T cell hybridoma. While monomers of MHC-peptide bound to the T cell, they showed no stimulatory activity. Dimers fully triggered the T cell hybridoma to secrete interleukin 2. This response was followed by a state in which the T cell was refractory to restimulation as a result of defective signal transduction through the T cell receptor.

Role of CD28 in Acute Graft-Versus-Host Disease

Blood ◽  
1998 ◽  
Vol 92 (8) ◽  
pp. 2963-2970 ◽  
Author(s):  
Xue-Zhong Yu ◽  
Paul J. Martin ◽  
Claudio Anasetti
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Mhc Class I ◽  
Graft Versus Host Disease ◽  
Interleukin 2 ◽  
Class I ◽  
Host Disease ◽  
Cd8 Cells ◽  
Graft Versus Host

Abstract Because CD28-mediated T-cell costimulation has a pivotal role in the initiation and maintenance of T-cell responses, we tested the hypothesis that CD28 is critical for the development of graft-versus-host disease (GVHD). We compared the in vivo effects of CD28−/− T cells transplanted from B6 donor with the CD28 gene deleted by homologous recombination with those of CD28+/+ T cells transplanted from wild-type C57BL/6 (B6) donor. Fifty million CD28−/− or CD28+/+ splenocytes from B6 mice were transplanted into unirradiated (B6 × DBA/2)F1 (BDF1) recipients. Unlike CD28+/+, CD28−/− T cells from B6 mice had lower levels of proliferation and interleukin-2 production, had a limited ability to generate cytotoxic T lymphocytes against the recipient, and did not induce immune deficiency, despite survival in the recipient for at least 28 days. The ability to prevent rejection was reduced by the absence of CD28, because as many as 1.0 × 107 CD28−/− CD8+ cells were needed to prevent rejection of major histocompatibility complex (MHC) class-I incompatible marrow in sublethally irradiated (550 cGy) bm1 recipients, whereas 8.0 × 105 CD28+/+CD8+ T cells were sufficient to produce a similar effect, indicating that CD28 on donor CD8+ cells helps to eliminate host immunity. Two million CD4+CD28−/− or CD28+/+ T cells were transplanted into sublethally irradiated (750 cGy), MHC class-II incompatible (B6 × bm12)F1 recipients. With CD28−/−cells, 44% of the recipients died at a median of 20 days compared with 94% at a median of 15 days with CD28+/+ cells (P &lt; .001). Two million CD8+CD28−/− or CD28+/+ T cells were transplanted into sublethally irradiated (750 cGy), MHC class-I incompatible (B6 × bm1) F1 recipients. With CD28−/−cells, 25% of the recipients died at a median of 41 days compared with 100% at a median of 15 days with CD28+/+ cells (P &lt; .001). (B6 × bm12)F1 and (B6 × bm1)F1 mice surviving after transplantation of CD28−/− cells recovered thymocytes, T cells, and B cells in numbers and function comparable with that of irradiation-control F1 mice. We conclude that CD28 contributes to the pathogenesis and the severity of GVHD. Our results suggest that the severity of GVHD could be decreased by the administration of agents that block CD28 function in T lymphocytes. © 1998 by The American Society of Hematology.

scholarly journals Antigen-specific recognition of autologous leukemia cells and allogeneic class-I MHC antigens by IL-2-activated cytotoxic T cells from a patient with acute T-cell leukemia

Blood ◽  
1989 ◽  
Vol 74 (1) ◽  
pp. 343-353
Author(s):  
P Fisch ◽  
G Weil-Hillman ◽  
M Uppenkamp ◽  
JA Hank ◽  
BP Chen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class I ◽  
Lymphoblastic Leukemia ◽  
Interleukin 2 ◽  
Class I ◽  
Target Cells ◽  
Class I Mhc ◽  
Blood Lymphocytes ◽  
Mhc Class I Antigens

Culturing of leukemic blood lymphocytes from a patient with acute T- cell lymphoblastic leukemia (T-ALL) with interleukin-2 (IL-2) yielded T- cell line AK-1 with a remarkable cytotoxic specificity. This line mediated strong lysis of tumor target lines expressing major histocompatibility complex (MHC) class I antigens, such as Raji, CEM, and Molt-4 cells, but no killing of K562 and Daudi cells, which are deficient in MHC class I. In contrast, lymphokine-activated killer (LAK) cells from normal donors destroyed all these tumor targets, without MHC restriction. Line AK-1, originating from residual normal T cells present in the leukemic blood, lysed autologous leukemic blasts and peripheral blood lymphocytes (PBL) from many but not all allogeneic individuals but failed to kill autologous remission lymphocytes. Destruction of the autologous leukemic targets by AK-1 could be inhibited by unlabeled competitor target cells that were lysed by AK-1, but not by target cells that were not lysed. This suggests that AK-1 specifically recognized an alien determinant on the autologous ALL cells, crossreactive with allogeneic MHC class I antigens. This reactivity with some degree of tumor specificity may be a leukemic equivalent to responses reported for populations of tumor infiltrating lymphocytes (TIL) seen in some solid tumors.

Single-cell analysis of the human NK cell response to missing self and its inhibition by HLA class I

Blood ◽  
2005 ◽  
Vol 105 (5) ◽  
pp. 2028-2035 ◽  
Author(s):  
Monia Draghi ◽  
Nobuyo Yawata ◽  
Michael Gleimer ◽  
Makoto Yawata ◽  
Nicholas M. Valiante ◽  
...  
Keyword(s):  
Nk Cells ◽  
Single Cell ◽  
Mhc Class I ◽  
Cell Response ◽  
Nk Cell ◽  
Intracellular Cytokine Staining ◽  
Interleukin 2 ◽  
Hla Class I ◽  
Inhibitory Response ◽  
Class I

AbstractNatural killer (NK) cells activate quickly in response to pathogens, tumors, and allogeneic hematopoietic cell transplants. Modulating the NK cell response are clonally distributed NK cell receptors that survey cells for change in the expression of major histocompatibility complex (MHC) class I and structurally related ligands. Here the enzyme-linked immunospot (ELISPOT) assay, intracellular cytokine staining (ICS), and short-term culture were used to quantify the response of bulk NK cell populations from human donors to HLA class I–deficient 221 cells and to 221 cells transfected with single HLA class I allotypes. NK cells in cultures containing interleukin-2 (IL-2) or IL-12 exhibited specificities of HLA class I–mediated inhibition that correlated well with those previously defined using NK cell clones in long-term culture and with the frequencies of cells expressing particular inhibitory HLA class I receptors. Culture with IL-12, but not IL-2, gave an increased frequency of cells expressing CD94: NKG2A but no change in killer immunoglobulin-like receptor (KIR) expression. For some heterozygote combinations of KIR3DL1 alleles, ICS can be used to compare the functional properties of the 2 allotypes. Thus, both the low-expressing KIR3DL1*005 and the high-expressing KIR3DL1*002 gave similar inhibitory response on challenge with an HLA-B*5801 ligand. The single-cell assays developed here should facilitate future population study and clinical analysis of human NK cell regulation by MHC class I.

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