MERTK inhibition alters the PD-1 axis and promotes anti-leukemia immunity

Lee-Sherick, Alisa B.; Jacobsen, Kristen M.; Henry, Curtis J.; Huey, Madeline G.; Parker, Rebecca E.; Page, Lauren S.; Hill, Amanda A.; Wang, Xiaodong; Frye, Stephen V.; Earp, H. Shelton; Jordan, Craig T.; DeRyckere, Deborah; Graham, Douglas K.

doi:10.1172/jci.insight.97941

Cited by 61 publications

(51 citation statements)

References 42 publications

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“…23 Similarly, in patients with pancreatic ductal adenocarcinoma receiving ipilimumab, a diverse baseline TCR repertoire was associated with longer median OS. 36 a b In our analysis of PBMC samples obtained early ontreatment (4 weeks), there was a significant association between a decrease in T cell clonality and OS and PFS. In our study, decrease in T cell clonality early on-treatment (4 weeks) and the improvement in OS and PFS can be a restoration of interferon-mediated effect on tumor-killing after using CTLA-4 blockers, increasing T cell activation and broadening the peripheral T cell repertoire compared with baseline.…”

Section: Discussionmentioning

confidence: 66%

“…In a previous study by Hopkins et al long-term survivors of pancreatic cancer treated with ipilimumab had significantly more expanded clones in comparison to short-term survivors (p < .05). 36 Further, as individual T cell clones present in tumors can also be tracked in the peripheral blood during treatment, we restricted our clonal analysis to measure only expanded clones that are also found in the tumor repertoire. Interestingly, we observed that responders had significantly more TIL expanded in the periphery at 4 weeks than non-responders, consistent with clonal expansion of tumor antigen-specific T cells.…”

Section: Discussionmentioning

confidence: 99%

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The impact of CTLA-4 blockade and interferon-α on clonality of T-cell repertoire in the tumor microenvironment and peripheral blood of metastatic melanoma patients

et al. 2019

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Patients with metastatic melanoma were treated with tremelimumab and interferon-α (IFN) in a previously reported clinical trial [NCT00610857]. Responses were assessed by RECIST criteria as complete (CR) or partial (PR), stable disease (SD) or progressive disease (PD). In this study, T-cell receptor (TCR) beta-chain repertoire was immunosequenced in peripheral blood mononuclear cells (PBMC) specimens (N = 33) and tumor samples (N = 18) utilizing the immunoSEQ® Assay to determine repertoire clonality and T cell fractions at pre-treatment (tumor and PBMC), one month (PBMC) and 3 months (PBMC) time points and evaluate its association with clinical outcomes. In the pretreatment tumor microenvironment (TME), T cell clonality was significantly (p = .035) different and greater in patients who achieved disease control (CR, PR, SD) versus those with non-disease control (PD) as best response to treatment. Further, there was significantly (p = .001) increased TCR fraction in tissue of responders (CR, PR) versus non-responders (PD, SD). In examining T cell clonality in the circulation (PBMC), no significant associations were found in the pretreatment samples. However, early on-treatment (4 weeks) there was a significant decrease in T cell clonality that was associated with improved overall survival (p = .01) and progression-free survival (p = .04). In addition, analysis of temporal changes in tumor-infiltrating lymphocytes (TIL) and peripheral TCR repertoire revealed that responders had significantly higher clonal expansion of TIL in the circulation at 4 weeks than non-responders (p = .036). Our study provided interesting mechanistic data related to CTLA-4 Blockade and IFN and potential biomarkers of immunotherapeutic benefit.

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Section: Discussionmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 99%

The impact of CTLA-4 blockade and interferon-α on clonality of T-cell repertoire in the tumor microenvironment and peripheral blood of metastatic melanoma patients

et al. 2019

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“…10 Harnessing the specific transcytosis activity of IgA could potentially allow access to therapeutic targets within the luminal side of mucosal tissues that are inefficiently targeted by current IgG therapeutics. 2,10,11 Contrary to other human immunoglobulin classes, IgA has the unique ability to naturally exist as both monomeric and polymeric soluble species, whereas only polymeric IgA can bind to pIgR for subsequent transcytosis. 1 Oligomerization of IgA is facilitated by an 18-residue C-terminal extension of the heavy chain (HC) called the tailpiece and the 137-amino acid joining chain (JC).…”

Section: Introductionmentioning

confidence: 99%

Production, characterization, andin vivohalf-life extension of polymeric IgA molecules in mice

Lombana¹,

Rajan²,

Zorn³

et al. 2019

mAbs

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IgA antibodies have broad potential as a novel therapeutic platform based on their superior receptor-mediated cytotoxic activity, potent neutralization of pathogens, and ability to transcytose across mucosal barriers via polymeric immunoglobulin receptor (pIgR)-mediated transport, compared to traditional IgG-based drugs. However, the transition of IgA into clinical development has been challenged by complex expression and characterization, as well as rapid serum clearance that is thought to be mediated by glycan receptor scavenging of recombinantly produced IgA monomer bearing incompletely sialylated N-linked glycans. Here, we present a comprehensive biochemical, biophysical, and structural characterization of recombinantly produced monomeric, dimeric and polymeric human IgA. We further explore two strategies to overcome the rapid serum clearance of polymeric IgA: removal of all N-linked glycosylation sites creating an aglycosylated polymeric IgA and engineering in FcRn binding with the generation of a polymeric IgG-IgA Fc fusion. While previous reports and the results presented in this study indicate that glycan-mediated clearance plays a major role for monomeric IgA, systemic clearance of polymeric IgA in mice is predominantly controlled by mechanisms other than glycan receptor clearance, such as pIgR-mediated transcytosis. The developed IgA platform now provides the potential to specifically target pIgR expressing tissues, while maintaining low systemic exposure.

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“…Since T cells have been believed not to express MERTK, previous results might need to be re-interpreted. To this end, it was previously shown that treatment of wildtype immunocompetent mice with MERTK-inhibitors decreased PD-1 expression on T cells [45]. PD-1 is solely expressed by previously activated T cells, is dependent on TCR signal strength and avidity, and is an identifying marker for tumor-reactive T cells [46].…”

Section: Tam Receptor Function In T Cellsmentioning

confidence: 99%

TAM-ing T cells in the tumor microenvironment: implications for TAM receptor targeting

Peeters

Rahbech

Straten

2019

Cancer Immunol Immunother

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The TAM receptors—TYRO3, AXL, MERTK—are pleiotropically expressed receptors in both healthy and diseased tissue. A complex of the ligands Protein S (PROS1) or Growth Arrest-Specific 6 (GAS6) with apoptotic phosphatidylserine activates the TAM receptors. Hence, this receptor family is essential for the efferocytosis of apoptotic material by antigen-presenting cells. In addition, TAM receptors are expressed by virtually all cells of the tumor microenvironment. They are also potent oncogenes, frequently overexpressed in cancer and involved in survival and therapy resistance. Due to their pro-oncogenic and immune-inhibitory traits, TAM receptors have emerged as promising targets for cancer therapy. Recently, TAM receptors have been described to function as costimulatory molecules on human T cells. TAM receptors’ ambivalent functions on many different cell types therefore make therapeutic targeting not straight-forward. In this review we summarize our current knowledge of the function of TAM receptors in the tumor microenvironment. We place particular focus on TAM receptors and the recently unraveled role of MERTK in activated T cells and potential consequences for anti-tumor immunity.

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MERTK inhibition alters the PD-1 axis and promotes anti-leukemia immunity

Cited by 61 publications

References 42 publications

The impact of CTLA-4 blockade and interferon-α on clonality of T-cell repertoire in the tumor microenvironment and peripheral blood of metastatic melanoma patients

The impact of CTLA-4 blockade and interferon-α on clonality of T-cell repertoire in the tumor microenvironment and peripheral blood of metastatic melanoma patients

Production, characterization, andin vivohalf-life extension of polymeric IgA molecules in mice

TAM-ing T cells in the tumor microenvironment: implications for TAM receptor targeting

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