Compromised antigen presentation ranks among the top mechanisms that render cancers non-immunogenic (non-responsive to immune-based therapies). Despite harboring the highest tumor mutational burden of all cancers, basal cell carcinomas (BCCs) have low immunogenicity.
Loss of human leukocyte antigens class I (HLA-I) components is particularly prevalent in immune-excluded cancers.
Tumor antigens are captured and displayed by antigen processing and presentation machinery (APM) on the cell surface by HLA-I, making it possible for CD8+ T cells to eliminate cancer cells. However, cancer cells have developed various means to limit APM and evade immune recognition.
Shawn Demehri, MD, Ph.D., a physician-investigator in the Cutaneous Biology Research Center and Krantz Family Center for Cancer Research at Massachusetts General Hospital and an Associate Professor of Dermatology at Harvard Medical School, is the senior author of a study in Cell Reports, titled “Epigenomic Regulation of Stemness Contributes to the Low Immunogenicity of the Most Mutated Human Cancer.”
To determine BCC’s immune state, Demehri’s research team studied a large collection of primary human BCCs compared to squamous cell carcinomas (SCCs), which have proven more responsive to immune-based therapies. They discovered that primary BCCs had an immune-excluded phenotype associated with minimal HLA-I expression by cancer cells, even during their early development.
The researchers also determined that a stem-like quiescent program that persisted from the tumor’s cell of origin suppressed APM genes in BCC cells, and that epigenomic reversal of APM gene suppression enabled BCC immunotherapy.
These findings reveal the cell of origin as the dominant determinant of cancer immunogenicity in BCCs and point to a new approach that could improve treatment.
Keratinocyte carcinoma, including BCCs and cutaneous SCCs, is the most common cancer with a continuous rise in incidence.
SCCs show a 49.3% objective response rate to PD-1 therapy, while metastatic BCC has only a 21% ORR to anti-PD-1 therapy.
Organ transplant recipients on systemic immunosuppressants have over 100 times higher risk of SCCs compared to the general population but only a six to 16 times higher risk of BCC, suggesting that BCC may lack immunogenicity.
Demehri explains, “To determine BCC’s immune state, we studied a large collection of primary human BCCs compared with SCCs. Although T cells were detectable in the stroma surrounding the BCC, significantly fewer CD4+ and CD8+ T cells infiltrated into BCC tumor foci compared with SCCs. A survey of other immune cells found that they were also significantly reduced in BCC compared to SCC.
“Single-cell RNA sequencing on BCC and SCC samples collected with similar cell preparation methods showed much smaller immune cell populations in BCC compared to SCC. These findings indicate that primary BCC has an immune-excluded phenotype, which leads to low immunogenicity of BCC compared with ‘immune infiltrated’ SCC.
“Importantly, early BCC with rare T cells in the stroma showed low HLA-I expression, indicating that low APM levels in BCC originate from an intrinsic mechanism integral to its developmental biology.
“We also found Foxc1 is a critical suppressor of IRF1 and HLA-I in BCC cells, reminiscent of its function in quiescent hair follicle stem cells. Foxc1 downregulates IRF1 and HLA-I expression by epigenomic mechanisms, which can be reversed to enable BCC immunotherapy.”
Clinical implications
“We demonstrate that topical entinostat treatment upregulates antigen presentation in BCC in vivo,” Demehri continues. “As such, combining entinostat with topical and systemic immunotherapy is key to enabling BCC immunotherapy.
“To accomplish this, we combined topical entinostat with an FDA-approved topical immunotherapy, imiquimod. The high efficacy of entinostat plus imiquimod in suppressing BCC development indicates that entinostat-induced APM expression in BCC cancer cells synergizes with immune cell activation by imiquimod to eliminate BCC in vivo.
“Based on our findings, a first-in-human clinical trial is warranted to investigate the efficacy of this combination therapy for BCC treatment in humans.”
More information:
Tomonori Oka et al, Epigenomic regulation of stemness contributes to the low immunogenicity of the most mutated human cancer, Cell Reports (2025). DOI: 10.1016/j.celrep.2025.115561
Citation:
Basal cell carcinoma’s low immunogenicity linked to suppression of antigen presentation from its cell of origin (2025, April 22)
retrieved 22 April 2025
from https://medicalxpress.com/news/2025-04-basal-cell-carcinoma-immunogenicity-linked.html
This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no
part may be reproduced without the written permission. The content is provided for information purposes only.
Compromised antigen presentation ranks among the top mechanisms that render cancers non-immunogenic (non-responsive to immune-based therapies). Despite harboring the highest tumor mutational burden of all cancers, basal cell carcinomas (BCCs) have low immunogenicity. Loss of human leukocyte antigens class I (HLA-I) components is particularly prevalent in immune-excluded cancers. Tumor antigens are captured and displayed by antigen processing and presentation machinery (APM) on the cell surface by HLA-I, making it possible for CD8+ T cells to eliminate cancer cells. However, cancer cells have developed various means to limit APM and evade immune recognition. Shawn Demehri, MD, Ph.D., a physician-investigator in the Cutaneous Biology Research Center and Krantz Family Center for Cancer Research at Massachusetts General Hospital and an Associate Professor of Dermatology at Harvard Medical School, is the senior author of a study in Cell Reports, titled “Epigenomic Regulation of Stemness Contributes to the Low Immunogenicity of the Most Mutated Human Cancer.” To determine BCC’s immune state, Demehri’s research team studied a large collection of primary human BCCs compared to squamous cell carcinomas (SCCs), which have proven more responsive to immune-based therapies. They discovered that primary BCCs had an immune-excluded phenotype associated with minimal HLA-I expression by cancer cells, even during their early development. The researchers also determined that a stem-like quiescent program that persisted from the tumor’s cell of origin suppressed APM genes in BCC cells, and that epigenomic reversal of APM gene suppression enabled BCC immunotherapy. These findings reveal the cell of origin as the dominant determinant of cancer immunogenicity in BCCs and point to a new approach that could improve treatment. Keratinocyte carcinoma, including BCCs and cutaneous SCCs, is the most common cancer with a continuous rise in incidence. SCCs show a 49.3% objective response rate to PD-1 therapy, while metastatic BCC has only a 21% ORR to anti-PD-1 therapy. Organ transplant recipients on systemic immunosuppressants have over 100 times higher risk of SCCs compared to the general population but only a six to 16 times higher risk of BCC, suggesting that BCC may lack immunogenicity. Demehri explains, “To determine BCC’s immune state, we studied a large collection of primary human BCCs compared with SCCs. Although T cells were detectable in the stroma surrounding the BCC, significantly fewer CD4+ and CD8+ T cells infiltrated into BCC tumor foci compared with SCCs. A survey of other immune cells found that they were also significantly reduced in BCC compared to SCC. “Single-cell RNA sequencing on BCC and SCC samples collected with similar cell preparation methods showed much smaller immune cell populations in BCC compared to SCC. These findings indicate that primary BCC has an immune-excluded phenotype, which leads to low immunogenicity of BCC compared with ‘immune infiltrated’ SCC. “Importantly, early BCC with rare T cells in the stroma showed low HLA-I expression, indicating that low APM levels in BCC originate from an intrinsic mechanism integral to its developmental biology. “We also found Foxc1 is a critical suppressor of IRF1 and HLA-I in BCC cells, reminiscent of its function in quiescent hair follicle stem cells. Foxc1 downregulates IRF1 and HLA-I expression by epigenomic mechanisms, which can be reversed to enable BCC immunotherapy.” “We demonstrate that topical entinostat treatment upregulates antigen presentation in BCC in vivo,” Demehri continues. “As such, combining entinostat with topical and systemic immunotherapy is key to enabling BCC immunotherapy. “To accomplish this, we combined topical entinostat with an FDA-approved topical immunotherapy, imiquimod. The high efficacy of entinostat plus imiquimod in suppressing BCC development indicates that entinostat-induced APM expression in BCC cancer cells synergizes with immune cell activation by imiquimod to eliminate BCC in vivo. “Based on our findings, a first-in-human clinical trial is warranted to investigate the efficacy of this combination therapy for BCC treatment in humans.” More information: Citation: This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no
Clinical implications
Tomonori Oka et al, Epigenomic regulation of stemness contributes to the low immunogenicity of the most mutated human cancer, Cell Reports (2025). DOI: 10.1016/j.celrep.2025.115561
Basal cell carcinoma’s low immunogenicity linked to suppression of antigen presentation from its cell of origin (2025, April 22)
retrieved 22 April 2025
from https://medicalxpress.com/news/2025-04-basal-cell-carcinoma-immunogenicity-linked.html
part may be reproduced without the written permission. The content is provided for information purposes only.
