Mutational landscape influences immunotherapy outcomes among patients with non-small-cell lung cancer with human leukocyte antigen supertype B44

Cummings, Amy L.; Gukasyan, Jaklin; Lu, Henry Y.; Grogan, Tristan; Sunga, Gemalene; Fares, Charlene M.; Hornstein, Nicholas; Zaretsky, Jesse M.; Carroll, James M.; Bachrach, Benjamin; Akingbemi, W.; Li, Debory; Noor, Zorawar S.; Lisberg, Aaron; Goldman, Jonathan W.; Elashoff, David; Bui, Alex A. T.; Ribas, Antoni; Dubinett, Steven M.; Rossetti, Maura; Garon, Edward B.

doi:10.1038/s43018-020-00140-1

Cited by 29 publications

(22 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We hope that since our predictions were monoallelic, validation may widen the horizons of neoantigenicity to enhance the repertoire of peptide recognition. Allele -based patient strati cation may thus identify individuals with an immune checkpoint blockade (ICB) bene t, as is reported in non-small-cell lung cancer and melanoma 43 . At the other end of the personalization spectrum, patients expressing HLA-I molecules with promiscuous peptide binding capabilities are indicated to display a signi cantly worse prognosis after ICB 44 .…”

Section: Discussionmentioning

confidence: 99%

Identification of cryptic neoepitopes generated by chimeric transcripts in ovarian cancer

Dixit

Wagle

Bapat

2022

Preprint

View full text Add to dashboard Cite

Background: Considerable recent interest lies in the immunogenicity of non-canonical neoantigens generated by alternative ORFs emerging from non-synonymous mutations or nucleotide insertions and deletions, exonization of untranslated regions of the genome, non-coding transcripts, transposable elements, etc. Amongst these ‘cryptic’ epitopes, those derived from chimeric transcripts which harbor sequences derived from more than one gene remain undefined, since the translational potential and immunogenicity of these transcripts is relatively unexplored.Methods: The present study was hence designed to predict and assess the neoepitopes generated by chimeric transcripts in ovarian cancer. Peptides identified in a customized targeted database were assessed for antigenicity. Further docking of peptide – MHC as well as peptide-MHC-TCR complexes provided proof-of-concept of antigenicity.Results: We identified peptides uniquely generated by chimeric transcripts, expressed by reading-frame as well as sense/anti-sense isoforms. Further assessment of the antigenicity of these peptides identified a small number of putative neoepitopes that are likely to be presented to MHC-I in an allele-specific manner, and further recognized by specific TCRs.Conclusions:Such generation of chimeric molecules by relaxed rigidity of canonical transcription and translation may present opportunities in immunotherapy.

show abstract

Section: Discussionmentioning

confidence: 99%

Identification of cryptic neoepitopes generated by chimeric transcripts in ovarian cancer

Dixit

Wagle

Bapat

2022

Preprint

View full text Add to dashboard Cite

show abstract

“…[63][64][65][66] However, we did not observe any associations of AI carrier status with ICPI response. Work by Chowell et al 49 and Cummings et al 152 showed that in melanoma the B44 supertype associates with extended survival after treatment with ICPIs. While none of our AI alleles fall within this supertype, we surprisingly observed that the B44 supertype trended towards an earlier age of diagnosis in our discovery cohort (Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

Autoimmune Alleles at the Major Histocompatibility Locus Modify Melanoma Susceptibility

Talwar

Laub

Pagadala

et al. 2021

Preprint

View full text Add to dashboard Cite

Autoimmunity and cancer represent two different aspects of immune dysfunction. Autoimmunity is characterized by breakdowns in immune self-tolerance, while impaired immune surveillance can allow for tumorigenesis. The class I major histocompatibility complex (MHC-I), which displays derivatives of the cellular peptidome for immune surveillance by CD8+ T cells, serves as a common genetic link between these conditions. As melanoma-specific CD8+ T-cells have been shown to target melanocyte-specific peptide antigens more often than melanoma-specific antigens, we investigated whether vitiligo and psoriasis predisposing MHC-I alleles conferred a melanoma protective effect. In individuals with cutaneous melanoma from both The Cancer Genome Atlas (N = 451) and an independent validation cohort (N = 586), MHC-I autoimmune allele carriers are significantly associated with a later age of melanoma diagnosis. MHC-I autoimmune allele contributions to melanoma risk are not captured by current polygenic risk scores (PRS) and incorporation of autoimmune MHC allele presence can improve relative risk stratification. Mechanisms of autoimmune protection were neither associated with improved melanoma-driver mutation association nor improved gene-level conserved antigen presentation relative to common alleles (population frequency > 1%). However, autoimmune alleles showed a marked affinity relative to common alleles for particular windows of melanocyte conserved antigens suggesting a potential relationship between antigen processing, binding, and cell-surface presentation. Overall, this study presents evidence that MHC-I autoimmune risk alleles modulate melanoma risk currently unaccounted for by current PRS.

show abstract

“…However, the relationship of HLA‐I zygosity and/or mean HED and better ICI efficacy has not been consistently found in more recent analyses for non‐melanoma cohorts [45,49–51]. Importantly, the HLA‐B44 supertype seemed to impart an opposite, negative effect in NSCLC, potentially due to NSCLC's distinct neoantigen landscape (leading to worse presentation on HLA‐B44 ) [52]. Therefore, caution must be applied when extrapolating HLA‐I associations between cancer types.…”

Section: Germline Genetic Featuresmentioning

confidence: 99%

‘Know thyself’ – host factors influencing cancer response to immune checkpoint inhibitors

Gunjur

Manrique-Rincón

Klein

et al. 2022

The Journal of Pathology

View full text Add to dashboard Cite

Immune checkpoint inhibitors (ICIs) have revolutionised oncology and are now standard-of-care for the treatment of a wide variety of solid neoplasms. However, tumour responses remain unpredictable, experienced by only a minority of ICI recipients across malignancy types. Therefore, there is an urgent need for better predictive biomarkers to identify a priori the patients most likely to benefit from these therapies. Despite considerable efforts, only three such biomarkers are FDA-approved for clinical use, and all rely on the availability of tumour tissue for immunohistochemical staining or genomic assays. There is emerging evidence that host factorsfor example, genetic, metabolic, and immune factors, as well as the composition of one's gut microbiotainfluence the response of a patient's cancer to ICIs. Tantalisingly, some of these factors are modifiable, paving the way for co-therapies that may enhance the therapeutic index of these treatments. Herein, we review key host factors that are of potential biomarker value for response to ICI therapy, with a particular focus on the proposed mechanisms for these influences.

show abstract

Mutational landscape influences immunotherapy outcomes among patients with non-small-cell lung cancer with human leukocyte antigen supertype B44

Cited by 29 publications

References 47 publications

Identification of cryptic neoepitopes generated by chimeric transcripts in ovarian cancer

Identification of cryptic neoepitopes generated by chimeric transcripts in ovarian cancer

Autoimmune Alleles at the Major Histocompatibility Locus Modify Melanoma Susceptibility

‘Know thyself’ – host factors influencing cancer response to immune checkpoint inhibitors

Contact Info

Product

Resources

About