Cancer immunotherapy: Challenges and limitations

Taefehshokr, Sina; Parhizkar, Aram; Hayati, Shima; Mousapour, Morteza; Mahmoudpour, Ali; Eleid, Liliane; Rahmanpour, Dara; Fattahi, Sahand; Shabani, Hadi; Taefehshokr, Nima

doi:10.1016/j.prp.2021.153723

Cited by 90 publications

(77 citation statements)

References 186 publications

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“…While both scenarios likely contribute to immune tolerance, it is generally believed that hot tumors may respond better to immune checkpoint inhibitors (ICIs) than cold tumors because the former have pre-existing cytotoxic cells potentially capable of recognizing tumor derived neoantigens. [4][5][6][7] For cold tumors, on the other hand, antitumor immunity is likely abrogated at a much earlier step-making this subtype potentially more challenging to treat with ICIs. Suppression of the TIME is driven by multiple mechanisms including increased expression of immune checkpoint molecules like programmed death-ligand 1 (PD-L1) on tumors and their cognate programmed cell death protein-1 (PD-1) receptors on lymphocytes, or decreased generation/presentation of mutationbased or expression-based neoantigens by cancer cells.…”

Section: What This Study Addsmentioning

confidence: 99%

Glutathione peroxidase 2 is a metabolic driver of the tumor immune microenvironment and immune checkpoint inhibitor response

Ahmed

Veeramachaneni

Deng

et al. 2022

J Immunother Cancer

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BackgroundThe existence of immunologically ‘cold tumors’ frequently found across a wide spectrum of tumor types represents a significant challenge for cancer immunotherapy. Cold tumors have poor baseline pan-leukocyte infiltration, including a low prevalence of cytotoxic lymphocytes, and not surprisingly respond unfavorably to immune checkpoint (IC) inhibitors. We hypothesized that cold tumors harbor a mechanism of immune escape upstream and independent of ICs that may be driven by tumor biology rather than differences in mutational neoantigen burden.MethodsUsing a bioinformatic approach to analyze TCGA (The Cancer Genome Atlas) RNA sequencing data we identified genes upregulated in cold versus hot tumors across four different smoking-related cancers, including squamous carcinomas from the oral cavity (OCSCC) and lung (LUSC), and adenocarcinomas of the bladder (BLCA) and lung (LUAD). Biological significance of the gene most robustly associated with a cold tumor phenotype across all four tumor types, glutathione peroxidase 2 (GPX2), was further evaluated using a combination of in silico analyses and functional genomic experiments performed both in vitro and in in vivo with preclinical models of oral cancer.ResultsElevated RNA expression of five metabolic enzymes including GPX2, aldo-keto reductase family 1 members AKR1C1, AKR1C3, and cytochrome monoxygenases (CP4F11 and CYP4F3) co-occurred in cold tumors across all four smoking-related cancers. These genes have all been linked to negative regulation of arachidonic acid metabolism—a well-established inflammatory pathway—and are also known downstream targets of the redox sensitive Nrf2 transcription factor pathway. In OCSCC, LUSC, and LUAD, GPX2 expression was highly correlated with Nrf2 activation signatures, also elevated in cold tumors. In BLCA, however, GPX2 correlated more strongly than Nrf2 signatures with decreased infiltration of multiple leukocyte subtypes. GPX2 inversely correlated with expression of multiple pro- inflammatory cytokines/chemokines and NF-kB activation in cell lines and knockdown of GPX2 led to increased secretion of prostaglandin E2 (PGE2) and interleukin-6. Conversely, GPX2 overexpression led to reduced PGE2 production in a murine OCSCC model (MOC1). GPX2 overexpressing MOC1 tumors had a more suppressive tumor immune microenvironment and responded less favorably to anti-cytotoxic T-lymphocytes-associated protein 4 IC therapy in mice.ConclusionGPX2 overexpression represents a novel potentially targetable effector of immune escape in cold tumors.

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Section: What This Study Addsmentioning

confidence: 99%

Glutathione peroxidase 2 is a metabolic driver of the tumor immune microenvironment and immune checkpoint inhibitor response

Ahmed

Veeramachaneni

Deng

et al. 2022

J Immunother Cancer

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“…25 However, some evidence suggest that the efficacy of ICI are controversial in the treatment of some cancer, such as gastric cancer, where the mechanisms and influence factors of poor efficacy have not been elucidated. 27,28 During H. pylori infection, on the one hand, virulence factors of H. pylori can activate the immune response and cause inflammation of gastric mucosa. 29 On the other hand, they can induce immune tolerance and cause immune escape to maintain the continuous colonization of H. pylori in gastric mucosa.…”

Section: Discussionmentioning

confidence: 99%

Effect ofHelicobacter pylorion immunotherapy is gaining more attention

et al. 2022

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Background Immunotherapy, especially immune checkpoint inhibitors, has been widely used in tumor therapy and have shown ideal clinical efficacy. However, some cancers still do not respond to PD‐1/PD‐L1 blockade therapy effectively. Helicobacter pylori infection might affect the curative effect of immunotherapy while it is rarely reported. We aimed to visualize the research hotspots and trends of H. pylori and immunotherapy using a bibliometric analysis to help understand the future development of basic and clinical research. Methods The relevant publications on H. pylori and immunotherapy were searched on April 20, 2022, in the Web of Science Core Collection Database (WOSCC). The document types were limited to articles and reviews. The VOSviewer 1.6.16 software was used to assess the co‐authorship, co‐occurrence, citation of countries, institutions, authors, journals, and hotspot keywords. The research status and trend change of H. pylori and immunotherapy were analyzed by bibliometric analysis. Results A total of 95 studies authored by 561 researchers were eventually included in this study. The majority of the retrieved studies were 55 (58%) original research articles. China conducted the greatest number of studies, followed by USA and Italy. The related topics included the following three aspects: the relationship between microorganisms and cancer, the relationship between gastric cancer and immunity, and the relationship between H. pylori and immunotherapy, including purified/cloned components of H. pylori acting as efficient adjuvant to boost tumor responses and H. pylori infection which modulate host immune responses and impact on the efficacy of antitumor immunity initiated by immune checkpoint inhibitors. The timing diagram revealed that the current research hotspots focused on effects of microorganisms on immunotherapy. Conclusion The effect of H. pylori on cancer immunotherapy is getting more and more attention in these years. It still remains uncertain, and more studies are needed in the future.

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“…After a long period of development, cancer immunotherapy has revolutionized oncology and provides new treatment options for many refractory tumors. At present, the most common cancer immunotherapy methods are adoptive T-cell therapy and chimeric antigen receptor T-cell immunotherapy (CAR-T) ( 14 ). Findings from previous studies showed that CAR-T has been widely applied in the treatment of multiple tumors, including B-cell acute lymphoblastic leukemia, and has achieved therapeutic effects.…”

Section: Introductionmentioning

confidence: 99%

Knowledge mapping and research hotspots of immunotherapy in renal cell carcinoma: A text-mining study from 2002 to 2021

Liu

Zhao

et al. 2022

Front. Immunol.

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BackgroundRenal cell carcinoma (RCC) is one of the most lethal urological malignancies, and because early-stage RCC is asymptomatic, many patients present metastatic diseases at first diagnosis. With the development of immunotherapy, the treatment of RCC has entered a new stage and has made a series of progress. This study mainly outlines the knowledge map and detects the potential research hotspots by using bibliometric analysis.MethodsPublications concerning RCC immunotherapy from 2002 to 2021 in the Web of Science Core Collection were collected. Visualization and statistical analysis were mainly performed by freeware tools VOSviewer, CiteSpace, R software, and Microsoft Office Excel 2019.ResultsA total of 3,432 papers were collected in this study, and the annual number of papers and citations showed a steady growth trend. The United States is the leading country with the most high-quality publications and is also the country with the most international cooperation. The University of Texas MD Anderson Cancer Center is the most productive organization. The Journal of Clinical Oncology is the highest co-cited journal, and Brian I. Rini is both the most prolific author and the author with the largest centrality. The current research hotspots may be focused on “immune checkpoint inhibitors (ICIs),” “PD-1,” and “mammalian target of rapamycin.”ConclusionImmunotherapy has a bright future in the field of RCC treatment, among which ICIs are one of the most important research hotspots. The main future research directions of ICI-based immunotherapy may focus on combination therapy, ICI monotherapy, and the development of new predictive biomarkers.

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Cancer immunotherapy: Challenges and limitations

Cited by 90 publications

References 186 publications

Glutathione peroxidase 2 is a metabolic driver of the tumor immune microenvironment and immune checkpoint inhibitor response

Glutathione peroxidase 2 is a metabolic driver of the tumor immune microenvironment and immune checkpoint inhibitor response

Effect ofHelicobacter pylorion immunotherapy is gaining more attention

Knowledge mapping and research hotspots of immunotherapy in renal cell carcinoma: A text-mining study from 2002 to 2021

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