Author Correction: Immunogenomic profiling determines responses to combined PARP and PD-1 inhibition in ovarian cancer

Färkkilä, Anniina; Gulhan, D.; Casado, Julia; Jacobson, Connor A.; Nguyen, Huy; Kochupurakkal, Bose; Maliga, Zoltan; Yapp, Clarence; Yuan, Chen; Schapiro, Denis; Zhou, Yinghui; Graham, James G.; Dezube, Bruce J.; Münster, Pamela N.; Santagata, Sandro; Garcia, Elizabeth; Rodig, Scott J.; Lako, Ana; Chowdhury, Dipanjan; Shapiro, Geoffrey I.; Matulonis, Ursula A.; Park, Peter J.; Hautaniemi, Sampsa; Sorger, Peter K.; Swisher, Elizabeth M.; D’Andrea, Alan D.; Konstantinopoulos, Panagiotis A.

doi:10.1038/s41467-020-16344-z

Cited by 8 publications

(5 citation statements)

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“…Future treatments for pancreatic cancer will likely be based on the development of new therapies based on the genomic and proteomic identification of cellular/immune processes and molecular pathways as therapeutic targets (35). Together with other reports in breast cancer (36), ovarian cancer (37), and non-small cell lung cancer (38), our study shows that simultaneous inhibition of PARP and PD-L1 confers therapeutic benefits. However, although the cytotoxic effects of PARPis have been well studied, the role of PARPis regarding how they modulate cancer-related immunity in pancreatic cancer remains largely unknown.…”

Section: Discussionsupporting

confidence: 87%

PARP Inhibitor Upregulates PD-L1 Expression and Provides a New Combination Therapy in Pancreatic Cancer

et al. 2021

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Despite recent improvements in treatment modalities, pancreatic cancer remains a highly lethal tumor with mortality rate increasing every year. Poly (ADP-ribose) polymerase (PARP) inhibitors are now used in pancreatic cancer as a breakthrough in targeted therapy. This study focused on whether PARP inhibitors (PARPis) can affect programmed death ligand-1 (PD-L1) expression in pancreatic cancer and whether immune checkpoint inhibitors of PD-L1/programmed death 1 (PD-1) can enhance the anti-tumor effects of PARPis. Here we found that PARPi, pamiparib, up-regulated PD-L1 expression on the surface of pancreatic cancer cells in vitro and in vivo. Mechanistically, pamiparib induced PD-L1 expression via JAK2/STAT3 pathway, at least partially, in pancreatic cancer. Importantly, pamiparib attenuated tumor growth; while co-administration of pamiparib with PD-L1 blockers significantly improved the therapeutic efficacy in vivo compared with monotherapy. Combination therapy resulted in an altered tumor immune microenvironment with a significant increase in windiness of CD8+ T cells, suggesting a potential role of CD8+ T cells in the combination therapy. Together, this study provides evidence for the clinical application of PARPis with anti-PD-L1/PD-1 drugs in the treatment of pancreatic cancer.

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Section: Discussionsupporting

confidence: 87%

PARP Inhibitor Upregulates PD-L1 Expression and Provides a New Combination Therapy in Pancreatic Cancer

et al. 2021

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“…OC is one of the subsets of cancers with modest responses to existing immune checkpoint blockade therapy. Patients with OC receiving checkpoint inhibitors (CPIs) also generated infrequent durable responses ( 24 ). However, evidence suggests that combinatorial methods might prove important to optimize OC patient response to immunotherapy ( 25 , 26 ).…”

Section: Resultsmentioning

confidence: 99%

Siglec-7 glyco-immune binding mAbs or NK cell engager biologics induce potent antitumor immunity against ovarian cancers

Bordoloi,

Kulkarni,

Adeniji

et al. 2023

Sci. Adv.

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Ovarian cancer (OC) is a lethal gynecologic malignancy, with modest responses to CPI. Engagement of additional immune arms, such as NK cells, may be of value. We focused on Siglec-7 as a surface antigen for engaging this population. Human antibodies against Siglec-7 were developed and characterized. Coculture of OC cells with PBMCs/NKs and Siglec-7 binding antibodies showed NK-mediated killing of OC lines. Anti–Siglec-7 mAb (DB7.2) enhanced survival in OC-challenged mice. In addition, the combination of DB7.2 and anti–PD-1 demonstrated further improved OC killing in vitro. To use Siglec-7 engagement as an OC-specific strategy, we engineered an NK cell engager (NKCE) to simultaneously engage NK cells through Siglec-7, and OC targets through FSHR. The NKCE demonstrated robust in vitro killing of FSHR + OC, controlled tumors, and improved survival in OC-challenged mice. These studies support additional investigation of the Siglec-7 targeting approaches as important tools for OC and other recalcitrant cancers.

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“…Anti-VEGF therapy-induced inhibition of adaptive immune response as a result of enriched PD-1 signaling on immune cells was seen in 60577 model. The dampening of T-cell response observed with long term cediranib treatment that facilitated anti-PD-1 combination in 60577 model, was a similar mechanism that dictated successful combination of PARP inhibitors with anti-PD-1 therapy in ovarian cancer patients (35).…”

Section: Discussionmentioning

confidence: 96%

Immune Mechanisms of Resistance to Cediranib in Ovarian Cancer

Gopinathan¹,

Berlato

Lakhani

et al. 2022

Molecular Cancer Therapeutics

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This paper investigates mechanisms of resistance to the VEGF receptor inhibitor cediranib in high-grade serous ovarian cancer, HGSOC, and defines rational combination therapies. We used three different syngeneic orthotopic mouse HGSOC models that replicated the human tumor microenvironment, TME. After 4-5 weeks treatment of established tumors, cediranib had anti-tumor activity with increased tumor T cell infiltrates and alterations in myeloid cells. However, continued cediranib treatment did not change overall survival or the immune microenvironment in two of the three models. Moreover, treated mice developed additional peritoneal metastases not seen in controls. Cediranib-resistant tumors had intrinsically high levels of IL-6 and JAK/STAT signaling and treatment increased endothelial STAT3 activation. Combination of cediranib with a murine anti-IL-6 antibody was superior to monotherapy, increasing mouse survival, reducing blood vessel density and pSTAT3, with increased T cell infiltrates in both models. In a third HGSOC model, that had lower inherent IL-6 JAK/STAT3 signaling in the TME but high PD1 signaling, long-term cediranib treatment significantly increased overall survival. When the mice eventually relapsed, pSTAT3 was still reduced in the tumors but there were high levels of immune cell PD1 and PDL1. Combining cediranib with an anti-PD1 antibody was superior to monotherapy in this model, increasing T cells and decreasing blood vessel densities. Bioinformatics analysis of two human HGSOC transcriptional datasets revealed distinct clusters of tumors with IL-6 and PD-1 pathway expression patterns that replicated the mouse tumors. Combination of anti-IL-6 or anti-PD1 in these patients may increase activity of VEGFR inhibitors and prolong disease-free survival.

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Author Correction: Immunogenomic profiling determines responses to combined PARP and PD-1 inhibition in ovarian cancer

Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Cited by 8 publications

References 0 publications

PARP Inhibitor Upregulates PD-L1 Expression and Provides a New Combination Therapy in Pancreatic Cancer

PARP Inhibitor Upregulates PD-L1 Expression and Provides a New Combination Therapy in Pancreatic Cancer

Siglec-7 glyco-immune binding mAbs or NK cell engager biologics induce potent antitumor immunity against ovarian cancers

Immune Mechanisms of Resistance to Cediranib in Ovarian Cancer

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