Changes of tumor microenvironment in non-small cell lung cancer after TKI treatments

Chen, Shanshan; Tang, Jingyi; Liu, Fen; Li, Wei; Yan, Ting; Shangguan, Dangang; Yang, Nong; Liao, Dehua

doi:10.3389/fimmu.2023.1094764

Cited by 15 publications

(9 citation statements)

References 117 publications

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“…Many targeted therapies, including osimertinib, can be cytostatic in vitro but cause tumor regression in vivo (69) . In a complete biological system in vivo , EGFR disruption upregulates pro-inflammatory stress pathways, leading to inflammatory cytokine secretion, immune cell infiltration, and reduction of regulatory T cells, all of which support an anti-tumor response (70) . Likewise, TKIs can show cytostatic activity in vitro at doses that are selective for their target (as seen in osimertinib in H1975 cells at lower doses [Fig.…”

Section: Resultsmentioning

confidence: 99%

CYpHER: Catalytic extracellular targeted protein degradation with high potency and durable effect

Crook,

Sevilla,

Young

et al. 2024

Preprint

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Many disease-causing proteins have multiple pathogenic mechanisms, and conventional inhibitors struggle to reliably disrupt more than one. Targeted protein degradation (TPD) can eliminate the protein, and thus all its functions, by directing a cell’s protein turnover machinery towards it. Two established strategies either engage catalytic E3 ligases or drive uptake towards the endolysosomal pathway. Here we describe CYpHER (CatalYticpH-dependentEndolysosomal delivery withRecycling) technology with potency and durability from a novel catalytic mechanism that shares the specificity and straightforward modular design of endolysosomal uptake. By bestowing pH-dependent release on the target engager and using the rapid-cycling transferrin receptor as the uptake receptor, CYpHER induces endolysosomal target delivery while re-using drug, potentially yielding increased potency and reduced off-target tissue exposure risks. The TfR-based approach allows targeting to tumors that overexpress this receptor and offers the potential for transport to the CNS. CYpHER function was demonstratedin vitrowith EGFR and PD-L1, andin vivowith EGFR in a model of EGFR-driven non-small cell lung cancer.

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Section: Resultsmentioning

confidence: 99%

CYpHER: Catalytic extracellular targeted protein degradation with high potency and durable effect

Crook,

Sevilla,

Young

et al. 2024

Preprint

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“…Some studies have shown that adequate immune infiltration and CD8 + T cell differentiation are also important in suppressing the development of metastasis [ 27 ]. Additionally, it has been reported that tumor tissue-resident memory CD8 + T cells are protective against cancer development by secreting various cytokines and/or triggering tumor cell death to maintain tumor-immune balance [ 11 ]. Although there are various subtypes of CD4 + T cells, these cells have different and even opposing effects that suppress or stimulate tumor development [ 1 , 7 , 11 , 23 ].…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, it has been reported that tumor tissue-resident memory CD8 + T cells are protective against cancer development by secreting various cytokines and/or triggering tumor cell death to maintain tumor-immune balance [ 11 ]. Although there are various subtypes of CD4 + T cells, these cells have different and even opposing effects that suppress or stimulate tumor development [ 1 , 7 , 11 , 23 ]. According to the study by Chen et al, TILs were found to increase after neoadjuvant therapy.…”

Section: Discussionmentioning

confidence: 99%

“…Patients with NSCLC receiving neoadjuvant chemotherapy followed by surgery were found to have higher infiltrating levels of epithelial CD3 + CD4 + T lymphocytes and CD68 + epithelial and stromal tumor-associated macrophages than patients with prior surgery [ 5 ]. It has been reported that neoadjuvant chemotherapy can reshape the tumor immune microenvironment and increase cytotoxic T cells and tissue-resident memory T cell infiltration [ 5 – 11 ].…”

Section: Introductionmentioning

confidence: 99%

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Prognostic significance of T lymphocyte subgroups (CD4 and CD8) in lung cancer patients after neoadjuvant chemotherapy

Elicora,

Yaprak Bayrak,

Vural

et al. 2024

J Cardiothorac Surg

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Objective The basis for current and future lung cancer immunotherapy depends on our knowledge of molecular mechanisms of interactions between tumor and immune system cells. Interactions that occur between different intratumoral populations of the same cells are important. In our study, we aimed to evaluate relationship between the clinical and prognostic features and T lymphocyte subgroups of patients with lung tumors after neoadjuvant treatment. Methods A total of 72 patients were included in our study, including study group, 39 of whom received neoadjuvant chemotherapy. Clinical/radiological/pathological findings of patients and CD4/CD8 staining rates in peritumoral/intratumoral areas were recorded. Results Our study revealed significantly lower intratumoral CD4 + T cell density and lower intratumoral CD4/CD8 ratio in primary tumor after neoadjuvant therapy (respectively, 0.012 and 0.016). Considering tumor types, when control-study groups were compared, inflammation was statistically significant only in adenocarcinoma subtype; intratumoral CD4/CD8 ratio was statistically significant only in squamous-cell carcinoma subtype (respectively, p = 0.0008 and p = 0.0139). When CD4 + T lymphocytes and CD8 + T lymphocytes and CD4/CD8 ratio were compared between control and study groups in low-stage patients according to clinical stages, only intratumoral CD4 + T lymphocyte values and intratumoral CD4/CD8 ratio were significant (respectively, p = 0.0291 ve p = 0.0154). Conclusion All cell types of innate and adaptive intratumoral immunity can affect lung cancer tissues simultaneously, and these interactions have a very complex structure. Understanding the tumor microenvironment and the different roles of associated cancer immune cells may lead to the discovery of new targets for immunological therapies and increased survival times in lung cancer.

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“…Additionally, EGFR-TKIs can increase T cell–mediated tumor death by potentiating MHC class I and II molecule activation in response to interferon γ [ 10 , 11 ]. Although TME changes induced by EGFR-TKI therapy could determine the treatment efficacy [ 12 ], very few studies have focused on such changes in the preclinical models. Herein, we not only report the clinical results of a phase II trial of neoadjuvant/adjuvant erlotinib therapy among patients with stage II/IIIA EGFRm NSCLC but also analyze the TME changes induced by erlotinib.…”

Section: Introductionmentioning

confidence: 99%

Tumor Microenvironment Modulation by Neoadjuvant Erlotinib Therapy and Its Clinical Impact on Operable EGFR-Mutant Non–Small Cell Lung Cancer

Ahn¹,

Park²,

Kim³

et al. 2024

Cancer Res Treat

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Purpose Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors have greatly improved survival in <i>EGFR</i>-mutant (EGFRm) non–small cell lung cancer (NSCLC); however, their effects on the tumor microenvironment (TME) are unknown. We assessed the changes induced by neoadjuvant erlotinib therapy (NE) in the TME of operable EGFRm NSCLC.Materials and Methods This was a single-arm phase II trial for neoadjuvant/adjuvant erlotinib therapy in patients with stage II/IIIA EGFRm NSCLC (<i>EGFR</i> exon 19 deletion or L858R mutations). Patients received up to 2 cycles of NE (150 mg/day) for 4 weeks, followed by surgery and adjuvant erlotinib or vinorelbine plus cisplatin therapy depending on observed NE response. TME changes were assessed based on gene expression analysis and mutation profiling.Results A total of 26 patients were enrolled; the median age was 61, 69% were female, 88% were stage IIIA, and 62% had L858R mutation. Among 25 patients who received NE, the objective response rate was 72% (95% confidence interval [CI], 52.4 to 85.7). The median disease-free and overall survival (OS) were 17.9 (95% CI, 10.5 to 25.4) and 84.7 months (95% CI, 49.7 to 119.8), respectively. Gene set enrichment analysis in resected tissues revealed upregulation of interleukin, complement, cytokine, transforming growth factor β, and hedgehog pathways. Patients with upregulated pathogen defense, interleukins, and T-cell function pathways at baseline exhibited partial response to NE and longer OS. Patients with upregulated cell cycle pathways at baseline exhibited stable/progressive disease after NE and shorter OS.Conclusion NE modulated the TME in EGFRm NSCLC. Upregulation of immune-related pathways was associated with better outcomes.

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Changes of tumor microenvironment in non-small cell lung cancer after TKI treatments

Cited by 15 publications

References 117 publications

CYpHER: Catalytic extracellular targeted protein degradation with high potency and durable effect

CYpHER: Catalytic extracellular targeted protein degradation with high potency and durable effect

Prognostic significance of T lymphocyte subgroups (CD4 and CD8) in lung cancer patients after neoadjuvant chemotherapy

Tumor Microenvironment Modulation by Neoadjuvant Erlotinib Therapy and Its Clinical Impact on Operable EGFR-Mutant Non–Small Cell Lung Cancer

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