Clinical Significance of <i>TLR1</i> I602S Polymorphism for Patients with Metastatic Colorectal Cancer Treated with FOLFIRI plus Bevacizumab

Okazaki, Satoshi; Loupakis, Fotios; Stintzing, Sebastian; Cao, Shu; Zhang, Wu; Yang, Dongyun; Ning, Yan; Sunakawa, Yu; Stremitzer, Stefan; Matsusaka, Satoshi; Berger, Martin D.; Parekh, Anish; West, Jordan David; Miyamoto, Yuji; Suenaga, Mitsukuni; Schirripa, Marta; Cremolini, Chiara; Falcone, Alfredo; DePaolo, R. William

doi:10.1158/1535-7163.mct-15-0931

Cited by 9 publications

(5 citation statements)

References 29 publications

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“…Here we found that LR1-N248S polymorphism was not only associated with poor survival outcome but might in uence the response to adjuvant chemotherapy. In addition to our nding, Okazaki et al also indicated that TLR1-I602S (rs5743618) could serve as a predictor of clinical response to FOLFIRI plus bevacizumab in patients with mCRC [41]. Moreover, Deng et al showed that TLR1/2 expression had a positive correlation with lung cancer patients' survival [42], suggesting TLR1/2 signaling may in uence the therapeutic response to chemotherapy by modulating antitumor immunity.…”

Section: Discussionsupporting

confidence: 68%

“…OXP can trigger immunogenic cell death (ICD) through the release of high mobility group box 1 (HMGB1) to promote DC maturation via TLR2 or TLR4, and induce antitumor immunity [32,39]. TLR1 forms a heterodimer with TLR2, were suggested to be essential in regulating mucosal immune response within the gut [40] and the polymorphism of TLR1 is associated with the response to FOLFIRI plus bevacizumab in metastatic CRC [41]. Therefore, we assumed that TLR1-N248S polymorphism may attenuate the HMGB1-activated TLR2 signaling for DC maturation by immunogenic chemotherapeutic agent OXP to in uence the therapeutic e cacy.…”

Section: Defective Tlr1 Signaling Attenuated Oxp-elicited Tlr2 Activa...mentioning

confidence: 99%

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TLR1-N248S polymorphism Reduces the Therapeutic Efficacy of Chemotherapy by Attenuating Antitumor Immunity in Locally Advanced Colorectal Cancer

Huang¹,

Chen

Chiang

et al. 2023

Preprint

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Regional lymph nodes metastasis is an important predictor for survival outcome and the indicator for postoperative adjuvant chemotherapy in patients with colorectal cancer (CRC) patient. Even the advance in the adjuvant chemotherapeutic regimen, the 5-year distant metastasis and survival are still unsatisfied. Here, we evaluate the clinical significance of single-nucleotide polymorphisms on TLR1 and TLR2, which are the receptors for HMGB1 that is the hallmark for immunogenic cell death (ICD), in patients with stage II-III colon carcinoma (COAD). We found patients with high cytosolic HMGB1 are associated with survival outcome in stage III COAD patients who received adjuvant chemotherapy. Moreover, patients with TLR1-N248S polymorphism (rs4833095) may influence the therapeutic efficacy of adjuvant chemotherapy, suggesting TLR1-N248S is an independent prognostic factor for locally advanced colon carcinoma patients. Moreover, patient bearing TLR1-N248S polymorphism had high risk of distant metastasis after first-line adjuvant chemotherapeutic regimen with 5 year by multivariate COX analysis [HR=1.694, 95%CI=1.063-2.698, p=0.027]. We found that defective TLR1 impaired TLR1/2 signaling on dendritic cells (DCs) maturation for antitumor immune response under immunogenic chemotherapy oxaliplatin (OXP) treatment. Defective TLR1 on DCs impaired its maturation ability by HMGB1 and reduced the secretion of IFN from T cells to eradicate the residual tumor cells in vitro. Moreover, systemic inhibition of TLR1/2 dramatically reduced the tumor-infiltrating immune cells by OXP treatment, leading to poor therapeutic response to OXP. On the contrary, administration with TLR1/2 agonist synergistically increased the benefit of OXP treatment and triggered high density of tumor-infiltrating immune cells. We also observed that less tumor-infiltrating cytotoxic T lymphocyte was located within tumor microenvironment in patients bearing TLR1-N248S polymorphism. Taken together, these results showed that patients bearing TLR1-N248S polymorphism might reduce the therapeutic response to adjuvant chemotherapy by attenuating antitumor immune response via impairing HMGB1-mediated DC maturation in locally advanced colon carcinoma patients.

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Section: Discussionsupporting

confidence: 68%

Section: Defective Tlr1 Signaling Attenuated Oxp-elicited Tlr2 Activa...mentioning

confidence: 99%

TLR1-N248S polymorphism Reduces the Therapeutic Efficacy of Chemotherapy by Attenuating Antitumor Immunity in Locally Advanced Colorectal Cancer

Huang¹,

Chen

Chiang

et al. 2023

Preprint

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“…In the discovery arm, patients with the TLR-1-rs5743618-TT genotype had shorter PFS and OS compared with GT/TT genotypes (HR:1.50, p = 0.046; HR:1.53, p = 0.025, respectively). In the same group, patients with the TAK1-rs1145727-AA genotype had a shorter OS than patients with GA/GG genotypes (23 vs. 26.8 months, p = 0.008) [47]. The TLR-1-rs5743618 polymorphism is a missense (Ser602Ile) variation in which the presence of the mutant G allele is associated with a decrease in IL-6 and TNF-α levels and therefore with a reduction in TLR-1-mediated immunity [130].…”

Section: Toll-like Receptors (Tlrs)mentioning

confidence: 88%

Pharmacogenetics Role of Genetic Variants in Immune-Related Factors: A Systematic Review Focusing on mCRC

et al. 2022

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Pharmacogenetics plays a key role in personalized cancer treatment. Currently, the clinically available pharmacogenetic markers for metastatic colorectal cancer (mCRC) are in genes related to drug metabolism, such as DPYD for fluoropyrimidines and UGT1A1 for irinotecan. Recently, the impact of host variability in inflammatory and immune-response genes on treatment response has gained considerable attention, opening innovative perspectives for optimizing tailored mCRC therapy. A literature review was performed on the predictive role of immune-related germline genetic biomarkers on pharmacological outcomes in patients with mCRC. Particularly, that for efficacy and toxicity was reported and the potential role for clinical management of patients was discussed. Most of the available data regard therapy effectiveness, while the impact on toxicity remains limited. Several studies focused on the effects of polymorphisms in genes related to antibody-dependent cellular cytotoxicity (FCGR2A, FCGR3A) and yielded promising but inconclusive results on cetuximab efficacy. The remaining published data are sparse and mainly hypothesis-generating but suggest potentially interesting topics for future pharmacogenetic studies, including innovative gene–drug interactions in a clinical context. Besides the tumor immune escape pathway, genetic markers belonging to cytokines/interleukins (IL-8 and its receptors) and angiogenic mediators (IGF1) seem to be the best investigated and hopefully most promising to be translated into clinical practice after validation.

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“…In patients with metastatic colorectal cancer (mCRC), TLR1 rs5743618 SNP was associated with a significant response to FOLFIRI plus bevacizumab chemotherapy. Based on these findings, TLR1 rs5743618 might be a predictive biomarker for the advantage of FOLFIRI plus bevacizumab response in mCRC patients [35]. According to Castano-Rodriguez and colleagues' review, rs5743618 polymorphism has also been associated with decreased risk of gastric cancer among the German population (OR < 1) [36].…”

Section: Tlr Polymorphisms and Their Role In Cancer Developmentmentioning

confidence: 99%

Toll-Like Receptors Gene Polymorphism and Susceptibility to Cancer Development

Semlali¹,

Alnemari²,

Almalki³

et al. 2018

Genetic Diversity and Disease Susceptibility

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Toll-like receptors (TLRs) play an important role in immune-surveillance and responses towards pathogenic and non-pathogenic microorganisms. They act as innate immune sensors against endogenous and exogenous danger signals by recognizing the pattern recognition molecules (DAMPs and PAMPs) and drive an adaptive immune response through their signaling pathways, which leads to NF-κB and IRF3 transactivation and induces different inflammatory cytokine genes. TLRs polymorphisms were investigated in various cancer types studies. However, precious studies have reported that the Polymorphisms on TLR1-TLR10 cluster have been associated with increased risk of prostate cancer. However, it has known that TLRs genetic variation is associated with increased the susceptibility to gastric cancer. A same synthetically meta-analysis also confirmed the association of TLRs with increased the gastrointestinal cancer but with decreased prostate cancer risk. Our previous studies have demonstrated a strong link between TLRs polymorphisms and colon cancer and breast cancer in Saudi Arabia population. Similar studies were analyzed with Korean patients with papillary thyroid cancer and their clinic-pathologic features in age matched controls by using direct sequencing. The general objective of this chapter was to investigate the role of different TLRs (i.e., TLR2, TLR4, and TLR6) polymorphisms and their association with cancer development.

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Clinical Significance of TLR1 I602S Polymorphism for Patients with Metastatic Colorectal Cancer Treated with FOLFIRI plus Bevacizumab

Cited by 9 publications

References 29 publications

TLR1-N248S polymorphism Reduces the Therapeutic Efficacy of Chemotherapy by Attenuating Antitumor Immunity in Locally Advanced Colorectal Cancer

TLR1-N248S polymorphism Reduces the Therapeutic Efficacy of Chemotherapy by Attenuating Antitumor Immunity in Locally Advanced Colorectal Cancer

Pharmacogenetics Role of Genetic Variants in Immune-Related Factors: A Systematic Review Focusing on mCRC

Toll-Like Receptors Gene Polymorphism and Susceptibility to Cancer Development

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