Broad Cross-Presentation of the Hematopoietically Derived PR1 Antigen on Solid Tumors Leads to Susceptibility to PR1-Targeted Immunotherapy

Alatrash, Gheath; Mittendorf, Elizabeth A.; Сергеева, Анна; Sukhumalchandra, Pariya; Qiao, Na; Zhang, Mao; John, Lisa S. St.; Ruisaard, Kathryn; Haugen, Christine E.; Al-Atrache, Zein; Jakher, Haroon; Philips, Anne V.; Ding, Xiaoling; Chen, Jie Qing; Wu, Yun; Patenia, Rebecca; Bernatchez, Chantale; Vence, Luis M.; Radvanyi, Laszlo G.; Hwu, Patrick; Clise-Dwyer, Karen; Ma, Qing; Lu, Shan; Molldrem, Jeffrey J.

doi:10.4049/jimmunol.1201221

Cited by 28 publications

(68 citation statements)

References 46 publications

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“…Several TCRm antibodies have been developed to various leukemia antigens and are in preclinical development. [13][14][15] WT1 encodes for a zinc finger transcription factor found in the embryonic development of multiple organ systems. [16][17][18] Importantly, multiple cancers have been identified with significantly increased expression of the WT1 product, including nearly all high-risk MDS, 19 CML, acute leukemias (AML, ALL) and their CD34…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of leukemia resistance to antibody dependent cellular cytotoxicity

et al. 2016

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Specific immunotherapy for acute leukemia remains a great unmet need. Native unmodified monoclonal antibody therapies, while promising, are inadequately effective for these malignancies, and multiple mechanisms for failure have been described. Antibody-dependent cellular cytotoxicity or phagocytosis is the primary modality of mAb-mediated cell killing in vivo, but ultimately leads to relapse of the leukemias, in model systems and in humans. By use of a T-cell receptor mimic mAb ESKM, derived against a WT1 peptide expressed in complex with HLA-A Ã 02:01, whose only mechanism of therapeutic action is ADCC, we evaluated the mechanisms of leukemic relapse from its potent therapeutic action in mouse xenograft models of human leukemia. Leukemia escape was not associated with loss of the antigenic target, downregulation of cell surface HLA, antibody pharmacokinetic or biodistribution issues, or development of leukemia cell-intrinsic resistance to ADCC. Interestingly, the rapidity of leukemic growth determined whether leukemia was able to evade cytotoxicity independent of the presence of sufficient effector cells. By engineering leukemia cells with upregulated p27Kip1 and slower cell cycling times, we show that relapse was inversely correlated with growth rates resulting in the eventual inadequacy of effector to target ratio. Moreover, lack of migration of effector cells into lymphomatous pockets of ALL also allowed local escape. Successful leukemia therapy with mAb might therefore be improved in similar situations by combination with measures to reduce burden and slow leukemia cell growth.

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Section: Introductionmentioning

confidence: 99%

Mechanisms of leukemia resistance to antibody dependent cellular cytotoxicity

et al. 2016

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“…Cell lines were validated in the institution’s sequencing and microarray facility using short tandem repeat DNA fingerprinting. The HLA-A2+ SKBR3 cell line (SKBR3-A2) was generated using lentiviral transduction, as previously described [8, 13]. Cell lines were cultured in Dulbecco’s Modified Eagle’s Medium (DMEM) with 10% fetal bovine serum (FBS), 100U/mL penicillin, and 100µg/mg streptomycin.…”

Section: Methodsmentioning

confidence: 99%

“…These dichotomous results have been attributed to a number of components of the tumor microenvironment, including tumor-associated neutrophils (TANs) and tumor-associated macrophages (TAMs) that have both pro- and anti-tumor effects on the tumor depending in part on other inflammatory mediators within the tumor milieu. TANs and TAMs within the tumor microenvironment produce azurophil granule serine proteases, including neutrophil elastase (NE), that have been implicated in modulating tumor behavior both favorably and unfavorably [5–8]. The exact mechanisms have not been elucidated.…”

Section: Introductionmentioning

confidence: 99%

“…Within the tumor microenvironment, NE is released from storage granules within TANs in response to interleukin 8 and tumor necrosis factor (TNF) alpha, which are increased at sites of inflammation [9, 10]. Although NE has been detected in tumor tissues, including breast cancer, where it was demonstrated to be a poor prognostic factor [6, 11], a number of more recent studies, including our own, have shown that TAN and soluble innate immune mediators derived from TAN, including NE, have beneficial anti-tumor immune effects [2, 7, 8]. We therefore sought to further study the mechanisms by which NE could contribute to favorable anti-tumor immunity.…”

Section: Introductionmentioning

confidence: 99%

“…In addition to endogenous expression by leukemia, our group has shown that non-hematopoietic cells can take up NE from the microenvironment and become susceptible to adaptive anti-tumor immune responses. Specifically, we showed that NE was cross-presented by breast cancer and melanoma cells and resulted in PR1 expression on the tumor cell surface, which enhanced the susceptibility of breast cancer and melanoma cells to lysis by PR1-targeting immunotherapies [8, 13]. We also demonstrated that NE uptake enhanced the CTL response targeting the peptide CCNE 144–152 , which is derived from the tumor antigen cyclin E (CCNE), a cell-cycle regulator with known prognostic value in breast cancer [7, 14, 15].…”

Section: Introductionmentioning

confidence: 99%

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Neutrophil elastase enhances antigen presentation by upregulating human leukocyte antigen class I expression on tumor cells

Chawla

Alatrash

Philips

et al. 2016

Cancer Immunol Immunother

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Neutrophil elastase (NE) is an innate immune cell-derived inflammatory mediator that we have shown increases the presentation of tumor-associated peptide antigens in breast cancer. In this study, we extend these observations to show that NE uptake has a broad effect on enhancing antigen presentation by breast cancer cells. We show that NE increases human leukocyte antigen (HLA) class I expression on the surface of breast cancer cells in a concentration and time-dependent manner. HLA class I upregulation requires internalization of enzymatically active NE. Western blots of NE-treated breast cancer cells confirm that the expression of total HLA class I as well as the antigen processing machinery proteins TAP1, LMP2, and calnexin do not change following NE treatment. This suggests that NE does not increase the efficiency of antigen processing; rather it mediates the upregulation of HLA class I by stabilizing and reducing membrane recycling of HLA class I molecules. Furthermore, the effects of NE extend beyond breast cancer since the uptake of NE by EBV-LCL increases the presentation of HLA class I-restricted viral peptides, as shown by their increased sensitivity to lysis by EBV-specific CD8+ T cells. Together, our results show that NE uptake increases the responsiveness of breast cancer cells to adaptive immunity by broad upregulation of membrane HLA class I, and support the conclusion that the innate inflammatory mediator NE enhances tumor cell recognition and increases tumor sensitivity to the host adaptive immune response.

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T Cell Receptor Mimic Antibodies

Alatrash

Molldrem

2018

Immunotherapy in Translational Cancer Research

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Broad Cross-Presentation of the Hematopoietically Derived PR1 Antigen on Solid Tumors Leads to Susceptibility to PR1-Targeted Immunotherapy

Cited by 28 publications

References 46 publications

Mechanisms of leukemia resistance to antibody dependent cellular cytotoxicity

Mechanisms of leukemia resistance to antibody dependent cellular cytotoxicity

Neutrophil elastase enhances antigen presentation by upregulating human leukocyte antigen class I expression on tumor cells

T Cell Receptor Mimic Antibodies

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