Ando Yukari, Miyadera Hiroko, Bando Hiroko, Hashimoto Sachie, Noguchi Emiko, Hara Hisato
Department of Breast and Endocrine Surgery, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan.
Department of Medical Genetics, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan.
BMC Cancer. 2025 Apr 4;25(1):610. doi: 10.1186/s12885-025-13992-6.
The high occurrence of treatment resistance in patients with hormone receptor-positive (HR +) breast cancer is a global health concern. Thus, effective immunotherapy must be developed. The public neoantigens, estrogen receptor 1 (ESR1) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), shared by HR + and endocrine-resistant breast cancer, could be ideal targets for immunotherapy; however, their presentation by human leukocyte antigen class II (HLA II) and recognition by CD4 + T cells remain largely unknown.
Seven mutations in ESR1 and ten mutations in PIK3CA were subjected to major histocompatibility complex (MHC)-peptide binding analysis and enzyme-linked immunospot (ELISPOT) assays using peripheral blood mononuclear cells (PBMCs) from healthy donors carrying DRB401:03, or DRB401:03 and DPA102:02-DPB105:01 (DP5). DRB4*01:03- or DP5-restricted peptides were inferred from binding measurements and ELISPOT assays. Other DRB1 alleles that can also present these mutant peptides were identified using binding measurements.
Positive IFN-γ responses by CD4 + T cells were detected for most peptides. The peptides that contain ESR1 (E380Q) and PIK3CA (N345K, E542K, E545K/A, E726K, H1047R/L/Y, and G1049R) are presumably restricted by DRB401:03, which is frequently found globally (carrier frequency: 35-63%), or by DRB401:03 and DRB104 alleles. Some PIK3CA (H1047R/L/Y) peptides can also be presented by DRB101:01, DRB109:01, DRB111:01, and DRB115:02. ESR1 (Y537S/N, D538G) peptides are potentially restricted by DP5, a frequently found allele in East Asian populations, and DRB101:01 and DRB1*15:01.
Mutations in ESR1 and PIK3CA were recognized by CD4 + T cells from healthy donors through potential restriction by common HLA II alleles. Further studies are warranted to elucidate the landscape of HLA II presentation and validate the clinical applicability of these mutations for the immunotherapy of patients with endocrine-resistant breast cancer.
激素受体阳性（HR +）乳腺癌患者中治疗耐药的高发生率是一个全球健康问题。因此，必须开发有效的免疫疗法。HR +和内分泌耐药性乳腺癌共有的公共新抗原，雌激素受体1（ESR1）和磷脂酰肌醇-4,5-二磷酸3-激酶催化亚基α（PIK3CA），可能是免疫疗法的理想靶点；然而，它们由人类白细胞抗原II类（HLA II）呈递以及被CD4 + T细胞识别的情况在很大程度上仍不清楚。
对ESR1中的7个突变和PIK3CA中的10个突变进行主要组织相容性复合体（MHC）-肽结合分析，并使用携带DRB401:03或DRB401:03以及DPA102:02-DPB105:01（DP5）的健康供体的外周血单个核细胞（PBMC）进行酶联免疫斑点（ELISPOT）分析。从结合测量和ELISPOT分析中推断出DRB4*01:03或DP5限制性肽。使用结合测量确定也能呈递这些突变肽的其他DRB1等位基因。
检测到大多数肽能引起CD4 + T细胞产生阳性IFN-γ反应。含有ESR1（E 380Q）和PIK3CA（N 345K、E 542K、E 545K/A、E 726K、H 1047R/L/Y和G 1049R）的肽可能受DRB401:03限制，DRB401:03在全球范围内很常见（携带频率：35 - 63%），或者受DRB401:03和DRB104等位基因限制。一些PIK3CA（H 1047R/L/Y）肽也可由DRB101:01、DRB109:01、DRB111:01和DRB115:02呈递。ESR1（Y 537S/N、D 538G）肽可能受DP5限制，DP5是东亚人群中常见的等位基因，也受DRB101:01和DRB115:01限制。
健康供体的CD4 + T细胞通过常见HLA II等位基因的潜在限制识别ESR1和PIK3CA中的突变。有必要进行进一步研究以阐明HLA II呈递的情况，并验证这些突变在内分泌耐药性乳腺癌患者免疫治疗中的临床适用性。
