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. 2024 May 14;25(10):5345.
doi: 10.3390/ijms25105345.

Clinical and Immunologic Characteristics of Colorectal Cancer Tumors Expressing LY6G6D

Adrián Sanvicente García  1   2 , Manuel Pedregal  3 , Lucía Paniagua-Herranz  1 , Cristina Díaz-Tejeiro  1 , Cristina Nieto-Jiménez  1 , Pedro Pérez Segura  4 , Gyöngyi Munkácsy  5   6 , Balázs Győrffy  5   6   7   8 , Emiliano Calvo  3   9 , Víctor Moreno  3 , Alberto Ocaña  1   3   4   10
Affiliations

Clinical and Immunologic Characteristics of Colorectal Cancer Tumors Expressing LY6G6D

Adrián Sanvicente García et al. Int J Mol Sci. .

Abstract

The identification of targets that are expressed on the cell membrane is a main goal in cancer research. The Lymphocyte Antigen 6 Family Member G6D (LY6G6D) gene codes for a protein that is mainly present on the surface of colorectal cancer (CRC) cells. Therapeutic strategies against this protein like the development of T cell engagers (TCE) are currently in the early clinical stage. In the present work, we interrogated public genomic datasets including TCGA to evaluate the genomic and immunologic cell profile present in tumors with high expression of LY6G6D. We used data from TCGA, among others, and the Tumor Immune Estimation Resource (TIMER2.0) platform for immune cell estimations and Spearman correlation tests. LY6G6D expression was exclusively present in CRC, particularly in the microsatellite stable (MSS) subtype, and was associated with left-side tumors and the canonical genomic subgroup. Tumors with mutations of APC and p53 expressed elevated levels of LY6G6D. This protein was expressed in tumors with an inert immune microenvironment with an absence of immune cells and co-inhibitory molecules. In conclusion, we described clinical, genomic and immune-pathologic characteristics that can be used to optimize the clinical development of agents against this target. Future studies should be performed to confirm these findings and potentially explore the suggested clinical development options.

Keywords: CRC; LY6G6D; TCEs; immune association.

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Conflict of interest statement

Alberto Ocaña declares current consulting fees from NMS, and previously from real-world clinical trials, viewpoint, Daichii, Entrechem, CancerAppy, Servier and Symphogen. Former employee of Symphogen. Founder and president of the not-for-profit cancer research foundation ACEPAIN. Victor Moreno declares consulting fees from Roche, Bayer, BMS, Janssen, Syneos, Affimed and AstraZeneca. Principal Investigator—Institutional Funding: AbbVie, AceaBio, Adaptimmune, ADC Therapeutics, Aduro, Agenus, Amcure, Amgen, Astellas, AstraZeneca Bayer Beigene BioInvent International AB, BMS, Boehringer, Boheringer, Boston, Celgene, Daichii Sankyo, DEBIOPHARM, Eisai, e-Terapeutics, Exelisis, Forma Therapeutics, Genmab, GSK, Harpoon, Hutchison, Immutep, Incyte, Inovio, Iovance, Janssen, Kyowa Kirin, Lilly, Loxo, MedSir, Menarini, Merck, Merus, Millennium, MSD, Nanobiotix, Nektar, Novartis, Odonate Therapeutics, Pfizer, PharmaMar, Principia, PsiOxus, Puma, Regeneron, Rigontec, Roche, Sanofi, Sierra Oncology, Synthon, Taiho, Takeda, Tesaro, Transgene, Turning Point Therapeutics, Upshersmith. Emiliano Calvo declares advisory board participation (financial interest) for Adcendo, Alkermes, Amunix, Anaveon, Amcure, AstraZeneca, BMS, Janssen, MonTa, MSD, Nanobiotix, Nouscom, Novartis, OncoDNA, PharmaMar, Roche/Genentech, Sanofi, Servier, SyneosHealth, TargImmune, and T-knife; research grants for Achilles and BeiGene; steering committee (financial interest) and IDMC participation for BeiGene (IDMC steering committee), EORTC IDMC chair (non-financial interest), MedSIR (steering committee), and Novartis (steering committee); honoraria for scientific board participation for Adcendo, Chugai Pharmaceuticals, and PsiOxus Therapeutics; employment at HM Hospitals Group and START Program of Early Phase Clinical Drug Development in Oncology, START corporation, Oncoart Associated, and International Cancer Consultants and is the founder and president of the not-for-profit Investigational Therapeutics in Oncological Sciences (INTHEOS) Foundation. There are no conflicts of interest to declare in relation to this manuscript. The rest of the authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
LY6G6D expression profile across several tumor tissues and their paired normal samples. (A) LY6G6D expression (Transcript per million—TPM) in different cancer types using GEPIA2 data. (B) Fold Change (FC) of the expression of LY6G6D in Normal vs. Tumoral tissue based on GEPIA2 data. (C) Correlation between LY6G6D expression (TPM) and patient’s age. UALCAN data. Statistically significant differences between normal and tumoral tissue are marked by an * (* for p < 0.05, *** for p < 0.001). (D) LY6G6D expression (log2 mRNA) differentiation between patient’s biological gender (F or M). Data obtained from CANCERTOOL. No statistical difference was found.
Figure 2
Figure 2
LY6G6D expression analysis in different scenarios. (A) LY6G6D expression based on the location of the tumor in the colon (Proximal vs. Distal). (B) LY6G6D expression in Rectum, Left colon or Right colon. (C) LY6G6D expression depending on microsatellite instability (MSI vs. MSS). (D) LY6G6D expression based on molecular subtypes of CRC (Canonical, Metabolic or Mesenchymal). Statistically significant differences are marked as: *** for p < 0.01 and **** for p < 0.001.
Figure 3
Figure 3
Mutational profile of CRC. (A) More frequent mutations in CRC represented as a bar graph. Data obtained from CBioportal (TCGA, Firehose Legacy). (B) Correlation between LY6G6D expression and these mutations in CRC. Conditions that are painted in the heatmap, in red for positive correlation and in blue for negative correlation, are statistically significant (p-value < 0.05).
Figure 4
Figure 4
LY6G6D expression level in association with immune populations in CRC. (A) Correlation analysis between LY6G6D levels and some relevant immune populations using TIMER2.0. Spearman’s correlation was used with purity adjustment. Conditions that are painted in the heatmap, in red for positive correlation and in blue for negative correlation, are statistically significant (p-value < 0.05). (B) Dot plot detail of the association displayed in (A). LY6G6D expression is represented in the y-axis as log2 (TPM) while infiltration level is in the x-axis.
Figure 5
Figure 5
Analysis of the expression of T cell activating genes (TCD8+ signature) in relation to LY6G6D expression or described mutations. (A) Heatmap representing the correlation between LY6G6D levels and the expression of the genes in the TCD8+ signature. (B) Heatmap showing the correlation between APC mutation and the expression of the cited genes of the TCD8+ signature. Conditions that are painted in the heatmap, in red for positive correlation and in blue for negative correlation, are statistically significant (p-value < 0.05) (C) Dot plot detail of the association studied in (A). LY6G6D expression is represented in the y-axis as log2 (TPM) while the expression level of the other gene is set in the x-axis (log2 (TPM)).
Figure 6
Figure 6
Association of LY6G6D expression levels with co-stimulatory immune checkpoints. (A) Heatmap showing the correlation between LY6G6D expression and the expression of selected immunomodulatory genes. Conditions that are painted in the heatmap, in red for positive correlation and in blue for negative correlation, are statistically significant (p-value < 0.05). (B) Dot plot detail of the association studied in (A). LY6G6D expression is represented in the y-axis as log2 (TPM) while the expression level of the co-stimulatory gene is set in the x-axis (log2 (TPM)).
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References

    1. Ocaña A., García-Alonso S., Amir E., Pandiella A. Refining Early Antitumoral Drug Development. Trends Pharmacol. Sci. 2018;39:922–925. doi: 10.1016/J.TIPS.2018.09.003. - DOI - PubMed
    1. Kaplon H., Crescioli S., Chenoweth A., Visweswaraiah J., Reichert J.M. Antibodies to watch in 2023. mAbs. 2023;15:2153410. doi: 10.1080/19420862.2022.2153410. - DOI - PMC - PubMed
    1. García-Alonso S., Ocaña A., Pandiella A. Trastuzumab Emtansine: Mechanisms of Action and Resistance, Clinical Progress, and Beyond. Trends Cancer. 2020;6:130–146. doi: 10.1016/J.TRECAN.2019.12.010. - DOI - PubMed
    1. Ball K., Dovedi S.J., Vajjah P., Phipps A. Strategies for clinical dose optimization of T cell-engaging therapies in oncology. mAbs. 2023;15:2181016. doi: 10.1080/19420862.2023.2181016. - DOI - PMC - PubMed
    1. Esapa B., Jiang J., Cheung A., Chenoweth A., Thurston D.E., Karagiannis S.N. Target Antigen Attributes and Their Contributions to Clinically Approved Antibody-Drug Conjugates (ADCs) in Haematopoietic and Solid Cancers. Cancers. 2023;15:1845. doi: 10.3390/CANCERS15061845. - DOI - PMC - PubMed

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