Mechanisms of drug resistance to immune checkpoint inhibitors in non-small cell lung cancer

Zhou, Kaiyu; Li, Shuo; Zhao, Yi; Cheng, Ke

doi:10.3389/fimmu.2023.1127071

Cited by 23 publications

(14 citation statements)

References 223 publications

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“…Upon CD155 binding to TIGIT, the ITT-like motif is phosphorylated and binds to Grb2, bringing about the recruitment of SH domain-containing inositol-5-phosphatase (SHIP1) and impeding multiple signaling pathways [28]. SHIP1 is a crucial inhibitor of the phosphatidylinositol 3-kinase (PI3K) signaling, as it hydrolyzes PI (3,4,5)P3, thereby inhibiting kinases containing pleckstrin homology (PH) structural domains, such as Akt, Btk, and phospholipase C-γ [34]. Moreover, premature binding of TIGIT to CD155 hinders phosphorylation of Erk and MEK kinases, which are initiators of the MAPK signaling cascade.…”

Section: Direct Inhibitory Effects Of Tigit In T and Nk Cellsmentioning

confidence: 99%

“…For instance, only 20.06% of lung cancer patients are expected to benefit from ICIs, with less than 1.5% of patients experiencing complete responses and around 15% showing partial responses [3]. This is partly due to the complex interplay between cancer cells and the immune system [4][5][6]. For example, some cancer cells can downregulate molecules that promote T-cell activation, leading to resistance to ICIs [7,8].…”

Section: Introductionmentioning

confidence: 99%

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Co-inhibition of TIGIT and PD-1/PD-L1 in Cancer Immunotherapy: Mechanisms and Clinical Trials

et al. 2023

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Over the past decade, immune checkpoint inhibitors (ICIs) have emerged as a revolutionary cancer treatment modality, offering long-lasting responses and survival benefits for a substantial number of cancer patients. However, the response rates to ICIs vary significantly among individuals and cancer types, with a notable proportion of patients exhibiting resistance or showing no response. Therefore, dual ICI combination therapy has been proposed as a potential strategy to address these challenges. One of the targets is TIGIT, an inhibitory receptor associated with T-cell exhaustion. TIGIT has diverse immunosuppressive effects on the cancer immunity cycle, including the inhibition of natural killer cell effector function, suppression of dendritic cell maturation, promotion of macrophage polarization to the M2 phenotype, and differentiation of T cells to regulatory T cells. Furthermore, TIGIT is linked with PD-1 expression, and it can synergize with PD-1/PD-L1 blockade to enhance tumor rejection. Preclinical studies have demonstrated the potential benefits of co-inhibition of TIGIT and PD-1/PD-L1 in enhancing anti-tumor immunity and improving treatment outcomes in several cancer types. Several clinical trials are underway to evaluate the safety and efficacy of TIGIT and PD-1/PD-L1 co-inhibition in various cancer types, and the results are awaited. This review provides an overview of the mechanisms of TIGIT and PD-1/PD-L1 co-inhibition in anti-tumor treatment, summarizes the latest clinical trials investigating this combination therapy, and discusses its prospects. Overall, co-inhibition of TIGIT and PD-1/PD-L1 represents a promising therapeutic approach for cancer treatment that has the potential to improve the outcomes of cancer patients treated with ICIs.

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Section: Direct Inhibitory Effects Of Tigit In T and Nk Cellsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Co-inhibition of TIGIT and PD-1/PD-L1 in Cancer Immunotherapy: Mechanisms and Clinical Trials

et al. 2023

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“…ICI efficacy has been associated with tumor mutational burden (higher is better), tumor microenvironment hematopoietic cellular profile, and even bowel microbiome. Additionally, various resistance mechanisms to ICIs have been documented to evolve over time [ 3 , 4 , 5 ]. Thus, there is a rationale for “educating” the immune system in conjunction with ICI treatment in order to maximize the benefit of anti-tumor immunotherapeutic strategies.…”

Section: Introductionmentioning

confidence: 99%

A Therapeutic Vaccine Targeting Rat BORIS (CTCFL) for the Treatment of Rat Breast Cancer Tumors

Loukinov

Anderson

Mkrtichyan

et al. 2023

IJMS

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Cancer testis antigens are ideal for tumor immunotherapy due to their testis-restricted expression. We previously showed that an immunotherapeutic vaccine targeting the germ cell-specific transcription factor BORIS (CTCFL) was highly effective in treating aggressive breast cancer in the 4T1 mouse model. Here, we further tested the therapeutic efficacy of BORIS in a rat 13762 breast cancer model. We generated a recombinant VEE-VRP (Venezuelan Equine Encephalitis-derived replicon particle) vector-expressing modified rat BORIS lacking a DNA-binding domain (VRP-mBORIS). Rats were inoculated with the 13762 cells, immunized with VRP-mBORIS 48 h later, and then, subsequently, boosted at 10-day intervals. The Kaplan–Meier method was used for survival analysis. Cured rats were re-challenged with the same 13762 cells. We demonstrated that BORIS was expressed in a small population of the 13762 cells, called cancer stem cells. Treatment of rats with VRP-BORIS suppressed tumor growth leading to its complete disappearance in up to 50% of the rats and significantly improved their survival. This improvement was associated with the induction of BORIS-specific cellular immune responses measured by T-helper cell proliferation and INFγ secretion. The re-challenging of cured rats with the same 13762 cells indicated that the immune response prevented tumor growth. Thus, a therapeutic vaccine against rat BORIS showed high efficacy in treating the rat 13762 carcinoma. These data suggest that targeting BORIS can lead to the elimination of mammary tumors and cure animals even though BORIS expression is detected only in cancer stem cells.

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“…These therapies have led to durable benefits in a small subset of NSCLC patients [1][2][3], however, the mechanism for this phenomenon is poorly understood. This has spurred a field of investigation into the immune microenvironment of lung tumours to determine biomarkers predictive of response to ICI therapy [4][5][6].…”

Section: Introductionmentioning

confidence: 99%

From Pixels to Insights: Unveiling Spatial Immune Associations of Immunotherapy Response in Non-Small Cell Lung Cancer using Multiplexed Tissue Imaging

Kulasinghe,

Monkman,

Moradi

et al. 2023

Preprint

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Insights into the spatial localisation of immune cells within tumours are key to understand the intercellular communications that dictate clinical outcomes. We applied a tiered approach to characterise the spatial organization and interactions in NSCLC tissues from thirty-five patients that subsequently received PD-1 axis immunotherapy (ICI therapy). Our analysis indicates that regulatory T cells are enriched in non-responding patients. Proximity interactions between Tregs and both monocytes(p=0.009) and CD8+ T cells(p=0.009) were frequently found in non-responding patients, while macrophages were more frequently located in proximity to antigen presenting HLADR+ tumour cells(p=0.01) within responding patients. Spatial compartmentalization of tissues into cellular neighbourhoods indicates that both macrophages(p=0.003) and effector CD4+ T cells(p=0.01) in mixed tumour neighbourhoods, and CD8+ T cells(p=0.03) in HLADR+ tumour neighbourhoods are positively associated with clinical response to ICI therapy. Evaluation of the inferred regulatory functions between immune cells relative to their tumour proximity by a SpatialScore metric suggests that macrophages may exhibit an immunosuppressive phenotype against both CD4+ and CD8+ T cells, and that this association scores more highly in ICI refractory patients. These spatial patterns are associated with overall survival in addition to ICI response and may indicate features relevant for the functional understanding of the tumour microenvironment.

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Mechanisms of drug resistance to immune checkpoint inhibitors in non-small cell lung cancer

Cited by 23 publications

References 223 publications

Co-inhibition of TIGIT and PD-1/PD-L1 in Cancer Immunotherapy: Mechanisms and Clinical Trials

Co-inhibition of TIGIT and PD-1/PD-L1 in Cancer Immunotherapy: Mechanisms and Clinical Trials

A Therapeutic Vaccine Targeting Rat BORIS (CTCFL) for the Treatment of Rat Breast Cancer Tumors

From Pixels to Insights: Unveiling Spatial Immune Associations of Immunotherapy Response in Non-Small Cell Lung Cancer using Multiplexed Tissue Imaging

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