Targeting LLT1 as a potential immunotherapy option for cancer patients nonresponsive to existing checkpoint therapies in multiple solid tumors

Sep 21, 2026

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High levels of LLT1 expression have been linked to tumor immune escape through interaction with CD161 on NK cells, creating an inhibitory signal that can limit anti-tumor immunity. Using TCGA across 33 cancers and CRI iAtlas in immune-checkpoint nonresponsive cohorts, the study evaluates survival associations, immune infiltration, immune gene signatures, and genomic biomarkers (TMB, MSI, MMR). Immunofluorescence validates LLT1 expression in resistant and sensitive cancer models.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages22

Reading Time55 min

AccessFree to download

Abstract

Background

Methods

Results

Conclusions

Keywords

Background

Mandal etal. BMC Cancer (2024) 24:1365 [https://doi.org/10.1186/s12885-024-13074-z](https://doi.org/10.1186/s12885-024-13074-z) BMC Cancer RESEARCH Open Access Targeting LLT1 as a potential immunotherapy option for cancer patients nonresponsive to existing checkpoint therapies in multiple solid tumors Tirtha Mandal1†, Soorya Gnanasegaran1†, Golding Rodrigues2†, Shalini Kashipathi1, AnuragTiwari1, Ashvini Kumar Dubey1, Sanghamitra Bhattacharjee 1, Yogendra Manjunath 1, Subith Krishna 1, M. S. Madhusudhan2 and Maloy Ghosh1* Abstract Background High levels of LLT1 expression have been found in several cancers, where it interacts with CD161 on NK cells to facilitate tumor immune escape. Targeting LLT1 could potentially relieve this inhibitory signal and enhance anti-tumor responses mediated through NK cells. Using the ‘The Cancer Genome Atlas’ (TCGA) database, we investigated the role of LLT1 in the tumor microenvironment (TME) across various cancers. Identifying such biomarkers could create new therapeutic options for patients in addition to complementing existing immunotherapies. Methods LLT1 expression was evaluated in 33 cancers using TCGA transcriptome data. Univariate Cox regres sion analysis was employed to assess the correlation of LLT1 expression with patient survival. The relationship between LLT1 expression with immune infiltrates, immune gene signatures, and cancer genomic biomarkers (TMB, MSI, and MMR) was also investigated. Immunofluorescence studies were conducted to validate LLT1 expression in tumors. Furthermore, using the CRI iAtlas data, we evaluated LLT1 distribution and its correlation with other immune checkpoint genes in patients non-responsive to existing immune checkpoint therapies across multiple solid cancers. Results High expression of LLT1 was observed in 12 cancers, including BRCA, CHOL, ESCA, GBM, HNSC, KIRC, KIRP, LIHC, LUAD, STAD, SARC, and PCPG. In certain cancers like COAD, KICH, and KIRC, high LLT1 expression was associated with poor prognosis. Further analysis revealed that upregulated LLT1 was associated with an abundance of NK and T cell infiltrates in theTME, as well as exhaustive immune biomarkers, and inversely associated with pro-inflammatory and tumor suppressor signatures. High LLT1 expression is also positively correlated with genomic biomarkers in certain cancers. Immunofluorescence studies confirmed moderate to high LLT1 expression in immune-resistant prostate cancer, glioma, ovarian cancer, and immune-sensitive liver cancer cell lines. An independent assessment of clinical cohorts from CRI iAtlas showed a correlation of upregulated LLT1 with multiple immunosuppressive genes in patients non-responsive to current ICIs. †Tirtha Mandal, Soorya Gnanasegaran and Golding Rodrigues contributed equally to this paper and share first authorship. *Correspondence: Maloy Ghosh [maloy.ghosh@zumutor.com](maloy.ghosh@zumutor.com) Full list of author information is available at the end of the article © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this lic

FAQs

What role does LLT1 play in tumor immune escape?

LLT1 interacts with CD161 on NK cells and facilitates tumor immune escape by promoting an inhibitory signal that reduces anti-tumor activity.

How was LLT1 evaluated across cancers in this study?

LLT1 expression was assessed in 33 cancers using TCGA transcriptome data, followed by survival correlation via univariate Cox regression and analyses relating LLT1 to immune infiltration, gene signatures, and genomic biomarkers.

What evidence supports LLT1 as a potential target for patients nonresponsive to existing therapies?

High LLT1 expression correlated with an immunosuppressive tumor microenvironment and with multiple immunosuppressive genes in nonresponsive patient cohorts from CRI iAtlas, and immunofluorescence validated LLT1 expression in multiple cancer cell lines.

Sep 21, 2026

Uploaded by Eden