Germline genomes have a dominant-heritable contribution to cancer immune evasion and immunotherapy response

Background:Immune evasion is a fundamental hallmark for cancer.At the early stages of tumor development,immune evasion strategies must be implemented by tumors to prevent attacks from the host immune systems.Blocking tumors5 immune evasion will re-activate the host immune systems to eliminate tumors.Immune-checkpoint therapy(ICT)which applies anti-PD-l/PD-Ll or anti-CTLA4 treatment has been a remarkable success in the past few years.However,〜70%of patients cannot gain any clinical benefits from ICT treatment due to the tumorimmunity system's complexity・In the past,germline pathogenic variants have been thought to have only minorheritable contributions to cancer.Results:Emerging evidence has shown that germline genomes play a dominant-heritable contribution to cancer via encoding the host immune system.The functional components of the immune system are encoded by the host genome,thus the germline genome might have a profound impact on cancer immune evasion and immunotherapy response.Indeed,recent studies showed that germline pathogenic variants can influence immune capacity in cancer patients at a population level by(i)shaping tumor somatic mutations,altering methylation patterns and antigen-presentation capacity or(ii)influencing NK cell's function to modulate lymphocyte infiltration in the tumor microenvironment.In addition,the HLA(types A,B or C)genotypes also shape the landscape of tumor somatic mutations.Conclusion:These results highlight the indispensable roles of germline genome in immunity and cancer development and suggest that germline genomics should be integrated into the research field of cancer biology and cancer immunotherapy.

Multi-cohort comprehensive analysis unveiling the clinical value and therapeutic effect of GNAL in glioma

Clinical data indicates that glioma patients have poor treatment outcomes and clinical prognosis.The role of olfactory signaling pathway-related genes(OSPRGs)in glioma has not been fully elucidated.In this study,we aimed to investigate the role and relationship between OSPRGs and glioma.Univariate and multivariate Cox regression analyses were performed to assess the relationship between OSPRGs and the overall survival of glioma based on public cohorts,and the target gene(G Protein Subunit Alpha L,GNAL)was screened.The association of GNAL expression with clinicopathological characteristics,gene mutation landscape,tumor immune microenvironment(TIME),deoxyribonucleic acid(DNA)methylation,and naris-occlusion controlled genes(NOCGs)was performed.Immunohistochemistry was used to evaluate GNAL level in glioma.Further analysis was conducted to evaluate the drug sensitivity,immunotherapy response,and functional enrichment of GNAL.GNAL was an independent prognostic factor,and patients with low GNAL expression have a poor prognosis.Expression of GNAL was closely associated with clinicopathological characteristics,DNA methylation,and several immune-related pathways.Immune infiltration analysis indicated that GNAL levels were negatively correlated with immune scores.GNAL low-expression group showed efficacy with anti-PD-1 therapy.Ten compounds with significantly different half-maximal inhibitory concentration(IC50)values between the GNAL high and low-expression groups were identified.Furthermore,its expression was associated with several immune cells,immune-related genes,and NOCGs.The expression of GNAL is closely associated with clinicopathological characteristics,TIME,and the response to therapeutic interventions,highlighting its potential as a prognostic biomarker for glioma.

Benign lymph node microenvironment is associated with response to immunotherapy

Introduction:Benign lymph nodes have been considered the hubs of immune surveillance in cancer patients.The microenvironment of these lymphoid tissues can be immune suppressed,hence allowing for tumor progression.Understanding the spectrum of benign findings in bystander lymph nodes in immune checkpoint blockade therapy could prove to be key to understanding the mechanism and assessing treatment response.Methods:Benign lymph nodes and spleen were evaluated from patients treated with immunotherapy who subsequently received postmortem examination.We used quantitative immunofluorescence(QIF)to assess tumor infiltrating lymphocytes(TIL)and macrophage marker expression and characterized activation status using a novelmultiplexed QIF assay including CD3,GranzymeB,and Ki67.We performedimmunohistochemistry to correlate results of QIF.Results:Benign lymph nodes from non-responders to immunotherapy showed significantly higher expression of cytotoxic markers and proliferation index(Ki67)in T cells compared to responders.Higher expression of PD-L1 in macrophages was also observed.There was no significant difference in CD3+expression,but higher levels of CD8+T cells as well as CD20+B cells were seen in lymph nodes of non-responders.No significant differences were seen between responder and non-responder splenic tissue.Findings were supported by traditional immunostaining methods.Conclusions:While most studies in biomarkers for immunotherapy focus on tumor microenvironment,we show that benign lymph node microenvironment may predict response to immunotherapy.In responding patients,bystander lymph nodes appear to have been mobilized,resulting in reduced cytotoxic T cells.Conversely,patients whose disease progressed on immunotherapy demonstrate higher levels of macrophages that express increased PD-L1,and activated T cells not recruited to the tumor site.

A Noninvasive Approach to Evaluate Tumor Immune Microenvironment and Predict Outcomes in Hepatocellular Carcinoma

It is widely recognized that tumor immune microenvironment(TIME)plays a crucial role in tumor progression,metastasis,and therapeutic response.Despite several noninvasive strategies have emerged for cancer diagnosis and prognosis,there are still lack of efective radiomic-based model to evaluate TIME status,let alone predict clinical outcome and immune checkpoint inhibitor(ICIs)response for hepatocellular carcinoma(HCC).In this study,we developed a radiomic model to evaluate TIME status within the tumor and predict prognosis and immunotherapy response.A total of 301 patients who underwent magnetic resonance imaging(MRI)examinations were enrolled in our study.The intra-tumoral expression of 17 immune-related molecules were evaluated using co-detection by indexing(CODEX)technology,and we construct Immunoscore(IS)with the least absolute shrinkage and selection operator(LASSO)algorithm and Cox regression method to evaluate TIME.Of 6115 features extracted from MRI,fve core features were fltered out,and the Radiomic Immunoscore(RIS)showed high accuracy in predicting TIME status in testing cohort(area under the curve=0.753).More importantly,RIS model showed the capability of predicting therapeutic response to anti-programmed cell death 1(PD-1)immunotherapy in an independent cohort with advanced HCC patients(area under the curve=0.731).In comparison with previously radiomicbased models,our integrated RIS model exhibits not only higher accuracy in predicting prognosis but also the potential guiding signifcance to HCC immunotherapy.

Co-delivery of nigericin and decitabine using hexahistidine-metal nanocarriers for pyroptosis-induced immunotherapeutics

Pyroptosis provides a new window for relieving the tumor immunosuppressive microenvironment(TIM)and promoting systemic immune responses for tumor treatments.However,gasdermin D(GSDMD),a key protein in the pyroptosis process mediated by caspase-1,is low expressed in the majority of tumor cells and small-molecule inhibitors of DNA methylation suffer from nonspecific or single-function defects.To address these issues,hexahistidine(His6)-metal assembly(HmA)was employed as the drug delivery vector to load nigericin(Nig)and decitabine(DAC)affording a dual-drug delivery system(Nig^(+)DAC)@HmA.The(Nig^(+)DAC)@HmA nanoparticles are efficiently internalized by cells through endocytosis,easily escape from the lysosome,and are highly distributed in the tumor sites.DAC up-regulates the expression of GSDMD which is then cleaved by the nucleotide-binding oligomerization domain-like receptor protein 3(NLRP3)inflammasome and caspase-1 protein activated by Nig.Effective cancer cell pyroptosis is thus achieved and induces a significant systemic antitumor immunity for impressive tumor suppression with negligible side effects in vivo.Our results suggest that such an easy-to-manipulate self-assembled nano-system(Nig^(+)DAC)@HmA provides a new anticancer path by enhancing pyroptosis through reinforced inflammation.