Immune checkpoint therapy—current perspectives and future directions

Sharma, Padmanee; Goswami, Sangeeta; Raychaudhuri, Deblina; Siddiqui, Bilal A.; Singh, Pratishtha; Nagarajan, Ashwat; Liu, Jielin; Subudhi, Sumit K.; Poon, Candice C.; Gant, Kristal L; Herbrich, Shelley M.; Anandhan, Swetha; Islam, Md. Saiful; Amit, Moran; Anandappa, Gayathri; Allison, James P.

doi:10.1016/j.cell.2023.03.006

Cited by 311 publications

(176 citation statements)

References 181 publications

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“…The reason for this phenomenon may be that pancreatic cancer shows a new high drug resistance to immune checkpoint therapy (possibly adaptive drug resistance) (27). Tumor heterogeneity is one of the keys to drug resistance mechanism (28), although immune checkpoint therapy brings considerable persistence and multi-directional selection opportunities to clinical treatment (29). In addition, immune in ltration also signi cantly affects the development of cancer (30).…”

Section: Discussionmentioning

confidence: 99%

Identification of a Disulfidptosis-related gene associated with the prognosis of pancreatic cancer

Wang

Fan

Zhou

et al. 2023

Preprint

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Background: Pancreatic adenocarcinoma(PAAD) is a digestive solid tumor with a poor prognosis among many common cancers. Now a new way of cell death has been discovered. This mode of death is known as disulfide death and may be associated with tumor progression. However, the role of this gene in PAAD and its relationship to prognosis remains unclear. This study aims to explore the prognostic role of disulfide death-related genes in breast cancer and their effects on immunity and interstitium. Result: In this study, PAAD samples from TCGA, GTEx, and GEO databases were used to investigate the expression of 10 disulfide death-related genes and the predictive potential of patients' prognosis and survival. Univariate Cox regression analysis was used to analyze 10 genes, and it was found that NCKAP1 and RPN1 were highly expressed in pancreatic cancer tissues and correlated with the overall survival of patients. Univariate and multivariate Cox regression analysis showed that NCKAP1 was an independent factor affecting the prognosis of patients. This study combined NCKAP1 with some clinical factors to construct an ideal prognostic model. In addition, in our study, NCKAP1 was found to be closely related to cancer immune response, and significantly correlated T-cell infiltration, chemotherapy drug sensitivity, and sulfur metabolic channels. The difference in the expression level of NCKAP1 in pancreatic cancer cells and normal controls was verified by the GEO cohort, which was consistent with the public database TCGA. Conclusion: NCLAP1 may play a role in inducing disulfdptosis and regulating tumor immunity, and can serve as a potential therapeutic target for PAAD.

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Section: Discussionmentioning

confidence: 99%

Identification of a Disulfidptosis-related gene associated with the prognosis of pancreatic cancer

Wang

Fan

Zhou

et al. 2023

Preprint

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“…Immune checkpoints are expressed by a broad range of immune and non‐immune cell populations, 4,5 and multiple cell types may play a role in the onset of irAEs. Understanding the mechanisms of irAEs may allow for more targeted treatment approaches that do not affect the antitumor immune response.…”

Section: The Molecular Relationship Between Iraes and Antitumor Immun...mentioning

confidence: 99%

“…As T cells are thought to be central to the antitumor responses driven by ICIs 4,9 and are found to predominate the immune cell infiltrate in irAE tissue biopsies across organ systems, 8,10,11,13,16,23,38,54–57 many studies have looked at the relationship of T cells in irAEs and paired tumors. While central and peripheral tolerance mechanisms cause many autoreactive T cells to become anergic or die during T‐cell development, autoreactive T cells are still commonly found in humans 14,44 and are anticipated to play a role in the development of irAEs.…”

Section: The Molecular Relationship Between Iraes and Antitumor Immun...mentioning

confidence: 99%

“…Currently approved ICIs target cytotoxic T‐lymphocyte–associated antigen 4 (CTLA‐4), programmed death 1 (PD‐1)/programmed death ligand 1 (PD‐L1), or lymphocyte activation gene‐3 (LAG‐3). Additionally, there are many more agents in preclinical and clinical development targeting other coinhibitory molecules, including the B and T lymphocyte attenuator (BTLA), T cell immunoglobulin and mucin‐domain containing‐3 (TIM‐3), and T cell immunoglobulin and immunoreceptor‐tyrosine‐based‐inhibitory‐motif domain (TIGIT), among others 4,5 . Depending on the drugs and doses used, 66%–96% of patients will have side effects from ICIs, and 7%–59% of patients will experience severe irAEs, which are also commonly referred to as “high‐grade” irAEs 6,7 .…”

Section: Introductionmentioning

confidence: 99%

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Effects of immune‐related adverse events (irAEs) and their treatment on antitumor immune responses

Blum

Rouhani

Sullivan

2023

Immunological Reviews

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SummaryImmune checkpoint inhibitors (ICIs) are potentially life‐saving cancer therapies that can trigger immune‐related adverse events (irAEs). irAEs can impact any organ and range in their presentation from mild side effects to life‐threatening complications. The relationship between irAEs and antitumor immune responses is nuanced and may depend on the irAE organ, the tumor histology, and the patient. While some irAEs likely represent an immune response against antigens shared between tumor cells and healthy tissues, other irAEs may be entirely unrelated to antitumor immune responses. Clinical observations suggest that low‐grade irAEs have a positive association with responses to ICIs, but the correlation between severe irAEs and clinical benefit is less clear. Currently, severe irAEs are typically treated by interrupting or permanently discontinuing ICI treatment and administering empirically selected systemic immunosuppressive agents. However, these interventions could potentially diminish the antitumor effects of ICIs. Efforts to understand the mechanistic relationship between irAEs and the tumor microenvironment have yielded meaningful insights and nominated therapeutic targets for irAE management that may preserve or even boost ICI efficacy. We explore the clinical and molecular relationship between irAEs and antitumor immunity as well as the role that irAE treatments may play in shaping antitumor immune responses.

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“…In the past ten years, immune checkpoint inhibitors(ICIs), speci cally anti-programmed cell death-1/ligand 1 (PD-1/PD-L1) inhibitors, have revolutionised the treatment of non-small cell lung cancer (NSCLC) and many other types of cancer (Reck et al 2022;Sharma et al 2021). ICIs are monoclonal antibodies that block inhibitory signals of T cell activation to induce tumor cell killing (Sharma et al 2023).…”

Section: Introductionmentioning

confidence: 99%

Risk factors and clinical outcomes of immune checkpoint inhibitor-related pneumonitis in patients with advanced non-small cell lung cancer：A single center experience

Wang¹,

Xiao²,

Liu³

2023

Preprint

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Purpose Immune checkpoint inhibitors (ICIs) can lead to pneumonitis, a potentially fatal complication. Identifying patients at risk of immune checkpoint inhibitor-related pneumonitis (CIP) prior to starting ICIs treatment is essential for managing CIP. We conducted this study with the purpose of determining the prognosis and risk factors for CIP. Methods In this study, 360 patients with non-small cell lung cancer (NSCLC) who underwent anti-programmed cell death-1/-ligand 1 (PD-1/PD-L1) inhibitors for at least one dose from 2019 to 2022 at Hubei Cancer Hospital were included. Risk factors correlated with CIP and mortality were assessed by regression analyses. Kaplan-Meier estimates were applied to examine survival times. Results There were 360 patients enrolled, the incidence of CIP was 8.6% (31/360). Of all CIP, 12 were graded 3 or higher based on the Common Terminology Criteria for Adverse Events (CTCAE 5.0). The median time to CIP onset was 90 (interquartile range [IQR], 37–160) days. A significant association for CIP was found with body mass index (BMI) (p=0.004) and chronic obstructive pulmonary disease (COPD) (p=0.003) on univariate and multivariate logistic regression analyses. In patients who developed CIP and those who did not, the progression free survival and overall survival were not statistically different. Additionally, early-onset CIP had a higher risk of mortality (p=0.039, HR=3.677, 95% CI, 1.071-12.554), after adjusting for sex, age and rechallenge. Conclusion Increased BMI and COPD were strongly associated with CIP. Early-onset CIP significantly increased the risk of mortality.

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Immune checkpoint therapy—current perspectives and future directions

Cited by 311 publications

References 181 publications

Identification of a Disulfidptosis-related gene associated with the prognosis of pancreatic cancer

Identification of a Disulfidptosis-related gene associated with the prognosis of pancreatic cancer

Effects of immune‐related adverse events (irAEs) and their treatment on antitumor immune responses

Risk factors and clinical outcomes of immune checkpoint inhibitor-related pneumonitis in patients with advanced non-small cell lung cancer：A single center experience

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