Conserved Interferon-γ Signaling Drives Clinical Response to Immune Checkpoint Blockade Therapy in Melanoma

Grasso, Catherine S.; Tsoi, Jennifer; Onyshchenko, Mykola; Ross‐Macdonald, Petra; Wind‐Rotolo, Megan; Champhekar, Ameya S.; Medina, Egmidio; Torrejon, Davis Y.; Shin, Daniel Sanghoon; Tran, Phuong; Kim, Yeon Joo; Puig-Saus, Cristina; Campbell, Katie M.; Vega-Crespo, Agustin; Quist, Michael J.; Martignier, Christophe; Luke, Jason J.; Wolchok, Jedd D.; Johnson, Douglas B.; Chmielowski, Bartosz; Hodi, F. Stephen; Bhatia, Shailender; Sharfman, William; Urba, Walter J.; Slingluff, Craig L.; Diab, Adi; Haanen, John B.A.G.; Algarra, Salvador Martín; Pardoll, Drew M.; Anagnostou, Valsamo; Topalian, Suzanne L.; Velculescu, Victor E.; Speiser, Daniel E.; Kalbasi, Anusha; Ribas, Antoni

doi:10.1016/j.ccell.2020.11.015

Cited by 76 publications

(83 citation statements)

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“…Our work informs and builds upon the prior pre-clinical and translational data supporting the intricate role of IFNγ in sensitivity and resistance to immunotherapy. Whereas initial IFNγ exposure may be fundamental to T cell activation and a hallmark of immune response, persistent IFNγ related effects and upregulation could signal immune dysfunction (Benci et al, 2016;Benci et al, 2019) and IFNγ insensitivity (Zaretsky et al 2016, Kalbasi et al 2020, Grasso et al 2020. In contrast to previous reports linking IFNγ insensitivity to mutations in the JAK-STAT pathway, we did not identify specific defects in the IFNγ signalling pathway to explain the dysfunctional nature of IFNγ response observed in a subset of patients.…”

Section: Discussioncontrasting

confidence: 72%

“…Along with case reports in other diseases, these studies have identified that loss of key proteins associated with antigen presentation or defects of the IFNγ signaling pathway can contribute to immune resistance (Gettinger et al, 2017;Le et al, 2017;Sade-Feldman et al, 2017;Zaretsky et al, 2016). Pre-clinical work has further highlighted how the relative acuity vs chronicity of IFNγ exposure can contribute to immune dysfunction and tumor resistance (Benci et al, 2016(Benci et al, , 2019Grasso et al, 2020). Improved understanding of the nature and biology underlying acquired resistance is imperative to develop more effective nextgeneration immunotherapies in the future.…”

Section: Introductionmentioning

confidence: 99%

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Clinical and molecular features of acquired resistance to immunotherapy in non-small cell lung cancer

Memon

Rizvi

Fromm

et al. 2021

Preprint

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Although cancer immunotherapy with PD-(L)1 blockade is now routine treatment for patients with lung cancer, remarkably little is known about acquired resistance. We examined 1,201 patients with NSCLC treated with PD-(L)1 blockade to clinically characterize acquired resistance, finding it to be common (occurring in more than 60% of initial responders), with persistent but diminishing risk over time, and with distinct metastatic and survival patterns compared to primary resistance. To examine the molecular phenotype and potential mechanisms of acquired resistance, we performed whole transcriptome and exome tumor profiling in a subset of NSCLC patients (n=29) with acquired resistance. Systematic immunogenomic analysis revealed that tumors with acquired resistance generally had enriched signals of inflammation (including IFNγ signaling and inferred CD8+ T cells) and could be separated into IFNγ upregulated and stable subsets. IFNγ upregulated tumors had putative routes of resistance with signatures of dysfunctional interferon signaling and mutations in antigen presentation genes. Transcriptomic profiling of cancer cells from a murine model of acquired resistance to PD-(L)1 blockade also showed evidence of dysfunctional interferon signaling and acquired insensitivity to in vitro interferon gamma treatment. In summary, we characterized clinical and molecular features of acquired resistance to PD-(L)1 blockade in NSCLC and found evidence of ongoing but dysfunctional IFN response. The persistently inflamed, rather than excluded or deserted, tumor microenvironment of acquired resistance informs therapeutic strategies to effectively reprogram and reverse acquired resistance.

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Section: Discussioncontrasting

confidence: 72%

Section: Introductionmentioning

confidence: 99%

Clinical and molecular features of acquired resistance to immunotherapy in non-small cell lung cancer

Memon

Rizvi

Fromm

et al. 2021

Preprint

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“…In particular, in PRAD, we found that TYHDF1 expression has a close association with TILs in the TME. For example, YTHDF1 expression has a close association with IFNgamma in PRAD, which is regarded as a hallmark of antitumor immunity (54). Moreover, YTHDF1 expression is related to all of the examined marker genes of CD8+ T cells, monocytes, tumorassociated macrophages (TAMs), M2 macrophages, Th1 cells, and other known immune stimulatory and immune suppressive cytokines, which proves the potential immune function of YTHDF1 in PRAD.…”

Section: Discussionmentioning

confidence: 68%

YTHDF1 Is a Potential Pan-Cancer Biomarker for Prognosis and Immunotherapy

Qiu

et al. 2021

Front. Oncol.

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BackgroundYTH N6-methyladenosine RNA binding protein 1 (YTHDF1) has been indicated proven to participate in the cross-presentation of tumor antigens in dendritic cells and the cross-priming of CD8+ T cells. However, the role of YTHDF1 in prognosis and immunology in human cancers remains largely unknown.MethodsAll original data were downloaded from TCGA and GEO databases and integrated via R 3.2.2. YTHDF1 expression was explored with the Oncomine, TIMER, GEPIA, and BioGPS databases. The effect of YTHDF1 on prognosis was analyzed via GEPIA, Kaplan-Meier plotter, and the PrognoScan database. The TISIDB database was used to determine YTHDF1 expression in different immune and molecular subtypes of human cancers. The correlations between YTHDF1 expression and immune checkpoints (ICP), tumor mutational burden (TMB), microsatellite instability (MSI), and neoantigens in human cancers were analyzed via the SangerBox database. The relationships between YTHDF1 expression and tumor-infiltrated immune cells were analyzed via the TIMER and GEPIA databases. The relationships between YTHDF1 and marker genes of tumor-infiltrated immune cells in urogenital cancers were analyzed for confirmation. The genomic alterations of YTHDF1 were investigated with the c-BioPortal database. The differential expression of YTHDF1 in urogenital cancers with different clinical characteristics was analyzed with the UALCAN database. YTHDF1 coexpression networks were studied by the LinkedOmics database.ResultsIn general, YTHDF1 expression was higher in tumors than in paired normal tissue in human cancers. YTHDF1 expression had strong relationships with prognosis, ICP, TMB, MSI, and neoantigens. YTHDF1 plays an essential role in the tumor microenvironment (TME) and participates in immune regulation. Furthermore, significant strong correlations between YTHDF1 expression and tumor immune-infiltrated cells (TILs) existed in human cancers, and marker genes of TILs were significantly related to YTHDF expression in urogenital cancers. TYHDF1 coexpression networks mostly participated in the regulation of immune response and antigen processing and presentation.ConclusionYTHDF1 may serve as a potential prognostic and immunological pan-cancer biomarker. Moreover, YTHDF1 could be a novel target for tumor immunotherapy.

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“…Therefore, IFN-γ secreted by CD8 + T cells would increase the number of MDSCs, Tregs and other immune suppressor cells within tumor, while it kill some cancer cells. With the recruitment of immune suppressor cells, immunosuppressive molecules such as IL-10 and TGF-β secreted from these cells would also increase, which in turn induce more immune suppressor cells within tumor, finally forming a vicious circle that cause the acquired drug resistance [38][39][40][41]. This mechanism is demonstrated in Fig.…”

Section: Mechanistic Comparison Of Plasmodium Immunotherapy With Checkpoint Blockade Therapymentioning

confidence: 97%

The mechanisms of action of Plasmodium infection against cancer

Chen

et al. 2021

Cell Commun Signal

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Our murine cancer model studies have demonstrated that Plasmodium infection activates the immune system that has been inhibited by cancer cells, counteracts tumor immunosuppressive microenvironment, inhibits tumor angiogenesis, inhibits tumor growth and metastasis, and prolongs the survival time of tumor-bearing mice. Based on these studies, three clinical trials of Plasmodium immunotherapy for advanced cancers have been approved and are ongoing in China. After comparing the mechanisms of action of Plasmodium immunotherapy with those of immune checkpoint blockade therapy, we propose the notion that cancer is an ecological disease and that Plasmodium immunotherapy is a systemic ecological counterattack therapy for this ecological disease, with limited side effects and without danger to public health based on the use of artesunate and other measures. Recent reports of tolerance to treatment and limitations in majority of patients associated with the use of checkpoint blockers further support this notion. We advocate further studies on the mechanisms of action of Plasmodium infection against cancer and investigations on Plasmodium-based combination therapy in the coming future.

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Conserved Interferon-γ Signaling Drives Clinical Response to Immune Checkpoint Blockade Therapy in Melanoma

Cited by 76 publications

References 0 publications

Clinical and molecular features of acquired resistance to immunotherapy in non-small cell lung cancer

Clinical and molecular features of acquired resistance to immunotherapy in non-small cell lung cancer

YTHDF1 Is a Potential Pan-Cancer Biomarker for Prognosis and Immunotherapy

The mechanisms of action of Plasmodium infection against cancer

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