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. 2024 Feb 13;25(4):2222.
doi: 10.3390/ijms25042222.

Genomic and Immunologic Correlates in Prostate Cancer with High Expression of KLK2

Lucía Paniagua-Herranz  1 , Irene Moreno  2 , Cristina Nieto-Jiménez  1 , Esther Garcia-Lorenzo  3 , Cristina Díaz-Tejeiro  1 , Adrián Sanvicente  1 , Bernard Doger  3 , Manuel Pedregal  3 , Jorge Ramón  2 , Jorge Bartolomé  1 , Arancha Manzano  1 , Balázs Gyorffy  4   5   6 , Álvaro Gutierrez-Uzquiza  7   8 , Pedro Pérez Segura  1 , Emiliano Calvo  2 , Víctor Moreno  3 , Alberto Ocana  1   9
Affiliations

Genomic and Immunologic Correlates in Prostate Cancer with High Expression of KLK2

Lucía Paniagua-Herranz et al. Int J Mol Sci. .

Abstract

The identification of surfaceome proteins is a main goal in cancer research to design antibody-based therapeutic strategies. T cell engagers based on KLK2, a kallikrein specifically expressed in prostate cancer (PRAD), are currently in early clinical development. Using genomic information from different sources, we evaluated the immune microenvironment and genomic profile of prostate tumors with high expression of KLK2. KLK2 was specifically expressed in PRAD but it was not significant associated with Gleason score. Additionally, KLK2 expression did not associate with the presence of any immune cell population and T cell activating markers. A mild correlation between the high expression of KLK2 and the deletion of TMPRSS2 was identified. KLK2 expression associated with high levels of surface proteins linked with a detrimental response to immune checkpoint inhibitors (ICIs) including CHRNA2, FAM174B, OR51E2, TSPAN1, PTPRN2, and the non-surface protein TRPM4. However, no association of these genes with an outcome in PRAD was observed. Finally, the expression of these genes in PRAD did not associate with an outcome in PRAD and any immune populations. We describe the immunologic microenvironment on PRAD tumors with a high expression of KLK2, including a gene signature linked with an inert immune microenvironment, that predicts the response to ICIs in other tumor types. Strategies targeting KLK2 with T cell engagers or antibody-drug conjugates will define whether T cell mobilization or antigen release and stimulation of immune cell death are sufficient effects to induce clinical activity.

Keywords: KLK2; T cell engagers; immunologic profile; prostate cancer; surfaceome.

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Conflict of interest statement

A.O. is a former employee of Symphogen, Copengahen, Denmark and a current consultant of NMS. There are no conflicts of interest to declare in relation to this work. I.M.reports an advisory role in ESAME, Exafield and Guidepoint outside the submitted work. A.M. reports a consulting role in Grunenthal, outside the submitted work. V.M. reports personal fees from Bristol-Myers Squibb, Bayer, Janssen, and Pieris outside the submitted work. E.C. reports grants and personal fees from Astellas, Novartis, Nanobiotix, Pfizer, Janssen-Cilag, PsiOxus Therapeutics, Merck, Bristol-Myers Squibb, Seattle Genetics, Boehringer Ingelheim, AstraZeneca, Roche/Genentech, Servier, Celgene, AbbVie, Amcure, Alkermes, PharmaMar, and BeiGene, outside the submitted work. P.P. reports grant/research support from Bristol-Myers Squibb, AstraZeneca, and MSD, outside the submitted work. The other authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
KLK2 expression profile across all tumor samples and paired normal tissues. (A) KLK2 expression levels in different cancers validated using GEPIA2 database. KLK2 was highly expressed (TPM > 600) in PRAD. (B) Heat map depicting fold change between tumor and non-transformed tissue for KLK2. The X marks the tumor types where there is no KLK2 expression. (C) Correlation between the KLK2 expression level and the CRISPR dependency score, using the methods described in material and methods.
Figure 2
Figure 2
Association of KLK2 expression levels with the immune infiltrates and T cell markers in PRAD. (A) Correlation of KLK2 expression levels and the presence of immune infiltrates (CD8+ T cells, CD4+ T cells, B cells, neutrophils, dendritic cells (DCs), and macrophages) using the Tumor Immune Estimation Resource (TIMER2.0). (B) Association of KLK2 with biomarkers of T cell activation. (C) Heat map depicting the Spearman’s correlation coefficient between KLK2 and T cell dysfunction and cytotoxicity markers.
Figure 3
Figure 3
The genomic alterations more frequent in PRAD. (A) Heat map of the more frequent (frequency > 1%) mutations, amplifications, and deletions in PRAD using cBioPortal. (B) Heat map depicting the Spearman’s correlation coefficient between KLK2 and the genomic alterations more frequent in PRAD using TIMER 2.0.
Figure 4
Figure 4
Expression profile of upregulated surface and non-surface proteins across PRAD samples and paired normal tissues when KLK2 is upregulated. Heat map depicting the Spearman’s correlation coefficient between KLK2 and (A) surface and (D) non-surface proteins in PRAD using TIMER 2.0. (B) Surface and (E) non-surface proteins expression profile across PRAD samples and paired normal tissues. Heat map depicting fold change between tumor and non-transformed tissue for (C) surface and (F) non-surface proteins.
Figure 5
Figure 5
Association between surface and non-surface proteins expression levels and overall survival (OS) in male patients treated with ICIs. Kaplan–Meier survival curves comparing low and high expression of CHRNA2, FAM174B, OR51E2, TSPAN1, PTPRN2, and TRPM4. HR: hazard ratio; FDR: false-discovery rate; p: rank p-value.
Figure 6
Figure 6
Association of surface and non-surface proteins expression levels with overall survival and immune infiltrates. (A) Kaplan–Meier survival curve of the association between transcriptome expression of CHRNA2, FAM174B, OR51E2, TSPAN1, PTPRN2, and TRPM4, and overall survival (OS) in male patients treated with ICIs. (B) Heat map depicting the Spearman’s correlation coefficient between surface and non-surface proteins expression and the presence of CD8+ T cells, CD4+ T cells, B cells, neutrophils, dendritic cells (DCs), and macrophages in PRAD using TIMER 2.0.
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References

    1. Ocana A., Garcia-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. Rudolph J., Settleman J., Malek S. Emerging Trends in Cancer Drug Discovery-From Drugging the “Undruggable” to Overcoming Resistance. Cancer Discov. 2021;11:815–821. doi: 10.1158/2159-8290.CD-21-0260. - DOI - PubMed
    1. Nieto-Jimenez C., Sanvicente A., Diaz-Tejeiro C., Moreno V., Lopez de Sa A., Calvo E., Martinez-Lopez J., Perez-Segura P., Ocana A. Uncovering therapeutic opportunities in the clinical development of antibody-drug conjugates. Clin. Transl. Med. 2023;13:e1329. doi: 10.1002/ctm2.1329. - DOI - PMC - PubMed
    1. Tong J.T.W., Harris P.W.R., Brimble M.A., Kavianinia I. An Insight into FDA Approved Antibody-Drug Conjugates for Cancer Therapy. Molecules. 2021;26:5847. doi: 10.3390/molecules26195847. - DOI - PMC - PubMed
    1. Fuca G., Spagnoletti A., Ambrosini M., de Braud F., Di Nicola M. Immune cell engagers in solid tumors: Promises and challenges of the next generation immunotherapy. ESMO Open. 2021;6:100046. doi: 10.1016/j.esmoop.2020.100046. - DOI - PMC - PubMed

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