Late-differentiated effector neoantigen-specific CD8+ T cells are enriched in non-small cell lung carcinoma patients responding to atezolizumab treatment

Fehlings, Michael G.; Nardin, Alessandra; Jhunjhunwala, Suchit; Kowanetz, Marcin; O'Gorman, Bill; Hegde, P.; Li, J.; Sumatoh, Hermi; Lee, B.; Kim, L.; Flynn, Shannon L.; Ballinger, Marcus; Newell, Evan W.; Yadav, M.

doi:10.1016/j.ejca.2019.01.027

Cited by 3 publications

(6 citation statements)

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“…Thanks to the development of molecular biology techniques, including next-generation sequencing, and the participation of bioinformatics, it is possible to use data to predict neoantigens, most often on the basis of their affinity to MHC-I. However, research in recent years has resulted in a much broader approach to the detection of neoantigens in lung cancer (especially NSCLC), taking into account both the stability of binding to MHC-I, as well as the level of gene expression or aggretopicity [ 340 , 341 , 342 , 343 ]. According to the literature, the median number of predicted neoantigens in NSCLC is quite variable.…”

Section: Resultsmentioning

confidence: 99%

The Importance of the Immune System and Molecular Cell Signaling Pathways in the Pathogenesis and Progression of Lung Cancer

Smok-Kalwat

Mertowska

Mertowski

et al. 2023

IJMS

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Lung cancer is a disease that in recent years has become one of the greatest threats to modern society. Every year there are more and more new cases and the percentage of deaths caused by this type of cancer increases. Despite many studies, scientists are still looking for answers regarding the mechanisms of lung cancer development and progression, with particular emphasis on the role of the immune system. The aim of this literature review was to present the importance of disorders of the immune system and the accompanying changes at the level of cell signaling in the pathogenesis of lung cancer. The collected results showed that in the process of immunopathogenesis of almost all subtypes of lung cancer, changes in the tumor microenvironment, deregulation of immune checkpoints and abnormalities in cell signaling pathways are involved, which contribute to the multistage and multifaceted carcinogenesis of this type of cancer. We, therefore, suggest that in future studies, researchers should focus on a detailed analysis of tumor microenvironmental immune checkpoints, and to validate their validity, perform genetic polymorphism analyses in a wide range of patients and healthy individuals to determine the genetic susceptibility to lung cancer development. In addition, further research related to the analysis of the tumor microenvironment; immune system disorders, with a particular emphasis on immunological checkpoints and genetic differences may contribute to the development of new personalized therapies that improve the prognosis of patients.

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Section: Resultsmentioning

confidence: 99%

The Importance of the Immune System and Molecular Cell Signaling Pathways in the Pathogenesis and Progression of Lung Cancer

Smok-Kalwat

Mertowska

Mertowski

et al. 2023

IJMS

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“…Most often, neoantigens have been predicted on the basis of their MHC-I binding affinity. [21][22][23][24] Recently, combining this with other metrics, such as MHC-I binding stability, abundance of gene expression, agretopicity (defined as the ratio of mutant to wildtype peptide-MHC binding affinity), and peptide foreignness, has been found to improve the performance of class I neoantigen prediction in patients with lung cancer. 25 To date, lung cancer neoantigen prediction has focused on NSCLC cohorts.…”

Section: Finding Neoantigens In Lung Cancermentioning

confidence: 99%

“…In the largest cohort to date of 14 patients with advanced NSCLC, tetramer staining and mass cytometry were used to reveal that only 20 of 782 (2.5%) predicted neoantigens induced a detectable CD8þ T-cell response in the blood. 21 Neoantigenspecific CD8þ T cells were infrequent and made up 0.01% to 0.65% of the CD8þ T-cell population. Smaller case series have suggested similar low frequencies.…”

Section: Finding Neoantigens In Lung Cancermentioning

confidence: 99%

“…In a study of 14 patients with advanced NSCLC, there was significant interpatient heterogeneity in the phenotype of circulating neoantigenspecific CD8þ T cells, with varying frequencies of cells expressing activation, costimulatory, or inhibitory markers. 21 Other groups have observed prominent programmed cell death protein-1 (PD-1) expression on neoantigen-reactive CD8þ T cells, 23,24 along with Granzyme B and LAG-3 coexpression. 23 These findings are consistent with those reported in other tumor types [31][32][33] and indicate an activated cytolytic phenotype but also evidence of immunoregulation through the up-regulation of immune checkpoint molecules that can inhibit antitumor immunity.…”

Section: What Does the Anti-neoantigen Immune Response Look Like?mentioning

confidence: 99%

“…24,26,29 Patients with dramatic responses had an up to 44fold increase in the frequency of neoantigen-specific CD8þ T cells as early as 3 to 4 weeks after commencement of ICI and persistence of these T-cell responses months after. 29,30 In a study of 14 patients treated with the anti-PD-L1 antibody, atezolizumab, neoantigen-specific T cells in responders to therapy had a late differentiated effector phenotype indicative of functional cytotoxic populations, whereas neoantigenspecific T cells in nonresponders had a memory-like phenotype, 21 suggesting the phenotype of neoantigenspecific T cells may be an important determinant of response to immunotherapy.…”

Section: Does the Neoantigen Load Or Immune Phenotype Correlate With ...mentioning

confidence: 99%

See 2 more Smart Citations

The Current Lung Cancer Neoantigen Landscape and Implications for Therapy

Creaney

Redwood

et al. 2021

Journal of Thoracic Oncology

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Identification and characterization of neoantigen-reactive CD8+ T cells following checkpoint blockade therapy in a pan-cancer setting

Moss,

Hansen,

de Lima

et al. 2024

Preprint

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Background Immune checkpoint blockade (ICB) has been approved as first-line or second-line therapies for an expanding list of malignancies. T cells recognizing mutation-derived neoantigens are hypothesized to play a major role in tumor elimination. However, the dynamics and characteristics of such neoantigen-reactive T cells (NARTs) in the context of ICB are still limitedly understood. Methods To explore this, tumor biopsies and peripheral blood were obtained pre- and post-treatment from 20 patients with solid metastatic tumors, in a Phase I basket trial. From whole-exome sequencing and RNA-seq data, patient-specific libraries of neopeptides were predicted and screened with DNA barcode-labeled MHC multimers for CD8+ T cell reactivity, in conjunction with the evaluation of T cell phenotype. Results We were able to detect NARTs in the peripheral blood and tumor biopsies for the majority of the patients; however, we did not observe any significant difference between the disease control and progressive disease patient groups, in terms of the breadth and magnitude of the detected NARTs. We also observed that the hydrophobicity of the peptide played a role in defining neopeptides resulting in NARTs response. A trend towards a treatment-induced phenotype signature was observed in the NARTs post-treatment, with the appearance of Ki67+ CD27+ PD-1+ subsets in the PBMCs and CD39+ Ki67+ TCF-1+ subsets in the TILs. Finally, the estimation of T cells from RNAseq was increasing post versus pre-treatment for disease control patients. Conclusion Our data demonstrates the possibility of monitoring the characteristics of NARTs from tumor biopsies and peripheral blood, and that such characteristics could potentially be incorporated with other immune predictors to understand further the complexity governing clinical success for ICB therapy.

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Late-differentiated effector neoantigen-specific CD8+ T cells are enriched in non-small cell lung carcinoma patients responding to atezolizumab treatment

Cited by 3 publications

References 0 publications

The Importance of the Immune System and Molecular Cell Signaling Pathways in the Pathogenesis and Progression of Lung Cancer

The Importance of the Immune System and Molecular Cell Signaling Pathways in the Pathogenesis and Progression of Lung Cancer

The Current Lung Cancer Neoantigen Landscape and Implications for Therapy

Identification and characterization of neoantigen-reactive CD8+ T cells following checkpoint blockade therapy in a pan-cancer setting

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