scholarly journals Novel Molecular Determinants of Response or Resistance to Immune Checkpoint Inhibitor Therapies in Melanoma

2022 ◽  
Vol 12 ◽  
Author(s):  
Wenjing Zhang ◽  
Yujia Kong ◽  
Yuting Li ◽  
Fuyan Shi ◽  
Juncheng Lyu ◽  
...  

BackgroundImmune checkpoint inhibitor (ICI) therapy dramatically prolongs melanoma survival. Currently, the identified ICI markers are sometimes ineffective. The objective of this study was to identify novel determinants of ICI efficacy.MethodsWe comprehensively curated pretreatment somatic mutational profiles and clinical information from 631 melanoma patients who received blockade therapy of immune checkpoints (i.e., CTLA-4, PD-1/PD-L1, or a combination). Significantly mutated genes (SMGs), mutational signatures, and potential molecular subtypes were determined. Their association with ICI responses was assessed simultaneously.ResultsWe identified 27 SMGs, including four novel SMGs (COL3A1, NRAS, NARS2, and DCC) that are associated with ICI efficacy and well-known driver genes. COL3A1 mutations were associated with improved ICI overall survival (hazard ratio (HR): 0.64, 95% CI: 0.45–0.91, p = 0.012), whereas immune resistance was observed in patients with NRAS mutations (HR: 1.42, 95% CI: 1.10–1.82, p = 0.006). The presence of the tobacco smoking-related signature was significantly correlated with inferior prognoses (HR: 1.42, 95% CI: 1.11–1.82, p = 0.005). In addition, the signature resembling that of alkylating agents and a newly discovered signature both exhibited extended prognoses (both HR < 1, p < 0.05). Based on the activities of the extracted 6 mutational signatures, we identified one immune subtype that was significantly associated with better ICI outcomes (HR: 0.44, 95% CI: 0.23–0.87, p = 0.017).ConclusionWe uncovered several novel SMGs and re-annotated mutational signatures that are linked to immunotherapy response or resistance. In addition, an immune subtype was found to exhibit favorable prognoses. Further studies are required to validate these findings.

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A711-A711
Author(s):  
Matthew Robinson ◽  
Kevin Vervier ◽  
Simon Harris ◽  
David Adams ◽  
Doreen Milne ◽  
...  

BackgroundThe gut microbiome of cancer patients appears to be associated with response to Immune Checkpoint Inhibitor (ICIs) treatment.1–4 However, the bacteria linked to response differ between published studies.MethodsLongitudinal stool samples were collected from 69 patients with advanced melanoma receiving approved ICIs in the Cambridge (UK) MELRESIST study. Pretreatment samples were analysed by Microbiotica, using shotgun metagenomic sequencing. Microbiotica’s sequencing platform comprises the world’s leading Reference Genome Database and advanced Microbiome Bioinformatics to give the most comprehensive and precise mapping of the gut microbiome. This has enabled us to identify gut bacteria associated with ICI response missed using public reference genomes. Published microbiome studies in advanced melanoma,1–3renal cell carcinoma (RCC) and non-small cell lung cancer (NSCLC)4 were reanalysed with the same platform.ResultsAnalysis of the MELRESIST samples showed an overall change in the microbiome composition between advanced melanoma patients and a panel of healthy donor samples, but not between patients who subsequently responded or did not respond to ICIs. However, we did identify a discrete microbiome signature which correlated with response. This signature predicted response with an accuracy of 93% in the MELRESIST cohort, but was less predictive in the published melanoma cohorts.1–3 Therefore, we developed a bioinformatic analytical model, incorporating an interactive random forest model and the MELRESIST dataset, to identify a microbiome signature which was consistent across all published melanoma studies. This model was validated three times by accurately predicting the outcome of an independent cohort. A final microbiome signature was defined using the validated model on MELRESIST and the three published melanoma cohorts. This was very accurate at predicting response in all four studies combined (91%), or individually (82–100%). This signature was also predictive of response in a NSCLC study and to a lesser extent in RCC. The core of this signature is nine bacteria significantly increased in abundance in responders.ConclusionsAnalysis of the MELRESIST study samples, precision microbiome profiling by the Microbiotica Platform and a validated bioinformatic analysis, have enabled us to identify a unique microbiome signature predictive of response to ICI therapy in four independent melanoma studies. This removes the challenge to the field of different bacteria apparently being associated with response in different studies, and could represent a new microbiome biomarker with clinical application. Nine core bacteria may be driving response and hold potential for co-therapy with ICIs.Ethics ApprovalThe study was approved by Newcastle & North Tyneside 2 Research Ethics Committee, approval number 11/NE/0312.ReferencesMatson V, Fessler J, Bao R, et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 2018;359(6371):104–108.Gopalakrishnan V, Spencer CN, Nezi L, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 2018;359(6371):97–103.Frankel AE, Coughlin LA, Kim J, et al. Metagenomic shotgun sequencing and unbiased metabolomic profiling identify specific human gut microbiota and metabolites associated with immune checkpoint therapy efficacy in melanoma patients. Neoplasia 2017;19(10):848–855.Routy B, Le Chatelier E, Derosa L, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 2018;359(6371):91–97.


PLoS ONE ◽  
2020 ◽  
Vol 15 (3) ◽  
pp. e0230306 ◽  
Author(s):  
Thomas T. DeLeon ◽  
Daniel R. Almquist ◽  
Benjamin R. Kipp ◽  
Blake T. Langlais ◽  
Aaron Mangold ◽  
...  

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21546-e21546
Author(s):  
Mat Robinson ◽  
Kevin Vervier ◽  
Amy Popple ◽  
Simon Harris ◽  
Robyne Hudson ◽  
...  

e21546 Background: Four independent groups have demonstrated that the pre-treatment gut microbiome of cancer patients impacts the subsequent response to Immune Checkpoint Inhibitor (ICIs) therapy [1-4]. However, the patient’s outcome was linked to different bacteria in each study, which has limited the development of drug response biomarkers and clinic-first design of novel microbiome-based therapeutics. Methods: The Cambridge (UK) MELRESIST study includes a cohort of advanced melanoma patients receiving approved ICIs. Pretreatment stool samples from MELRESIST were analysed by Microbiotica using shotgun metagenomic sequencing. Microbiotica’s platform comprises the world’s leading Reference Genome Database to give the most comprehensive and precise mapping of the gut microbiome. Results: MELRESIST samples showed an overall difference in the microbiome composition between advanced melanoma patients and healthy donors, but not between patients who did or did not respond to ICIs. However, we did identify a discrete microbiome signature that differentiated responders and non-responders with an accuracy of 93%. We extended this signature by reanalysing three published melanoma cohorts [1-3] using the Microbiotica platform, and a propriety bioinformatic model. The resultant bacterial signature was very accurate at predicting response in all 4 published studies combined (91%), and each cohort individually (82-100%). We validated the model using independent validation cohorts and the signature using lung and renal cancer studies [4]. At the core of our microbiome signature was 9 bacteria most significantly associated with ICI efficacy. All 9 were overrepresented in patients who responded to immunotherapy suggesting high abundance of these bacteria is a central driver of ICI response. A consortium comprised of all 9 strains had very potent anti-tumor efficacy in a cancer syngeneic mouse model. The bacteria also demonstrate multiple interactions with primary human immune cells in vitro leading to dendritic cells activation, Cytotoxic T lymphocyte activation and tumor cell killing. These validate the potential of this consortium as a novel therapy for use in combination with ICIs. Conclusions: We have identified a unique microbiome signature predictive of ICI response in 4 independent melanoma cancer cohorts. This removes a major challenge to the field, and could represent a new highly accurate biomarker with clinical application. Nine core bacteria appear to be driving response, and demonstrate anti-tumor activity in vivo and in vitro. This consortium holds great potential as a co-therapy with ICIs. References:1 Matson V et al, Science (2018) 359:104; 2 Gopalakrishnan V et al, Science (2018) 359:97; 3 Frankel AE et al, Neoplasia (2017) 19:848; 4 Routy B et al, Science (2018) 359:91.


2020 ◽  
Vol 2 (Supplement_2) ◽  
pp. ii3-ii3
Author(s):  
Soma Sengupta ◽  
Tahseen Nasti ◽  
Milota Kaluzova ◽  
Laura Kallay ◽  
Johannes Melms ◽  
...  

Abstract Most metastatic melanoma patients exhibit poor and variable response to radiotherapy and targeted therapies, including immune checkpoint inhibitors. There is a need for therapeutics that can potentiate existing treatments to positively impact clinical outcomes of metastatic melanoma patients. We reanalyzed melanoma TCGA transcriptomes and identified, as linked to previously defined molecular subgroups, enhanced expression of genes coding for subunits of the Type A GABA receptor (GABAAR), a chloride ion channel and major inhibitory neurotransmitter receptor. Using whole-cell patch clamp electrophysiology, we find that melanoma cells possess GABAARs that control membrane permeability to anions. Select benzodiazepines, by enhancing GABAAR mediated anion transport, depolarize melanoma cell mitochondrial membrane potential and impair cell viability in vitro. Using a syngeneic melanoma mouse model, we find that a benzodiazepine promotes reduction in tumor volume when administered alone and potentiated radiation or immune checkpoint inhibitor α-PD-L1. When a benzodiazepine is combined with concurrent α-PD-L1 and a sub-lethal radiation dose, there is near complete loss of tumor, beyond what is observed for benzodiazepine with radiation or α-PD-L1. Mechanistically, benzodiazepine with radiation or α-PD-L1 results in ipsilateral and an abscopal tumor volume reduction commensurate with enhanced infiltration into the tumor milieu of polyfunctional CD8 T-cells. There is also an increased expression of genes with roles in the cytokine-cytokine receptor and p53 signaling pathways. This study provides evidence for melanoma cell GABAARs as a therapeutic vulnerability with benzodiazepines promoting both direct and immune-mediated anti-tumor activity.


Biomolecules ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1107
Author(s):  
Juwon Lee ◽  
Youngjin Han ◽  
Wenyu Wang ◽  
HyunA Jo ◽  
Heeyeon Kim ◽  
...  

The interaction of immune checkpoint molecules in the tumor microenvironment reduces the anti-tumor immune response by suppressing the recognition of T cells to tumor cells. Immune checkpoint inhibitor (ICI) therapy is emerging as a promising therapeutic option for cancer treatment. However, modulating the immune system with ICIs still faces obstacles with severe immunogenic side effects and a lack of response against many cancer types. Plant-derived natural compounds offer regulation on various signaling cascades and have been applied for the treatment of multiple diseases, including cancer. Accumulated evidence provides the possibility of efficacy of phytochemicals in combinational with other therapeutic agents of ICIs, effectively modulating immune checkpoint-related signaling molecules. Recently, several phytochemicals have been reported to show the modulatory effects of immune checkpoints in various cancers in in vivo or in vitro models. This review summarizes druggable immune checkpoints and their regulatory factors. In addition, phytochemicals that are capable of suppressing PD-1/PD-L1 binding, the best-studied target of ICI therapy, were comprehensively summarized and classified according to chemical structure subgroups. It may help extend further research on phytochemicals as candidates of combinational adjuvants. Future clinical trials may validate the synergetic effects of preclinically investigated phytochemicals with ICI therapy.


2021 ◽  
Vol 12 ◽  
Author(s):  
Fuyan Shi ◽  
Wenjing Zhang ◽  
Yichen Yang ◽  
Yitao Yang ◽  
Junyi Zhao ◽  
...  

BackgroundDespite the acknowledged sex-related differences in immune response and immune checkpoint inhibitor (ICI) efficacy, little is known about the sex disparities in melanoma of novel genomic determinants for ICI therapies.MethodsPretreatment genomic profiles and clinical characteristics of 631 melanoma patients treated with ICIs (i.e., inhibitors of CTLA-4, PD-1/PD-L1, or both) were comprehensively curated. Genomic factors, i.e., significantly mutated genes (SMGs), mutational signatures, and molecular subtypes were identified, and their associations with ICI treatment efficacy in male and female patients were evaluated.ResultsOf the 15 SMGs identified in this study, three genes (i.e., CFH, DGKG, and PPP6C) were found to exhibit sex differences with respect to ICI efficacy. Among these, CFH mutations exhibited both response rate and survival benefits in male, but not in female patients. A total of four mutational signatures (i.e., signatures 1, 4, 7, and 11) were extracted. Male patients with signature 4 (also known as smoking-related signature) had an inferior ICI response rate and overall survival. However, this association was not significant in females. An immune subtype based on mutational activities was found to be significantly associated with poor ICI survival in female patients.ConclusionWe uncovered several sex-dependent genomic correlates of response to ICI treatment, such as male-biased CFH mutations and signature 4 and the female-biased immune resistance subtype. The findings derived from this research provide clues for exploring different immunotherapeutic approaches in male and female patients with melanoma.


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