As well as our funders @NIH_CommonFund @LungAssociation @BWFUND @DorisDukeFdn, and our institutions @IcahnMountSinai @FIMM_UH @SinaiImmunol @IcahnInstitute @broadinstitute

This study would not have been possible without all of our amazing collaborators (@fran_mj88 @MiriamMerad @PaoloBoffett @evotobi @VRoudko @ninajmar @ZeynepHG @tiedesaatio @drsamuelejones), all participants in the UK Biobank and FinnGen.

Overall, our study is just one step towards implicating immunity as a critical component of cancer risk. Hopefully, this will motivate consideration of HLA genetics in the clinic and spur further research into immuno-preventative / diagnostic measures for early cancer detection.

And, although we focused on lung cancer, HLA-II heterozygosity protects against other cancer types too- with strong effects observed in lymphoma.

We found that HLA-II LOH is associated with higher TMB & larger neopeptide repertoire at baseline (LOH pre-loss compared to tumors w/o LOH), suggesting that HLA-II LOH is selected for in lung cancer through preferential loss of HLA-II alleles with larger neopeptide repertoires.

Finally, we performed LOH analyses to show that LOH of HLA-II is just as common as loss of HLA-I- across three independent NSCLC cohorts (TCGA, PCAWG, Hartwig)!

We performed fine-mapping and structural analyses to show that heterozygosity within the HLA-II peptide binding groove is critical for these effects. Further, scRNA-seq analyses showed that smoking upregulated macrophage and epithelial cell HLA-II in the normal and tumor lungs.

The association of HLA-II heterozygosity with reduced risk of lung cancer in smokers was independent of known clinical/demographic variables, lung cancer PRS, individual HLA allele effects, etc.

So we asked- is HLA heterozygosity associated with lung cancer risk? We used population-level HLA/longitudinal data from @uk_biobank & @FinnGen_FI to check- no signal for HLA-I heterozygosity, but HLA-II heterozygosity is associated with reduced risk of lung cancer in smokers!

Similarly, foundational work from @NickyMcGranahan and @CharlesSwanton showing HLA-I LOH in lung cancer + our studies showing that HLA-I heterozygosity predicts immunotherapy success, have emphasized the importance of germline and somatic HLA diversity in cancer outcomes.

Smoking is a major cancer risk factor that profoundly influences the mutational landscape- seminal work by @GeneCollector, and others has shown that the increased HLA-neoantigen burden caused by smoking sensitizes lung cancer to immune checkpoint inhibitors.

We know that cancer risk is driven by inherited genetic variation, DNA replication errors, and environmental factors. But what about the immune system, and Ehrlich, Thomas, and Burnet’s theory of “immunosurveillance”? Does the immune system protect against cancer risk?

Does the immune system protect against cancer? Today our study on HLA immunogenetics and lung cancer risk has been published in @ScienceMagazine led by @chirag_msk @AnniinaTervi @MiriamSaffern @EricWil39327976 @HannaMOllila @diegochowell

Fantastic story with very significant clinical implications if validated across other settings

Very proud of my first graduate student @MiriamSaffern selected as a winner of the @LaskerFDN essay contest @SinaiImmunol

Excited to be part of this fantastic work with Nina Bhardwaj @bengrbm on shared neo-antigens in MSI-H cancers. Fundamental observation with significant implications! @CellCellPress https://t.co/bsUadHgoQb

Great work @kenpitter @danalynnecasey @xrtGenomics @jeremy_setton

37 new datasets in a variety of #immune cell types added to ImmuneRegulation; explore them at https://t.co/DJxZscdTIa @hipcProject @ImmPortDB @ImmuneSpace @IcahnInstitute @SinaiGenetics @SinaiImmunol @KroganLab @kevansf @florian_krammer @SesmaLab @MiriamMerad @VirusesImmunity

Dear scientists. We have collected 2,648 signatures in 36hrs and we can do better- Please continue to sign, RT and distribute widely. The more we sign, the more we will be heard - Thank you all @Vilcek #StopTheVisaBan #ImmigrantScience #ScienceWithoutBorders

just beautiful! A distal enhancer at risk locus 11q13.5 promotes suppression of colitis by T reg cells | Nature