key: cord-0077440-zk0jq9p9 authors: Le Naour, Julie; Sztupinszki, Zsofia; Carbonnier, Vincent; Casiraghi, Odile; Marty, Virginie; Galluzzi, Lorenzo; Szallasi, Zoltan; Kroemer, Guido; Vacchelli, Erika title: A loss-of-function polymorphism in ATG16L1 compromises therapeutic outcome in head and neck carcinoma patients date: 2022-04-17 journal: nan DOI: 10.1080/2162402x.2022.2059878 sha: 73c68c1ad27732fc7f2712341793883b5591c6fb doc_id: 77440 cord_uid: zk0jq9p9 The anticancer immune response is shaped by immunogenic cell stress and death pathways. Thus, cancer cells can release danger-associated molecular patterns that act on pattern recognition receptors expressed by dendritic cells and their precursors to elicit an antitumor immune response. Here, we investigated the impact of single nucleotide polymorphisms (SNPs) in genes affecting this cancer-immunity dialogue in the context of head and neck squamous cell carcinoma (HNSCC). We observed that homozygosity for a loss-of-function SNP (rs2241880, leading to the substitution of a threonine residue in position 300 by an alanine) affecting autophagy related 16 like 1 (ATG16L1) is coupled to poor progression-free survival in platinum-treated HNSCC patients. This result was obtained on a cohort of patients enrolled at the Gustave Roussy Cancer Campus and was validated on an independent cohort of The Cancer Genome Atlas (TCGA). Homozygosity in rs2241880 is well known to predispose to Crohn’s disease, and epidemiological associations between Crohn’s disease and HNSCC have been reported at the levels of cancer incidence and prognosis. We speculate that rs2241880 might be partially responsible for this association. Head and neck squamous cell carcinoma (HNSCC) is a frequent cancer derived from the mucosal epithelium of the upper respiratory tract (nasal cavity and paranasal sinuses, larynx) and upper digestive tract (oral cavity and pharynx). [1] [2] [3] [4] [5] [6] [7] HNSCC is determined by well-known risk factors (age, alcohol abuse, tobacco, and human papillomavirus (HPV)) that benefits from early detection, yet is difficult to treat due to the frequent incidence of comorbidities. [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] Surgical removal of the tumor (if operable) is usually followed by adjuvant chemotherapy and/or radiotherapy, and prognosis is determined by localization, size, histological grade, HPV status, presence of local and distant metastases, as well as comorbidities. [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] There is abundant evidence that infiltration of HNSCC by cytotoxic T lymphocytes (CTL) impacts prognosis in a favorable fashion, while immunosuppressive regulatory T cell (Treg) indicates poor prognosis. [33] [34] [35] [36] [37] [38] [39] [40] [41] Moreover, HNSCC often responds to immunotherapy targeting the programmed death protein 1 (PD1)/programmed death-ligand 1 (PD-L1) interaction. [42] [43] [44] [45] [46] [47] [48] [49] [50] [51] [52] In the past, we observed that a set of single-nucleotide polymorphisms (SNPs) affecting a set of genes involved in the immunogenic cell death (ICD) process 1,53-65 dictate the response to adjuvant chemotherapy of breast and colorectal cancer patients. 66, 67 This process involves pattern recognition receptors [68] [69] [70] (such as formyl peptide receptor 1 (FPR1); [71] [72] [73] [74] [75] [76] purinergic receptor P2X, ligand-gated ion channel, 7 (P2RX7) [77] [78] [79] [80] [81] [82] and toll like receptor 4 (TLR4) [83] [84] [85] [86] [87] [88] ) that can be mutated in substantial fraction of the world population (allelic frequency of rs867228 in FPR1: ~20%; rs3751143 in P2RX7: ~19%; rs4986790 in TLR4: ~6%). Moreover, ICD involves autophagy, [89] [90] [91] [92] [93] [94] [95] [96] [97] which can be compromised by a loss-offunction polymorphism (rs2241880, allelic frequency ~50%) in autophagy related 16 like 1 (ATG16L1). 98 This SNP, which predisposes to inflammatory bowel disease (IBD) if present in homozygosity, [99] [100] [101] [102] [103] compromises autophagic flux and related vesicular trafficking processes. [104] [105] [106] [107] [108] Driven by this consideration, we wondered whether such SNPs might impact the therapeutic response of HNSCC patients as well. Here, we show that a loss-of-function polymorphism in the gene coding for ATG16L1 is associated with poor prognosis of HNSCC patients undergoing platinumbased adjuvant chemotherapy. Two-hundred forty-two head and neck squamous cell carcinoma (HNSCC) patients were enrolled in the study. In accordance with national and European legislation, the institutional review board approved the study, and written informed consent was obtained from all the included patients as to the use of their tissue samples for research purposes. A retrospective chart review followed by prospective survival data was conducted on all patients diagnosed between 2004 and 2009 at the Gustave Roussy Cancer Center. Paraffin-embedded tumor blocks (obtained at the time of surgery) were collected. The amount and quality of 193 paraffin blocks were judged adequate for histological evaluation. DNA from tumor specimens was extracted, yielding sufficient material to analyze specimens from 187 patients (180 for rs867228) related to missing information in the clinical database. Tobacco and alcohol consumption were a common feature of all patients enrolled in this study. Tumor localization and human papilloma virus (HPV) status (for nasoand oropharyngeal cancer) were investigated to consider all relevant clinicopathological variables. Distant metastases were observed in only two patients, and this covariate has been discarded in the analysis. This cohort included mostly male patients (83.4% men versus 16.6% women), and tumors were usually located in the pharynx (60. 4%) and larynx (25.1%). Most (80.2%) of the patients were diagnosed with stage IV and 19.8% with stage III disease. All patients received platinum/5-fluorouracil-based induction chemotherapy, followed by platinum-based maintenance chemoradiotherapy. Almost half of the patients received taxane-based therapy (8.3% docetaxel and 42.5% paclitaxel). The Cancer Genome Atlas (TCGA) clinical data was downloaded from Huang et al. 109 Genotyping. Genomic DNA was isolated from paraffinembedded tumors by means of the DNeasy blood and tissue kit (Qiagen, Valencia, CA) or Maxwell 16 FFPE Tissue LEV DNA Purification kit (Promega, Madison, WI, USA). Genespecific primers and genotype-specific probes (Life Technologies, Carisbad, CA, USA) were used to amplify the rs2241880 single nucleotide polymorphism (SNP) affecting autophagy related 16 Like 1 (ATG16L1), rs867228 in the formyl peptide receptor 1 (FPR1) gene, rs3751143 in the purinergic receptor P2X, ligand-gated ion channel, 7 (P2RX7) gene and rs4986790 in the toll like receptor 4 (TLR4) gene. Genotypes were determined by comparing the signals from fluorescent probes (FAM and VIC) and by calculating the natural logarithm of the ratio between FAM and VIC signals (log (FAM/VIC)). Progression-free survival (PFS) and overall survival (OS) determined from the date of diagnosis were used as primary end-points. Cox proportional hazards regression modeling was employed to check the association between survival and SNPs coded by two different models (dominant or recessive). Dominant or recessive models were evaluated independently as long as the proportion of cases in the smallest group was greater than 5% (Gustave Roussy cohort, hereafter called IGR cohort) or if there were more than 10 platinum-treated patients in the subgroup (TCGA platinum-based patients). For the IGR cohort, the most suitable model was selected on the basis of the smallest p value as determined by the likelihood ratio test (LRT). Hazard ratios alongside their 95% confidence intervals are presented for the model including the SNP alone and after accounting for nodal status (pN, N0 versus N1 versus N2 versus N3), tumor stage (pT, T0-1 versus T2 versus T3 versus T4) and tumor location (oral cavity versus larynx versus pharynx). Association with clinicopathological parameters (age at diagnosis, tumor size, nodal status, tumor stage and tumor localization) was estimated using Firth's penalized-likelihood logistic regression (dominant and recessive models) and reported as odds ratio alongside 95% confidence interval and p values. Survival rates were estimated using Kaplan-Meier method. For TCGA, as previously reported 110, 111 clinical data were accessed via the TCGAbiolinks R package. The groups were compared using the twosided Mann-Whitney U test. PFS and OS were used as primary end-points and were determined either for the entire cohort of patients or the subgroups receiving platinum-based chemotherapy. According to the number of patients and events by genotype, PFS and OS for the whole HNSCC TCGA population were plotted over 200 months while PFS and OS for the platinum-based subgroups were plotted over 80 and 100 months, respectively. Driven by previous results from our laboratory, we profiled a cohort of 187 advanced HNSCC patients (Table 1) for SNPs affecting a set of ICD-relevant genes. DNA samples from these patients, treated at the Gustave Roussy Cancer Campus (also known as Institut Gustave Roussy (IGR)) with platinum-based induction chemotherapy followed by platinum-based maintenance chemoradiotherapy, were genotyped at several loci, including ATG16L1 (r2241880), 99,100 FPR1 (rs867228), 66, 110, 67, 110, 112, 113 P2RX7 (rs3751143) [113] [114] [115] [116] [117] and TLR4 (rs4986790). 114, 115, [118] [119] [120] [121] [122] [123] All SNPs were found at frequencies that did not differ from those reported for the general Caucasian population. The effect of each SNP on progression-free survival (PFS) and overall survival (OS) was determined (Table 2) . Firstly, we compared patients that were homozygous for the wild type alleles of FPR1 (Table 3) or P2RX7 (Table 3 ) with those bearing one or two copies of the loss-of-function alleles (GT/TT for FPR1 and AC/CC for P2RX7), and then plotted the Kaplan-Meier survival curves for PFS and OS. Notably, FPR1 (Table 4 , Figures S1A and S1B) P2RX7 (Table 4 , Figures S2A and S2B ) polymorphisms completely failed to influence progression-free or overall survival of HNSCC patients. Additionally, as previously described by Bergmann and colleagues, 124 we noticed a weak but non-significant (p < .0658, HR 2.2, CI [1.03;4.7]) effect, of rs4986790 in TLR4 on PFS but not OS (Tables 3 and 4 , Figures S3A and S3B) . To corroborate these results in an independent cohort of patients, we interrogated The Cancer Genome Atlas (TCGA) database 125 and found that neither FPR1 nor TLR4 nor P2RX7 polymorphisms impacted the investigated endpoints in HNSCC patients (Table 5 , Figures S1C, S1D, S2C, S2D, S3C, and S3D). This held true for P2RX7 and TLR4 also upon the stratification of patients based on their allocation to platinum-based chemotherapy ( 110 suggesting that in this cancer context only homozygosity might impact OS and PFS. Altogether, these data call for further analyses in other cohorts. By analogy to previous results obtained for non-small cell lung carcinoma patients, 114 we hypothesized that the intrinsic characteristics of HNSCC (which near-to-always is chemoresistant and associated with poor prognosis) and/or the type of therapy that is employed to treat this malignancy (which is mainly based on cisplatin, a DNA damaging agent that is weak ICD inducer) may explain why the aforementioned SNPs fail to influence the clinical progression of the HNSCC. [126] [127] [128] [129] [130] One of the ICD-relevant pathways involves the autophagy-dependent lysosomal secretion of adenosine triphosphate (ATP), the ligand of P2RX7. [131] [132] [133] [134] [135] [136] The relevance of the autophagic pathway in the context of the HNSCC has already been described: rs1864183 in ATG10, rs3759601 in ATG2B and rs2241880 in ATG16L1 were found to be associated with an higher susceptibility to develop HNSCC (laryngeal, pharyngeal, and oral carcinoma, respectively) in a Spanish population. 137 Given these premises, we decided to investigate the role of rs2241880 in our cohort of patients, knowing that rs2241880 affects ATG16L1, which encodes a central adaptor required for the formation of the autophagosome. 135, [138] [139] [140] [141] Moreover, rs2241880, which consists in an A > G mutation, leading to the substitution of a threonine residue in position 300 to an alanine (the risk allele), sensitizes ATG16L1 to GGhomoe-3 mediated degradation, culminating in decreased autophagy. 100, 142 Since the most common genotype ATG16L1 AG does not cause a full loss-offunction, 100,142 a recessive genetic model was applied for this gene. Patients with the ATG16L1 GG genotype exhibited significantly reduced PFS, independently of major clinicopathological variables both in IGR and in the TCGA (platinum-based) cohorts. We found an effect of the rs2241880 SNP on PFS (Tables 3 and 4 (Table 5 , Figure 2a and 2b) . Altogether, our results confirm that an impaired autophagic machinery culminates in an unsuccessful ICD, underscoring the likely relevance of this pathway in HNSCC patients receiving platinum-based chemoradiotherapy. It should be noted that rs2241880 has been associated with inflammatory bowel disease, in particular Crohn's disease. [143] [144] [145] [146] [147] Several studies have been performed to evaluate the putative association between IBD and HNSCC Particularly, in a large cohort of IBD patients (more than 7000), rs2241880 has been correlated with an increased risk of developing oral (especially tongue) carcinoma. 149 Similarly, a Dutch study reported that IBD is associated with impaired survival of patients with oral cavity carcinoma and that advanced age at IBD diagnosis can be considered as a risk factor for the development of this malignancy. 150 Additionally, IBD patients are more prone to develop mouth cancer, and the mechanisms of carcinogenesis may be linked to long-lasting inflammation, immunosuppressive treatments and to their HPV status. 151 The role of ATG16L1 loss-of-function alleles has also been reported for other cancers than HNSCC. Indeed, rs2241880 has been described as a risk factor both for developing hepatocellular carcinoma in the context of cirrhosis, 152 breast cancer, 153 and gastric cancer. 154 Moreover, the ATG16L1 AG genotype was found to be associated with an earlier age at diagnosis of melanoma. 155 All these observations underscore the implications of ATG16L1 T300A in several types of cancer and, more specifically, its prognostic value in HNSCC. In summary, it appears that rs2241880 in ATG16L1 has a negative prognostic impact on a segment of patients with HNSCC, in particular those who undergo platinum-based chemotherapy. Although there is no formal evidence for this conjecture, it is tempting to speculate that the well-studied association between IBD and poor-prognosis HNSCC is in part determined by rs2241880, knowing that this SNP is among the major predisposing factors for the development of Crohn's disease. Future studies should investigate this possible mechanistic link. We acknowledge Dr. David P. Enot for his precious help with the statistical analyses of the IGR dataset. We thank Kariman Chaba for her contribution in the preparation of the IGR samples. We acknowledge Dr Stephan Temam for the IGR cohort samples and his supervision during the clinical analyses. The results shown here are partly based upon data generated by the TCGA Research Network: http://cancergenome.nih.gov. GK is supported by the Ligue contre le Cancer (équipe labellisée); Agence National de la Recherche Czech Republic), Onxeo (Paris, France), Ricerchiamo (Brescia, Italy), and Noxopharm (Chatswood, Australia). GK has been holding research contracts with Daiichi Sankyo, Eleor, Kaleido, Lytix Pharma, PharmaMar, Samsara, Sanofi, Sotio, Vascage and Vasculox/Tioma. GK is on the Board of Directors of the Bristol Myers Squibb Foundation France. GK is a scientific co-founder of everImmune, Osasuna Therapeutics, Samsara Therapeutics, Therafast Bio. GK is the inventor of patents covering therapeutic targeting of aging, cancer, cystic fibrosis and metabolic disorders. The other authors declare no conflicts of interest. LG has been holding research contracts with Lytix Biopharma and Phosplatin, and has received consulting/advisory honoraria from Boehringer Ingelheim, AstraZeneca, OmniSEQ, Onxeo, The Longevity Labs, Inzen, Sotio, and the Luke Heller TECPR2 Foundation. The author(s) reported there is no funding associated with the work featured in this article. The IGR data that support the findings of this study are available on reasonable request from the corresponding authors. Patient-specific IGR data are not publicly available due to ethical restrictions. The TCGA data that support the findings of this study are openly available at http://cancergenome.nih.gov. The molecular landscape of head and neck cancer Head and neck cancer The localization and risk factors of squamous cell carcinoma in the oral cavity: a retrospective study of 1501 cases Oral human papilloma virus infection: an overview of clinical-laboratory diagnosis and treatment Target volume selection and delineation (T and N) for primary radiation treatment of oral cavity, oropharyngeal, hypopharyngeal and laryngeal squamous cell carcinoma Diagnostic tumor markers in head and neck squamous cell carcinoma (HNSCC) in the clinical setting Localization-specific LKB1 loss in head and neck squamous cell carcinoma metastasis Cisplatin eligibility issues and alternative regimens in locoregionally advanced head and neck cancer: recommendations for clinical practice Human Papillomavirus-Negative Pharyngeal Cancer The epidemiology and risk factors of head and neck cancer: a focus on human papillomavirus Descriptive epidemiology and risk factors for head and neck cancer Human papillomavirus in non-oropharyngeal head and neck cancers: a systematic literature review Prevalence of human papillomavirus in oropharyngeal cancer: a systematic review Salvage surgery for recurrent squamous cell carcinoma of the head and neck: systematic review and meta-analysis Respiratory and pulmonary complications in head and neck cancer patients: evidence-based review for the COVID-19 era A study on histological grading of oral squamous cell carcinoma and its co-relationship with regional metastasis Non-HPV-related head and neck squamous cell carcinoma in a young patient cohort Head and neck squamous cell carcinoma in the young patient Head and neck squamous cell carcinoma in young patients Prognostic factors in head and neck cancer: histologic grading, DNA ploidy, and nodal status Single nucleotide polymorphism rs6942067 is a risk factor in young and in non-smoking patients with hpv negative head and neck squamous cell carcinoma Chemotherapy and immunotherapy for recurrent and metastatic head and neck cancer: a systematic review Head and neck squamous cell carcinoma HPV-associated head and neck cancer: unique features of epidemiology and clinical management Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial Human papillomavirus infection in head and neck squamous cell carcinomas: transcriptional triggers and changed disease patterns A Review of HPV-Related Head and Neck Cancer Treatment strategy and outcomes in locally advanced head and neck squamous cell carcinoma: a nationwide retrospective cohort study (KCSG HN13-01) Epidemiology of head and neck squamous cell carcinomas: impact on staging and prevention strategies Human papillomavirus as a driver of head and neck cancers A current update on human papillomavirus-associated head and neck cancers Tumor infiltrating lymphocytes and survival in patients with head and neck squamous cell carcinoma Quantification of tumor infiltrating Foxp3+ regulatory T cells enables the identification of high-risk patients for developing synchronous cancers over upper aerodigestive tract Focus on TILs: prognostic significance of tumor infiltrating lymphocytes in head and neck cancers Immunological network in head and neck squamous cell carcinoma-a prognostic tool beyond HPV status The immune infiltration in HNSCC and its clinical value: A comprehensive study based on the TCGA and GEO databases Characterization of tumor-associated T-lymphocyte subsets and immune checkpoint molecules in head and neck squamous cell carcinoma Tumor microenvironment in head and neck squamous cell carcinoma: functions and regulatory mechanisms Intratumoral regulatory T cells upregulate immunosuppressive molecules in head and neck cancer patients Infiltration of FoxP3+ regulatory T cells is a strong and independent prognostic factor in head and neck squamous cell carcinoma Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study Checkpoint immunotherapy in head and neck cancers Pembrolizumab plus cetuximab in patients with recurrent or metastatic head and neck squamous cell carcinoma: an open-label, multi-arm, non-randomised, multicentre, phase 2 trial Nivolumab for recurrent squamous-cell carcinoma of the head and neck Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial Biomarkers for immunotherapy response in head and neck cancer Crosstalk between PD-1/PD-L1 blockade and its combinatorial therapies in tumor immune microenvironment: a focus on HNSCC The society for immunotherapy of cancer consensus statement on immunotherapy for the treatment of squamous cell carcinoma of the head and neck (HNSCC) Immunotherapy for head and neck cancer: recent advances and future directions Impact of PD-L1 expression and human papillomavirus status in anti-PD1/PDL1 immunotherapy for head and neck squamous cell carcinoma-Systematic review and meta-analysis Addition of camrelizumab to docetaxel, cisplatin, and radiation therapy in patients with locally advanced esophageal squamous cell carcinoma: a phase 1b study Linking cellular stress responses to systemic homeostasis The unfolded protein response in immunogenic cell death and cancer immunotherapy Immunogenic cell death in cancer and infectious disease Consensus guidelines for the definition, detection and interpretation of immunogenic cell death Trial watch: chemotherapy-induced immunogenic cell death in immuno-oncology Targeting immunogenic cell death in cancer Immunogenic cell death in cancer therapy: present and emerging inducers Reversible binding of polymyxin B and neomycin to the solid part of faeces Targeted scavenging of extracellular ROS relieves suppressive immunogenic cell death Immunogenic cell death and DAMPs in cancer therapy Cellular cytotoxicity is a form of immunogenic cell death Immunogenic cell death in colon cancer prevention and therapy Radiochemotherapy-induced elevations of plasma HMGB1 levels predict therapeutic responses in cancer patients Impact of Pattern Recognition Receptors on the Prognosis of Breast Cancer Patients Undergoing Adjuvant Chemotherapy Chemotherapy-induced antitumor immunity requires formyl peptide receptor 1 Promising targets based on pattern recognition receptors for cancer immunotherapy Pattern recognition receptors in cancer progression and metastasis Mozer-Lisewska I. Significance and role of pattern recognition receptors in malignancy FPR1 is the plague receptor on host immune cells Polymorphisms of the formylpeptide receptor gene (FPR1) and susceptibility to stomach cancer in 1531 consecutive autopsy cases The role of formyl peptide receptor 1 gene polymorphisms in human colorectal cancer Bidirectional regulation of neutrophil migration by mitogen-activated protein kinases Polymorphism of formyl peptide receptor 1 (FPR1) reduces the therapeutic efficiency and antitumor immunity after neoadjuvant chemoradiotherapy (CCRT) treatment in locally advanced rectal cancer G protein-coupled receptor FPR1 as a pharmacologic target in inflammation and human glioblastoma The P2X7 Receptor in Infection and Inflammation P2RX7 functions as a putative biomarker of gastric cancer and contributes to worse prognosis P2RX7: a receptor with a split personality in inflammation and cancer Association between the rs3751143 polymorphism of P2RX7 gene and chronic lymphocytic leukemia: a meta-analysis Predicted the P2RX7 rs3751143 polymorphism is associated with cancer risk: a meta-analysis and systematic review P2X7 receptor: a critical regulator and potential target for breast cancer The role of toll-like receptor 4 in tumor microenvironment The role of toll-like receptor 4 (TLR4) in cancer progression: a possible therapeutic target? The pathologic role of toll-like receptor 4 in prostate cancer TLR4 is essential for dendritic cell activation and anti-tumor T-cell response enhancement by DAMPs released from chemically stressed cancer cells TLR4 polymorphisms and expression in solid cancers TLR4-Based Immunotherapeutics in Cancer: a Review of the Achievements and Shortcomings An immunosurveillance mechanism controls cancer cell ploidy Cell death and immunity in cancer: from danger signals to mimicry of pathogen defense responses ER stress, autophagy and immunogenic cell death in photodynamic therapy-induced anti-cancer immune responses Immunogenic Cell Death: a Step Ahead of Autophagy in Cancer Therapy Autophagy Inflammation, and Immunity: a Troika Governing Cancer and Its Treatment Anti-tumor immunity influences cancer cell reliance upon ATG7 Redox signaling in the pathogenesis of human disease and the regulatory role of autophagy PT-112 induces immunogenic cell death and synergizes with immune checkpoint blockers in mouse tumor models Autophagy in major human diseases Prognostic correlation of an autophagy-related gene signature in patients with head and neck squamous cell carcinoma The Crohn's disease polymorphism, ATG16L1 T300A, alters the gut microbiota and enhances the local Th1/Th17 response A Crohn's disease variant in Atg16l1 enhances its degradation by caspase 3 ATG16L1: a multifunctional susceptibility factor in Crohn disease Inflammatory bowel disease: between genetics and microbiota The ATG16L1 risk allele associated with Crohn's disease results in a Rac1-dependent defect in dendritic cell migration that is corrected by thiopurines Impaired autophagy of an intracellular pathogen induced by a Crohn's disease associated ATG16L1 variant A non-canonical autophagy-dependentrole of the ATG16L1T300A variant in urothelial vesicular trafficking and uropathogenic Escherichia coli persistence AXL targeting abrogates autophagic flux and induces immunogenic cell death in drug-resistant cancer cells Vesicular trafficking: molecular tools and targets Biology and trafficking of ATG9 and ATG16L1, two proteins that regulate autophagosome formation A TLR3 ligand reestablishes chemotherapeutic responses in the context of FPR1 deficiency A major genetic accelerator of cancer diagnosis: rs867228 in FPR1 Pattern recognition receptor polymorphisms as predictors of oxaliplatin benefit in colorectal cancer Activation of the NLRP3 inflammasome in dendritic cells induces IL-1beta-dependent adaptive immunity against tumors Loss-of-function alleles of P2RX7 and TLR4 fail to affect the response to chemotherapy in non-small cell lung cancer Negative prognostic impact of regulatory T cell infiltration in surgically resected esophageal cancer post-radiochemotherapy Association between P2RX7 gene and Hepatocellular Carcinoma Susceptibility: a case-control study in a chinese han population 1513A>C polymorphism in the P2X7 receptor gene in patients with papillary thyroid cancer: correlation with histological variants and clinical parameters Yet another pattern recognition receptor involved in the chemotherapy-induced anticancer immune response: formyl peptide receptor-1 Immunosurveillance in esophageal carcinoma: the decisive impact of regulatory T cells Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy Immunogenic death of colon cancer cells treated with oxaliplatin Expression and polymorphism of toll-like receptor 4 and effect on NF-kappaB mediated inflammation in colon cancer patients Association of inherited variation in Toll-like receptor genes with malignant melanoma susceptibility and survival Tolllike receptor 4 single-nucleotide polymorphisms Asp299Gly and Thr399Ile in head and neck squamous cell carcinomas Comprehensive molecular portraits of human breast tumours Precision medicine approaches to overcome resistance to therapy in head and neck cancers Mechanisms of resistance in head and neck cancer Cisplatin exposure causes c-Mycdependent resistance to CDK4/6 inhibition in HPV-negative head and neck squamous cell carcinoma Best Practice in Systemic Therapy for Head and Neck Squamous Cell Carcinoma Expression of ras cellular oncogenes during development of Drosophila melanogaster To inhibit or to boost the ATP/P2RX7 pathway to fight cancer-that is the question ATPdependent recruitment, survival and differentiation of dendritic cell precursors in the tumor bed after anticancer chemotherapy Molecular mechanisms of ATP secretion during immunogenic cell death Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice Autophagy in natural and therapy-driven anticancer immunosurveillance Autophagy-dependent ATP release from dying cells via lysosomal exocytosis Analysis of autophagy gene polymorphisms in Spanish patients with head and neck squamous cell carcinoma Regulation mechanisms and signaling pathways of autophagy The autophagosome: origins unknown, biogenesis complex Mechanisms governing autophagosome biogenesis Cargo recognition and trafficking in selective autophagy Stressful genetics in Crohn's disease Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis ATG16L1 T300A polymorphism and Crohn's disease susceptibility: evidence from 13,022 cases and 17,532 controls Classification of genetic profiles of Crohn's disease: a focus on the ATG16L1 gene A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1 The Crohn's disease-associated polymorphism in ATG16L1 (rs2241880) reduces SHIP gene expression and activity in human subjects Investigation of ATG16L1 rs2241880 polymorphism with cancer risk: a meta-analysis Increased risk of oral cancer in patients with inflammatory bowel diseases Risk factors and clinical outcomes of head and neck cancer in inflammatory bowel disease: a nationwide cohort study Mouth cancer in inflammatory bowel diseases The ATG16L1 gene variant rs2241880 (p.T300A) is associated with susceptibility to HCC in patients with cirrhosis Role of ATG16LI (rs2241880) and Interleukin 10 (rs1800872) Polymorphisms in Breast Cancer Among Egyptian Patients ATG16L1 T300A polymorphism is correlated with gastric cancer susceptibility Variants in autophagy-related genes and clinical characteristics in melanoma: a population-based study