Zie ook in gerelateerde artikelen

20 april 2024: Bron: Nat Commun 15, 2863 (2024)

Specifieke immuungenen van uitgezaaide oogmelanoom voorspellen de resistentie en gevoeligheid voor immuuntherapie met TIL therapie (adoptieve tumor-infiltrerende lymfocyten therapie)  bij een aantal van deze patiënten. Een oogmelanoom wordt gezien als een 'koude tumor' en lijkt daarom niet gevoelig voor immuuntherapie met anti-PD medicijnen - Checkpointremmers. 

"Wij demonstreren dat adoptieve overdracht van deze transcriptomisch geselecteerde TIL tumorimmuniteit kan bevorderen bij patiënten met uitgezaaide uveaal melanoom / oogmelanoom wanneer andere immuuntherapieën daar niet toe in staat zijn," aldus hoofdonderzoeker Udai Kammula, van de University of Pittsburgh's UPMC Hillman Cancer Center and director of the UPMC Hillman Cancer Center's solid tumor cell therapy program.

Voor hun studie analyses vertrouwden de onderzoekers op 10x op Genomics gebaseerde RNA-sequencing om transcriptomische, genomische en immuuncelpatronen te profileren in 100 monsters van uitzaaiingen van uveale melanoom / oogmelanoom van 84 patiënten.

In tegenstelling tot een huidmelanoom, waar immuuntherapie met anti-PD medicijnen - checkpointremmers vaak gunstig is blijkt een oogmelanoom grotendeels resistent gebleven tegen dergelijke behandelingen, in overeenstemming met de opvatting dat dergelijke tumoren immunologisch 'koud' zijn.
Toch suggereerden de multiomische analyses van het team dat T-celinfiltratie voorkomt in een significante subset van oogmelanoomuitzaaiingen, waarbij tumor-reactieve TIL's opduiken in 55 procent van de uitgezaaide tumoren.

"Onze bevindingen stellen vast dat uitgezaaide oogmelanoom geen immunologisch 'koude tumor' is", aldus de onderzoekers, "maar in plaats daarvan herbergde meer dan de helft van de geanalyseerde oogmelanoom uitzaaiingen tumor-reactieve TIL, ondanks dat ze een van de laagste mutaties hadden."

"We ontdekten dat TIL's van uitgezaaide oogmelanoom het potentieel hebben om de tumor aan te vallen, maar iets in de micro-omgeving van de tumor sluit ze af, zodat ze zich in een slapende of rustige toestand bevinden", aldus Kammula in een verklaring. "Door deze cellen te bevrijden van de onderdrukkende omgeving en ze in het laboratorium te laten groeien, kunnen we hun tumorbestrijdende vermogen redden wanneer ze weer in de patiënt worden ingebracht."

Met dat in gedachten kwamen de onderzoekers met een zogenaamde ‘uveal melanoma immunogenomic score’ (UMIS), gebaseerd op de expressie van bijna 2.400 immuun- en ontstekingsgerelateerde genen. Toen de onderzoekers de UMIS-scores vergeleken met het niveau van antitumorreactiviteit van TIL-culturen die zich uitbreidden ten opzichte van de initiële reeks gevallen van gemetastaseerd oogmelanoom, zagen ze verbeterde tumorspecifieke activiteit voor TIL's van de UMIS met hoge scores. Deze bevindingen werden ondersteund door UMIS-profielen voor zes adoptie-TIL-therapie-responders en 13 non-responders.

“Het gebruik van een biopsie om de UMIS van een patiënt te berekenen zou nutteloze therapieën kunnen helpen voorkomen en patiënten onnodig aan invasieve operaties kunnen onderwerpen,” aldus Udai Kammula in een verklaring.

Het studierapport is gratis in te zien en gepubliceerd in Nature. Hier het summiere abstract:

Uveal melanoma immunogenomics predict immunotherapy resistance and susceptibility

Nature Communications volume 15, Article number: 2863 (2024) Cite this article

Abstract

Immune checkpoint inhibition has shown success in treating metastatic cutaneous melanoma but has limited efficacy against metastatic uveal melanoma, a rare variant arising from the immune privileged eye. To better understand this resistance, we comprehensively profile 100 human uveal melanoma metastases using clinicogenomics, transcriptomics, and tumor infiltrating lymphocyte potency assessment. We find that over half of these metastases harbor tumor infiltrating lymphocytes with potent autologous tumor specificity, despite low mutational burden and resistance to prior immunotherapies. However, we observe strikingly low intratumoral T cell receptor clonality within the tumor microenvironment even after prior immunotherapies. To harness these quiescent tumor infiltrating lymphocytes, we develop a transcriptomic biomarker to enable in vivo identification and ex vivo liberation to counter their growth suppression. Finally, we demonstrate that adoptive transfer of these transcriptomically selected tumor infiltrating lymphocytes can promote tumor immunity in patients with metastatic uveal melanoma when other immunotherapies are incapable.

Data availability

Bulk total RNAseq raw sequencing data generated in this study have been deposited in the database of Genotypes and Phenotypes (dbGaP) under accession number phs003330.v1.p1 [https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs003330.v1.p1]. These data are available under restricted access for patient confidentiality reasons and access can be obtained by request via the dbGaP system by following the instructions provided by the website. Approval is determined by the National Cancer Institute Data Access Committee, which can be emailed at ncidac@mail.nih.gov. Access to data is generally granted within a month of successful application and available indefinitely thereafter. Selected raw data are protected and are not publicly available due to data privacy laws but may be shared upon request. Source data are provided with this paper.

Code availability

Software packages were implemented as described in the “Methods” and no custom packages were created.

Acknowledgements

We thank the members of the UPMC clinical trial and research teams for their efforts in this study and the Surgery Branch, NCI, for providing selective tumor samples. We thank Clinigen for providing interleukin-2 for clinical and research studies and thank all the patients who participated in this study. This research was supported by the UPMC Immune Transplant and Therapy Center and in part by the University of Pittsburgh Center for Research Computing, RRID:SCR_022735, through the resources provided. Specifically, this work used the HTC cluster, which is supported by NIH award number S10OD028483. This work utilized the UPMC Hillman Cancer Center Immunologic Monitoring and Cellular Products Laboratory, a shared resource at the University of Pittsburgh supported by the CCSG P30 CA047904. S.L.-M. was supported by a National Institutes of Health National Cancer Institute training grant (T32CA113263).

Author information

Authors and Affiliations

  1. UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA

    Shravan Leonard-Murali, Chetana Bhaskarla, Ghanshyam S. Yadav, Sudeep K. Maurya, Chenna R. Galiveti, Joshua A. Tobin, Rachel J. Kann, Eishan Ashwat, Patrick S. Murphy, Uma R. Chandran, Yen-Michael S. Hsu & Udai S. Kammula

  2. Solid Tumor Cellular Immunotherapy Program, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA

    Shravan Leonard-Murali, Chetana Bhaskarla, Ghanshyam S. Yadav, Sudeep K. Maurya, Chenna R. Galiveti, Joshua A. Tobin, Patrick S. Murphy & Udai S. Kammula

  3. Division of Surgical Oncology, Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA

    Shravan Leonard-Murali, Chetana Bhaskarla, Ghanshyam S. Yadav, Sudeep K. Maurya, Chenna R. Galiveti, Joshua A. Tobin & Udai S. Kammula

  4. Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA, USA

    Shravan Leonard-Murali

  5. Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, PA, USA

    Anish B. Chakka, Vishal Soman, Paul G. Cantalupo & Uma R. Chandran

  6. UPMC Genome Center, University of Pittsburgh, Pittsburgh, PA, USA

    Xinming Zhuo, Gopi Vyas, Dara L. Kozak, Lindsey M. Kelly & Ed Smith

  7. UPMC Immunologic Monitoring and Cellular Products Laboratory, University of Pittsburgh, Pittsburgh, PA, USA

    Yen-Michael S. Hsu

  8. Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    Yen-Michael S. Hsu

Contributions

S.L.-M., C.B., G.Y., S.M., C.G., J.T., E.A. and P.M. carried out the experiments. S.L.-M., R.K. and U.K. analyzed data and prepared visualizations. S.L.-M., P.M., A.C., V.S., P.C. and U.C. designed the RNAseq bioinformatic pipeline. S.L.-M., P.M., E.S., G.V., L.K., D.K. and X.Z. performed next-generation sequencing. U.K. conducted associated TIL ACT clinical trials. Y.-M.H. and U.K. supervised TIL manufacturing associated with TIL ACT clinical trials. S.L.-M. collected clinicogenomic patient and metastasis data. S.L.-M. and U.K. conceived the project, designed the experiments, and wrote the manuscript.

Corresponding author

Correspondence to Udai S. Kammula.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethical approval

We have complied with all relevant ethical regulations in the conduct and reporting of this study.

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oogmelanoom, immuuncelkenmerken, T-cel therapie, adoptieve tumor-infiltrerende lymfocyten - TIL, koude tumoren


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