Faculty Opinions recommendation of Improved prediction of immune checkpoint blockade efficacy across multiple cancer types.

Targeted therapies represent attractive combination partners with immune checkpoint blockade (ICB) to increase the population of patients who benefit or to interdict the emergence of resistance. We demonstrate that targeting WEE1 up-regulates immune signaling through the double-stranded RNA (dsRNA) viral defense pathway with subsequent responsiveness to immune checkpoint blockade even in cGAS/STING-deficient tumors, which is a typical phenotype across multiple cancer types. WEE1 inhibition increases endogenous retroviral elements (ERVs) expression by relieving SETDB1/H3K9me3 repression through down-regulating FOXM1. ERVs trigger dsRNA stress and interferon response, increasing recruitment of anti-tumor T cells with concurrent PD-L1 elevation in multiple tumor models. Furthermore, combining WEE1 inhibition and PD-L1 blockade induced striking tumor regression in a CD8+ T cell–dependent manner. A WEE1 inhibition–induced viral defense signature provides a potentially informative biomarker for patient selection for combination therapy with WEE1 and ICB. WEE1 inhibition stimulates anti-tumor immunity and enhances sensitivity to ICB, providing a rationale for the combination of WEE1 inhibitors and ICB in clinical trials.

Download Full-text

Improved prediction of immune checkpoint blockade efficacy across multiple cancer types

Nature Biotechnology ◽

10.1038/s41587-021-01070-8 ◽

2021 ◽

Author(s):

Diego Chowell ◽

Seong-Keun Yoo ◽

Cristina Valero ◽

Alessandro Pastore ◽

Chirag Krishna ◽

...

Keyword(s):

Immune Checkpoint ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Multiple Cancer ◽

Cancer Types

Download Full-text

Association of the diversity and composition of the gut microbiome with responses and survival (PFS) in metastatic melanoma (MM) patients (pts) on anti-PD-1 therapy.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.3008 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 3008-3008 ◽

Cited By ~ 16

Author(s):

Jennifer Ann Wargo ◽

Vancheswaran Gopalakrishnan ◽

Christine Spencer ◽

Tatiana Karpinets ◽

Alexandre Reuben ◽

...

Keyword(s):

Gut Microbiome ◽

Immune Checkpoint ◽

Immune Checkpoint Blockade ◽

Large Cohort ◽

Checkpoint Blockade ◽

Cancer Types ◽

Pre Treatment ◽

Immune Profiling ◽

Made In

3008 Background: Significant advances have been made in cancer therapy with immune checkpoint blockade. However, responses in pts with MM are variable, and insights are needed to identify biomarkers of response and strategies to overcome resistance. There is a growing appreciation of the role of the microbiome in cancer, and evidence in murine models that modulation of the gut microbiome may enhance responses to immune checkpoint blockade, though this has not been well studied in pts. Thus we evaluated the microbiome in a large cohort of pts with MM, focusing on responses to anti-PD-1. Methods: We collected oral (n = 234) and gut microbiome samples (n = 120) on a large cohort of of MM patients (n = 221). Of note, the majority of pts were treated with PD-1 based therapy (n = 105). Pts on anti-PD1 were classified as either responders (R) or non-responders (NR) based on RECIST criteria, and 16S rRNA and whole genome shotgun (WGS) sequencing were performed. Immune profiling (via immunohistochemistry, flow cytometry, cytokines and gene expression profiling) was also done in available pre-treatment tumors at baseline. Results: Significant differences in diversity and composition of the gut microbiome were noted in R vs NR to anti-PD-1, with a higher diversity of bacteria in R vs NR (p = 0.03). Differences were also noted in the composition of gut bacteria, with a higher abundance of Clostridiales in R and of Bacteroidales in NR. Immune profiling demonstrated increased tumor immune infiltrates in R pts , with a higher density of CD8+T cells; this correlated with abundance of specific bacteria enriched in the gut microbiome (r = 0.59, 0.014). Other features of enhanced immunity were also noted, and WGS revealed differential metabolic signatures in R vs NR. Furthermore, diversity (p = 0.009; HR = 7.67) and abundance of specific bacteria in R (p = 0.007; HR = 3.88) was associated with improved PFS to anti-PD-1 therapy. Conclusions: Diversity and composition of the gut microbiome differ in R vs NR pts with MM receiving anti-PD-1 therapy. These have potentially far-reaching implications, though results need to be validated in larger cohorts across cancer types.

Download Full-text

Targeting Multiple Receptors to Increase Checkpoint Blockade Efficacy

International Journal of Molecular Sciences ◽

10.3390/ijms20010158 ◽

2019 ◽

Vol 20 (1) ◽

pp. 158 ◽

Cited By ~ 9

Author(s):

David J. Zahavi ◽

Louis M. Weiner

Keyword(s):

Tumor Immunity ◽

Immune Checkpoint ◽

Treatment Strategy ◽

Immune Checkpoint Blockade ◽

Tumor Formation ◽

Checkpoint Blockade ◽

Immune Checkpoints ◽

Multiple Receptors ◽

Cancer Types ◽

Receptor Targets

Immune checkpoint blockade therapy is a powerful treatment strategy for many cancer types. Many patients will have limited responses to monotherapy targeted to a single immune checkpoint. Both inhibitory and stimulatory immune checkpoints continue to be discovered. Additionally, many receptors previously identified to play a role in tumor formation and progression are being found to have immunomodulatory components. The success of immunotherapy depends on maximizing pro-anti-tumor immunity while minimizing immunosuppressive signaling. Combining immune checkpoint targeted approaches with each other or with other receptor targets is a promising schema for future therapeutic regimen designs.

Download Full-text

Resistance to Immune Checkpoint Blockade in Uterine Leiomyosarcoma: What Can We Learn from Other Cancer Types?

Cancers ◽

10.3390/cancers13092040 ◽

2021 ◽

Vol 13 (9) ◽

pp. 2040

Author(s):

Wout De Wispelaere ◽

Daniela Annibali ◽

Sandra Tuyaerts ◽

Diether Lambrechts ◽

Frédéric Amant

Keyword(s):

Immune Checkpoint ◽

Gynecological Cancer ◽

Single Agent ◽

Acquired Resistance ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Clinical Activity ◽

Uterine Leiomyosarcoma ◽

Mechanisms Of Resistance ◽

Cancer Types

The onset of immune checkpoint blockade (ICB) therapy over the last decade has transformed the therapeutic landscape in oncology. ICB has shown unprecedented clinical activity and durable responses in a variety of difficult-to-treat cancers. However, despite these promising long-term responses, a majority of patients fail to respond to single-agent therapy, demonstrating primary or acquired resistance. Uterine leiomyosarcoma (uLMS) is a rare high-risk gynecological cancer with very limited treatment options. Despite research indicating a strong potential for ICB in uLMS, a clinical trial assessing the response to immunotherapy with single-agent nivolumab in advanced-stage uLMS showed no clinical benefit. Many mechanisms of resistance to ICB have been characterized in a variety of tumor types, and many more continue to be uncovered. However, the mechanisms of resistance to ICB in uLMS remain largely unexplored. By elucidating and targeting mechanisms of resistance, treatments can be tailored to improve clinical outcomes. Therefore, in this review we will explore what is known about the immunosuppressive microenvironment of uLMS, link these data to possible resistance mechanisms extrapolated from other cancer types, and discuss potential therapeutic strategies to overcome resistance.

Download Full-text

High tumor mutation burden fails to predict immune checkpoint blockade response across all cancer types

Annals of Oncology ◽

10.1016/j.annonc.2021.02.006 ◽

2021 ◽

Author(s):

D.J. McGrail ◽

P.G. Pilié ◽

N.U. Rashid ◽

L. Voorwerk ◽

M. Slagter ◽

...

Keyword(s):

Immune Checkpoint ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Tumor Mutation Burden ◽

Mutation Burden ◽

Cancer Types

Download Full-text

Age-Related Differences in Molecular Profiles for Immune Checkpoint Blockade Therapy

Frontiers in Immunology ◽

10.3389/fimmu.2021.657575 ◽

2021 ◽

Vol 12 ◽

Author(s):

Qi-jie Zhang ◽

Jiao-chen Luan ◽

Le-bin Song ◽

Rong Cong ◽

Cheng-jian Ji ◽

...

Keyword(s):

Elderly Patients ◽

Immune Checkpoint ◽

Treatment Efficacy ◽

Young Patients ◽

The Elderly ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Age Related ◽

Cancer Types ◽

Molecular Profiles

Immune checkpoint blockade (ICB) therapies have significantly improved the prognosis and shown considerable promise for cancer therapy; however, differences in ICB treatment efficacy between the elderly and young are unknown. We analyzed the studies enrolled in the meta-analysis using the deft approach, and found no difference in efficacy except melanoma patients receiving anti–PD-1 therapy. Similarly, higher treatment response rate and more favorable prognosis were observed in elderly patients in some cancer types (e.g., melanoma) with data from published ICB treatment clinical trials. In addition, we comprehensively compared immunotherapy-related molecular profiles between elderly and young patients from public trials and The Cancer Genome Atlas (TCGA), and validated these findings in several independent datasets. We discovered a divergent age-biased immune profiling, including the properties of tumors (e.g., tumor mutation load) and immune features (e.g., immune cells), in a pancancer setting across 27 cancer types. We believe that ICB treatment efficacy might vary depending on specific cancer types and be determined by both the tumor internal features and external immune microenvironment. Considering the high mutational properties in elderly patients in many cancer types, modulating immune function could be beneficial to immunotherapy in the elderly, which requires further investigation.

Download Full-text

Hiding in the dark: pan-cancer characterization of expression and clinical relevance of CD40 to immune checkpoint blockade therapy

Molecular Cancer ◽

10.1186/s12943-021-01442-3 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Chi Yan ◽

Ann Richmond

Keyword(s):

Immune Checkpoint ◽

Tumor Response ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Type I ◽

List Type ◽

Cancer Types ◽

Pan Cancer ◽

Cancer Bioinformatics

Highlights CD40 expression correlates with the type I anti-tumor response and better survival. Pan-cancer bioinformatics characterization reveals reduced CD40 expression in 11 cancer types, including RASmut melanoma compared to nevi. RAS mutation correlates with reduced CD40 expression in malignant melanoma. CD40 expression is associated with better response to immune checkpoint blockade therapy in melanoma.

Download Full-text