Interferon Receptor Signaling Pathways Regulating PD-L1 and PD-L2 Expression

García-Díaz, Ángel; Shin, Daniel Sanghoon; Moreno, Blanca Homet; Saco, Justin D.; Escuin-Ordinas, Helena; Rodriguez, Gabriel Abril; Zaretsky, Jesse M.; Sun, Lingyun; Hugo, Willy; Wang, Xiaoyan; Parisi, Giulia; Puig-Saus, Cristina; Torrejon, Davis Y.; Graeber, Thomas G.; Comin-Anduix, Begoñya; Hu‐Lieskovan, Siwen; Damoiseaux, Robert; Lo, Roger S.; Ribas, Antoni

doi:10.1016/j.celrep.2017.04.031

Cited by 1,361 publications

(1,082 citation statements)

References 49 publications

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“…4 Previous studies have established that expression of PD-L1 on most tumors is initially induced in response to IFNγ secreted by CD8 T cells recruited to the tumor site as part of adaptive tumor resistance. 5,6 Thus, treatment with adoptive transfer of IFNγ producing cell populations, such as activated NK cells, should lead to an increase in PD-L1 expression on tumor targets. NK cells not only produce IFNγ and other cytokines, which are secreted upon recognition of the tumor, but also recruit and orchestrate responses by other immune cells such as T- and dendritic cells in the tumor bed.…”

Section: Introductionmentioning

confidence: 99%

PD-L1 blockade enhances anti-tumor efficacy of NK cells

2018

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Anti-PD-1/anti-PD-L1 therapies have shown success in cancer treatment but responses are limited to ~ 15% of patients with lymphocyte infiltrated, PD-L1 positive tumors. Hence, strategies that increase PD-L1 expression and tumor infiltration should make more patients eligible for PD-1/PD-L1 blockade therapy, thus improving overall outcomes. PD-L1 expression on tumors is induced by IFNγ, a cytokine secreted by NK cells. Therefore, we tested if PM21-particle expanded NK cells (PM21-NK cells) induced expression of PD-L1 on tumors and if anti-PD-L1 treatment enhanced NK cell anti-tumor efficacy in an ovarian cancer model. Studies here showed that PM21-NK cells secrete high amounts of IFNγ and that adoptively transferred PM21-NK cells induce PD-L1 expression on SKOV-3 cells in vivo. The induction of PD-L1 expression on SKOV-3 cells coincided with the presence of regulatory T cells (Tregs) in the abdominal cavity and within tumors. In in vitro experiments, anti-PD-L1 treatment had no direct effect on cytotoxicity or cytokine secretion by predominantly PD-1 negative PM21-NK cells in response to PD-L1+ targets. However, significant improvement of NK cell anti-tumor efficacy was observed in vivo when combined with anti-PD-L1. PD-L1 blockade also resulted in increased in vivo NK cell persistence and retention of their cytotoxic phenotype. These results support the use of anti-PD-L1 in combination with NK cell therapy regardless of initial tumor PD-L1 status and indicate that NK cell therapy would likely augment the applicability of anti-PD-L1 treatment.

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Section: Introductionmentioning

confidence: 99%

PD-L1 blockade enhances anti-tumor efficacy of NK cells

2018

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“…A third Investigators were requested to maintain one untreated lesion for the duration of the trial to enable the assessment of systemic antitumor immune responses. PD-L1 expression and expression of an IFN-γ gene signature, which has been associated with increased PD-L1 expression, have been identified as positive predictor of response to PD-1 and PD-L1 antibody therapy [11,63,64]. IT-Tavo-EP has been shown to increase IFN-γ gene expression potentially priming less inflamed tumors to respond to PD-1 and PD-L1 antibodies.…”

Section: Preclinical Studiesmentioning

confidence: 99%

Melanoma Treatment with Intratumoral Electroporation of Tavokinogene Telseplasmid (pIL-12, Tavokinogene Telseplasmid)

Canton¹,

Shirley²,

Wright³

et al. 2017

Immunotherapy

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Tumors evade detection and/or clearance by the immune system via multiple mechanisms. IL-12 is a potent immunomodulatory cytokine that plays a central role in immune priming. However, systemic delivery of IL-12 can result in life-threatening toxicity and therefore has shown limited efficacy at doses that can be safely administered. We developed an electroporation technique to produce highly localized IL-12 expression within tumors leading to regression of both treated and untreated lesions in animal models and in patients with a favorable safety profile. Furthermore, intratumoral tavokinogene telseplasmid electroporation can drive cellular immune responses, converting ‘cold’ tumors into ‘hot’ tumors. Clinical trials are ongoing to determine whether intratumoral tavokinogene telseplasmid electroporation synergizes with checkpoint blockade therapy in immunologically cold tumors predicted not to respond to PD-1 antibody monotherapy.

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“…Several components of the IFNγ signaling pathway including STAT1, STAT2, STAT3, and IRF1 were upregulated in anti-PD-1 responding tumors (Garcia-Diaz et al 2017), and loss of function mutations in JAK1/JAK2 have been implicated to confer resistance to anti-PD-1 therapy (Zaretsky et al 2016; Shin et al 2017). As such, expression of IFNγ pathway signatures may represent surrogate markers of immune activity and response to immune checkpoint therapy.…”

Section: Introductionmentioning

confidence: 99%

“…Innate and acquired resistance mechanisms can be tumor intrinsic, involving changes in the cancer cells, or tumor extrinsic, attributed to alterations in the tumor micro-environment (Sharma et al 2017). Tumor intrinsic mechanisms include downregulation or loss of antigens and antigen presentation molecules (Zaretsky et al 2016), disruption in the IFNγ signaling pathway (Zaretsky et al 2016; Garcia-Diaz 2017) and T cell exclusion (Liu et al 2013; Peng et al 2016). Tumor extrinsic mechanisms involve inhibition of innate and adaptive immune cell function and infiltration, and enrichment of immunosuppressive cells or molecules [reviewed in (Sharma et al 2017; Jenkins et al 2018)].…”

Section: Introductionmentioning

confidence: 99%

Immune cell profiling in the age of immune checkpoint inhibitors: implications for biomarker discovery and understanding of resistance mechanisms

Lim

Rizos

2018

Mamm Genome

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Immunotherapy has changed the landscape of cancer treatment. The introduction of immune checkpoint inhibitors has seen tremendous success in improving overall survival of patients with advanced metastatic cancers and has now become the standard of care for multiple tumor types. However, efficacy of immune checkpoint blockade appears to be limited to immunogenic cancers, and even amongst immune-reactive cancers, response rates are low and variable between patients. Recent data have also demonstrated the rapid emergence of resistance to immune checkpoint inhibitors, with some patients progressing on treatment within one year. Significant research efforts are now directed at identifying predictive biomarkers and mechanisms of resistance to immune checkpoint blockade. These studies are underpinned by comprehensive and detailed profiling of the immune milieu. In this review, we discuss the utility and efficacy of immune cell profiling to uncover biomarkers of response and mechanisms of resistance to immune checkpoint inhibitors.

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Interferon Receptor Signaling Pathways Regulating PD-L1 and PD-L2 Expression

Cited by 1,361 publications

References 49 publications

PD-L1 blockade enhances anti-tumor efficacy of NK cells

PD-L1 blockade enhances anti-tumor efficacy of NK cells

Melanoma Treatment with Intratumoral Electroporation of Tavokinogene Telseplasmid (pIL-12, Tavokinogene Telseplasmid)

Immune cell profiling in the age of immune checkpoint inhibitors: implications for biomarker discovery and understanding of resistance mechanisms

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