Mutation patterns in genes encoding interferon signaling and antigen presentation: A pan-cancer survey with implications for the use of immune checkpoint inhibitors

2017 ◽  
Vol 56 (8) ◽  
pp. 651-659 ◽  
Author(s):  
Jan Budczies ◽  
Michael Bockmayr ◽  
Frederick Klauschen ◽  
Volker Endris ◽  
Stefan Fröhling ◽  
...  
Keyword(s):  
Antigen Presentation ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Interferon Signaling ◽  
Genes Encoding ◽  
Pan Cancer

scholarly journals Pan-Cancer Analysis Identifies Liver Metastases as Negative Predictive Factor for Immune Checkpoint Inhibitors Treatment Outcome

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiao-Juan Chen ◽  
Aiqun Ren ◽  
Liang Zheng ◽  
En-Dian Zheng ◽  
Tao Jiang
Keyword(s):  
Combination Therapy ◽  
Liver Metastases ◽  
Predictive Factor ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Intrinsic Resistance ◽  
The Impact ◽  
Pan Cancer ◽  
Negative Predictive Factor

This study aimed to investigate the predictive value of liver metastases (LM) in patients with various advanced cancers received immune-checkpoint inhibitors (ICIs). First, clinical and survival data from a published cohort of 1,661 patients who received ICIs therapy were downloaded and analyzed. Second, a retrospective review of 182 patients with advanced non-small-cell lung cancer (NSCLC) who received PD-1/PD-L1 monotherapy was identified. Third, a meta-analysis of published trials was performed to explore the impact of LM on the efficacy of anti-PD-1/PD-L1 based therapy in advanced lung cancers. Pan-cancer analysis revealed that patients with LM had significantly shorter overall survival (OS) than those without LM (10 vs. 20 months; P < 0.0001). Subgroup analysis showed that the presence of LM was associated with markedly shorter OS than those without LM in ICI monotherapy group (P < 0.0001), but it did not reach the statistical significance in ICI-based combination therapy (P = 0.0815). In NSCLC, the presence of LM was associated with significantly inferior treatment outcomes in both pan-cancer and real-world cohort. Interestingly, ICI-based monotherapy and combination therapy could simultaneously prolong progression-free survival (PFS) and OS than chemotherapy in patients without LM. However, ICI-based monotherapy could not prolong PFS than chemotherapy in patients with LM while ICI-based combination therapy could dramatically prolong both PFS and OS. Together, these findings suggested that the presence of LM was the negative predictive factor in cancer patients received ICIs monotherapy, especially in NSCLC. ICI-based combination therapy might overcome the intrinsic resistance of LM to ICIs while the optimal combinatorial strategies remain under further investigation.

scholarly journals Characterization of tumor mutation burden, PD-L1 and DNA repair genes to assess relationship to immune checkpoint inhibitors response in metastatic renal cell carcinoma

2020 ◽  
Vol 8 (1) ◽  
pp. e000319 ◽  
Author(s):  
Matthew Kyle Labriola ◽  
Jason Zhu ◽  
Rajan Gupta ◽  
Shannon McCall ◽  
Jennifer Jackson ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Dna Repair ◽  
Antigen Presentation ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Dna Repair Genes ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Repair Genes

BackgroundImmune checkpoint inhibitors (ICIs) have expanded treatment options for metastatic renal cell carcinoma (mRCC); however, there are limited predictive biomarkers for response to ICIs in this indication, with programmed death-ligand 1 (PD-L1) status demonstrating little predictive utility in mRCC. While predictive of ICI response in other tumor types, the utility of tumor mutation burden (TMB) in mRCC is unclear. Here, we assess TMB, loss of antigen presentation genes and PD-L1 status correlated with outcomes to ICI treatment in mRCC.MethodsTumor samples from 34 patients with mRCC treated with ICI therapy at Duke Cancer Institute were retrospectively evaluated using Personal Genome Diagnostics elio tissue complete (RUO version), a tumor genomic profiling assay for somatic variants, TMB, microsatellite status and genomic status of antigen presentation genes. Tumor samples were also analyzed with the Dako 28-8 PD-L1 immunohistochemistry assay. Deidentified clinical information was extracted from the medical record, and tumor response was evaluated based on the Response Evaluation Criteria In Solid Tumors (RECIST) V.1.1 criteria.ResultsPatients were stratified by overall response following ICI therapy and designated as progressive disease (PD; n=18) or disease control groups (DC; n=16). TMB scores ranged from 0.36 to 12.24 mutations/Mb (mean 2.83 mutations/Mb) with no significant difference between the PD and DC groups (3.01 vs 2.63 mutations/Mb, respectively; p=0.7682). Interestingly, 33% of PD patients displayed loss of heterozygosity of major histocompatibility complex class I genes (LOH-MHC) vs 6% of DC patients. Nine of 34 samples were PD-L1-positive (4 in the PD group; 5 in the DC group), suggesting no correlation between PD-L1 expression and response to ICI therapy. Notably, the DC group displayed an enrichment of mutations in DNA repair genes (p=0.04), with 68.8% exhibiting at least one mutated homologous recombination repair (HRR)-related gene compared with only 38.9% of the PD group (p=0.03).ConclusionsOverall, neither TMB nor PD-L1 correlated with ICI response and TMB was not significantly associated with PD-L1 expression. The higher incidence of LOH-MHC in PD group suggests that loss of antigen presentation may restrict response to ICIs. Separately, enrichment of HRR gene mutations in the DC group suggests potential utility in predicting ICI response and a potential therapeutic target, warranting future studies.

scholarly journals Impact of proton therapy on antitumor immune response

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Céline Mirjolet ◽  
Anaïs Nicol ◽  
Emeric Limagne ◽  
Carole Mura ◽  
Corentin Richard ◽  
...  
Keyword(s):  
Immune Response ◽  
Proton Therapy ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Sequencing Analysis ◽  
Rna Seq ◽  
Interferon Signaling ◽  
Functional Profiling ◽  
Photon Radiotherapy

AbstractRadiotherapy delivered using photons induces an immune response that leads to modulation of the tumor microenvironment. Clinical studies are ongoing to evaluate immune checkpoint inhibitors in association with photon radiotherapy. At present, there is no publication on the radio-induced immune response after proton therapy. Balb/c mice bearing subcutaneous CT26 colon tumors were irradiated by a single fraction of 16.4 Gy using a proton beam extracted from a TR24 cyclotron. RNA sequencing analysis was assessed at 3 days post-treatment. Proton therapy immune response was monitored by flow cytometry using several panels (lymphoid, myeloid cells, lymphoid cytokines) at 7 and 14 days post-irradiation. RNA-Seq functional profiling identified a large number of GO categories linked to “immune response” and “interferon signaling”. Immunomonitoring evaluation showed induced tumor infiltration by immune cells. This is the first study showing the effect of proton therapy on immune response. These interesting results provide a sound basis to assess the efficacy of a combination of proton therapy and immune checkpoint inhibitors.

scholarly journals MDM2/4 amplification predicts poor response to immune checkpoint inhibitors: a pan-cancer analysis

ESMO Open ◽  
2020 ◽  
Vol 5 (1) ◽  
pp. e000614 ◽  
Author(s):  
Wenfeng Fang ◽  
Huaqiang Zhou ◽  
Jiayi Shen ◽  
Jianwen Li ◽  
Yaxiong Zhang ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Poor Response ◽  
Pan Cancer

scholarly journals Impact of proton therapy on antitumor immune response

2021 ◽  
Author(s):  
Céline Mirjolet ◽  
Anaïs Nicol ◽  
Emeric Limange ◽  
Carole Mura ◽  
Corentin Richard ◽  
...  
Keyword(s):  
Immune Response ◽  
Proton Therapy ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Sequencing Analysis ◽  
Rna Seq ◽  
Interferon Signaling ◽  
Functional Profiling ◽  
Photon Radiotherapy

Abstract Radiotherapy delivered using photons induces an immune response that leads to modulation of the tumor microenvironment. Clinical studies are ongoing to evaluate immune checkpoint inhibitors in association with photon radiotherapy. At present, there is no publication on the radio-induced immune response after proton therapy. Balb/c mice bearing subcutaneous CT26 colon tumors were irradiated by a single fraction of 16.4 Gy using a proton beam extracted from a TR24 cyclotron. RNA sequencing analysis was assessed at 3 days post-treatment. Proton therapy immune response was monitored by flow cytometry using several panels (lymphoid, myeloid cells, lymphoid cytokines) at 7 and 14 days post-irradiation. RNA-Seq functional profiling identified a large number of GO categories linked to “immune system” and “interferon signaling”. Immunomonitoring evaluation showed induced tumor infiltration by immune cells. This is the first study showing the effect of proton therapy on immune response. These interesting results provide a sound basis to assess the efficacy of a combination of proton therapy and immune checkpoint inhibitors.

scholarly journals Pan‐cancer analysis identifies TERT alterations as predictive biomarkers for immune checkpoint inhibitors treatment

2020 ◽  
Vol 10 (2) ◽  
Author(s):  
Tao Jiang ◽  
Qingzhu Jia ◽  
Wenfeng Fang ◽  
Shengxiang Ren ◽  
Xiaoxia Chen ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Pan Cancer

Association of KMT2C mutations with favorable outcomes with immune checkpoint inhibitors across multiple tumor types.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2600-2600
Author(s):  
Chunling Liu ◽  
Qianqian Duan ◽  
Qin Zhang
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Multivariable Analysis ◽  
Cox Proportional Hazards ◽  
Multiple Cancer ◽  
Multiple Tumor ◽  
Potential Biomarker ◽  
Chinese Cohort ◽  
Pan Cancer

2600 Background: The KMT2 (lysine methyltransferase) family of histone modifying proteins play important roles in regulating developmental pathways, and mutations in the genes encoding these proteins have been strongly linked to many solid tumor cancers. Recently, there is emerging evidence that KMT2 family genes are involved in sensitivity to immune checkpoint inhibitors (ICIs) by modulating the immune environment. Here we explored the relationship between KMT2C mutation and its efficacy of immunotherapy. Methods: 1661 patients with next-generation sequencing (NGS) and immunotherapy data obtained from MSKCC clinical cohort were used to explore the association with KMT2C mutation and TMB and efficacy of ICIs. TMB was defined as the total number of somatic nonsynonymous mutations in the coding region. NGS data of 6624 pan-cancer patients who also detected MSI and PD-L1 expression from the Chinese clinical dataset were also analyzed relevance of mutation and these immune-related indicators. Results: In total, 9.81% (163/1661) patients in MSKCC cohort harbored KMT2C mutation. In the Chinese cohort, the KMT2C mutation ratio (11.19%, 741/6624) was similar to MSKCC. The TMB level of KMT2C mutation group in both MSKCC cohort and Chinese pan-cancer patient cohort was significantly higher than wild-type group (P < 0.001). A multivariable analysis across the pan-cancer cohort using Cox proportional-hazards regression demonstrated that KMT2C mutation was significantly associated with better OS (hazard ratio, 0.69; 95%CI, 0.52-0.90; P = 0.006), and association remained significant with bladder (P = 0.039), colorectal (P = 0.024), melanoma (P < 0.001) and renal (P < 0.001), adjusting for cancer age, sex, metastases or primary. In addition, in Chinese cohort, KMT2C mutation was associated with higher PD-L1 positive expression (≥1%) (P = 0.01203) and MSI-H (P < 0.001). Conclusions: KMT2C mutation shows impressive association with efficacy of ICIs. Meanwhile, KMT2C-mutant group has a higher TMB, PD-L1 expression and MSI-H. These results indicated that KMT2C mutation may serve as a good potential biomarker of ICI benefit in patients with multiple cancer types.

Sign in / Sign up

Export Citation Format

Share Document