MHC class II genotypes are independent predictors of anti-PD1 immunotherapy response in melanoma.

Journal

Communications medicine

ISSN: 2730-664X

Titre abrégé: Commun Med (Lond)

Pays: England

ID NLM: 9918250414506676

Informations de publication

Date de publication:
30 Sep 2024

Historique:

received: 03 08 2023

accepted: 17 09 2024

medline: 1 10 2024

pubmed: 1 10 2024

entrez: 30 9 2024

Statut: epublish

Résumé

Immune checkpoint blockade is a highly successful anti-cancer immunotherapy. Both CTLA4 and PD1 checkpoint blockers are clinically available for melanoma treatment, with anti-PD1 therapy reaching response rates of 35-40%. These responses, which are mediated via neoantigen presentation by the polymorphic MHC complex, are hard to predict and the tumor mutation burden is currently one of the few available biomarkers. While MHC genotypes are expected to determine therapy responses, association studies have remained largely elusive. We developed an overall MHC genotype binding score (MGBS), indicative of a patient's MHC class I (MHC-I) and class II (MHC-II) neoantigen binding capacity and solely based on the germline MHC-I (MGBS-I) and MHC-II (MGBS-II) genotypes. These scores were then correlated to survival and clinical responses following anti-PD1 immunotherapy in a previously published dataset of 144 melanoma patients. We demonstrate that MGBS scores are TMB-independent predictors of anti-PD1 immunotherapy responses in melanoma. Opposite outcomes were found for both MHC classes, with high MGBS-I and MGBS-II predicting good and bad outcomes, respectively. Interestingly, high MGBS-II is mainly associated with treatment response failure in a subgroup of anti-CTLA4 pretreated patients. Our results suggest that MGBS, calculated solely from the MHC genotype, has clinical potential as a non-invasive and tumor-independent biomarker to guide anti-cancer immunotherapy in melanoma. Many cancer patients are successfully treated with immunotherapy, which boosts the immune system to eliminate cancer cells. While this therapy is successful in around half of skin cancer melanoma patients, it is currently hard to determine in advance which patients respond well. Immune cells react to tumor proteins that are presented at the cancer cell surface by molecules called MHC. These are unique for every patient. We aimed to determine whether the ability of MHC to bind to tumor proteins determines how well therapy works and developed a new way to quantify this interaction. Surprisingly, less ability for tumor proteins to bind to the unconventional class II MHC resulted in better clinical outcome in patients with melanoma. Our results provide new understanding of tumor-immune interaction and the new method may help determine which patients with melanoma will respond to therapy.

Sections du résumé

BACKGROUND BACKGROUND

METHODS METHODS

We developed an overall MHC genotype binding score (MGBS), indicative of a patient's MHC class I (MHC-I) and class II (MHC-II) neoantigen binding capacity and solely based on the germline MHC-I (MGBS-I) and MHC-II (MGBS-II) genotypes. These scores were then correlated to survival and clinical responses following anti-PD1 immunotherapy in a previously published dataset of 144 melanoma patients.

RESULTS RESULTS

We demonstrate that MGBS scores are TMB-independent predictors of anti-PD1 immunotherapy responses in melanoma. Opposite outcomes were found for both MHC classes, with high MGBS-I and MGBS-II predicting good and bad outcomes, respectively. Interestingly, high MGBS-II is mainly associated with treatment response failure in a subgroup of anti-CTLA4 pretreated patients.

CONCLUSIONS CONCLUSIONS

Our results suggest that MGBS, calculated solely from the MHC genotype, has clinical potential as a non-invasive and tumor-independent biomarker to guide anti-cancer immunotherapy in melanoma.

Many cancer patients are successfully treated with immunotherapy, which boosts the immune system to eliminate cancer cells. While this therapy is successful in around half of skin cancer melanoma patients, it is currently hard to determine in advance which patients respond well. Immune cells react to tumor proteins that are presented at the cancer cell surface by molecules called MHC. These are unique for every patient. We aimed to determine whether the ability of MHC to bind to tumor proteins determines how well therapy works and developed a new way to quantify this interaction. Surprisingly, less ability for tumor proteins to bind to the unconventional class II MHC resulted in better clinical outcome in patients with melanoma. Our results provide new understanding of tumor-immune interaction and the new method may help determine which patients with melanoma will respond to therapy.

Autres résumés

Type: plain-language-summary (eng)

Identifiants

DOI: 10.1038/s43856-024-00612-w PMID: 39349759

pubmed: 39349759

doi: 10.1038/s43856-024-00612-w

pii: 10.1038/s43856-024-00612-w

doi:

Types de publication

Journal Article

Langues

eng

Pagination

184

Subventions

Organisme : Bijzonder Onderzoeksfonds (Special Research Fund)

ID : BOF.STG.2019.0073.01

Informations de copyright

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