Pharmacological inhibition of HPK1 synergizes with PD-L1 blockade to provoke antitumor immunity against tumors with low antigenicity.
Biochem Biophys Res Commun
; 715: 149995, 2024 Jun 30.
Article
en En
| MEDLINE
| ID: mdl-38685185
ABSTRACT
Immune checkpoint inhibitors have significantly transformed the landscape of cancer therapy. Nevertheless, while these inhibitors are highly effective for certain patient groups, many do not benefit due to primary or acquired resistance. Specifically, these treatments often lack sufficient therapeutic efficacy against cancers with low antigenicity. Thus, the development of an effective strategy to overcome cancers with low antigenicity is imperative for advancing next-generation cancer immunotherapy. Here, we show that small molecule inhibitor of hematopoietic progenitor kinase 1 (HPK1) combined with programmed cell death ligand 1 (PD-L1) blockade can enhance T-cell response to tumor with low antigenicity. We found that treatment of OT-1 splenocytes with HPK1 inhibitor enhanced the activation of signaling molecules downstream of T-cell receptor provoked by low-affinity-antigen stimulation. Using an in vivo OT-1 T-cell transfer model, we demonstrated that combining the HPK1 inhibitor with the anti-PD-L1 antibody significantly suppressed the growth of tumors expressing low-affinity altered peptide ligand of chicken ovalbumin, while anti-PD-L1 antibody monotherapy was ineffective. Our findings offer crucial insights into the potential for overcoming tumors with low antigenicity by combining conventional immune checkpoint inhibitors with HPK1 inhibitor.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Proteínas Serina-Treonina Quinasas
/
Antígeno B7-H1
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Ratones Endogámicos C57BL
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Biochem Biophys Res Commun
Año:
2024
Tipo del documento:
Article
Pais de publicación:
Estados Unidos