Immune evasion in primary testicular and central nervous system lymphomas: HLA loss rather than 9p24.1/<i>PD-L1/PD-L2</i> alterations

Minderman, Marthe; Amir, Avital L.; Kraan, Willem; Schilder-Tol, Esther J.M.; Oud, Monique E.C.M.; Scheepstra, Cornelis G.; Noorduyn, Arnold L; Kluin, Philip M.; Kersten, Marie José; Spaargaren, Marcel; Pals, Steven T.

doi:10.1182/blood.2021011366

Cited by 10 publications

(17 citation statements)

References 18 publications

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“…Although WT1 mutations have not been described in PTL, 15,35 WT1 may be an additional circuit contributing to the activation Mitogen‐Activated Protein Kinase (MAPK) and JAK‐STAT signaling seen in PTL, as described for WT1 in other cancer 36 . In addition, genetic aberrations such as loss of 9p24 and HLA locus have been recently implicated with immune evasion in PTL 37 . Hence, data related to high WT1 expression in PTL presented here can be exploited for devising future studies for evaluation of immunotherapy in PTL, as being used in other cancers 38 …”

Section: Discussionmentioning

confidence: 99%

“…36 In addition, genetic aberrations such as loss of 9p24 and HLA locus have been recently implicated with immune evasion in PTL. 37 Hence, data related to high WT1 expression in PTL presented here can be exploited for devising future studies for evaluation of immunotherapy in PTL, as being used in other cancers. 38 Growing evidence suggests that miRNAs likely play a role in the pathogenesis of all human malignancies 39 through tumor suppression and other mechanisms related to oncogenesis.…”

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confidence: 94%

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Primary testicular lymphoma demonstrates overexpression of the Wilms tumor 1 gene and different mRNA and miRNA expression profiles compared to nodal diffuse large B‐cell lymphoma

Mansoor

Akhter

Shabani‐Rad

et al. 2023

Hematological Oncology

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Diffuse large B‐cell lymphoma (DLBCL) shows a high degree of clinical and biological heterogeneity. Primary testicular lymphoma (PTL) is an extranodal variant of DLBCL associated with a higher risk of recurrence, including contralateral testicles and central nervous system sanctuary sites. Several molecular aberrations, including somatic mutation of MYD88, CD79B, and upregulation of NF‐kB, PDL‐1, and PDL‐2, are thought to contribute to the pathogenesis and poor prognosis of PTL. However, additional biomarkers are needed that may improve the prognosis and help understand the PTL biology and lead to new therapeutic targets. RNA from diagnostic tissue biopsies of the PTL‐ABC subtype and matched nodal DLBCL‐ABC subtype patients was evaluated by mRNA and miRNA expression. Screening of 730 essential oncogenic genes was performed, and their epigenetic connections were examined using the nCounter PAN‐cancer pathway, and Human miRNA assays with the nCounter System (NanoString Technologies). PTL and nodal DLBCL patients were comparable in age, gender, and putative cell of origin (p > 0.05). Wilms tumor 1 (WT1) expression in PTL exceeded that in nodal DLBCL (>6‐fold; p = 0.01, FDR <0.01) and WT1 associated pathway genes THBS4, PTPN5, PLA2G2A, and IFNA17 were upregulated in PTL (>2.0‐fold, p < 0.01, FDR <0.01). Additionally, miRNAs targeting WT1 (hsa15a‐5p, hsa‐miR‐16‐5p, has‐miR‐361‐5p, has‐miR‐27b‐3p, has‐miR‐199a‐5p, has‐miR‐199b‐5p, has‐miR‐132‐3p, and hsa‐miR‐128‐3p) showed higher expression in PTL compared to nodal DLBCL (≥2.0‐fold; FDR 0.01). Lower expression of BMP7, LAMB3, GAS1, MMP7, and LAMC2 (>2.0‐fold, p < 0.01) was observed in PTL compared to nodal DLBCL. This research revealed higher WT1 expression in PTL relative to nodal DLBCL, suggesting that a specific miRNA subset may target WT1 expression and impact the PI3k/Akt pathway in PTL. Further investigation is needed to explore WT1's biological role in PTL and its potential as a therapeutic target.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 94%

Primary testicular lymphoma demonstrates overexpression of the Wilms tumor 1 gene and different mRNA and miRNA expression profiles compared to nodal diffuse large B‐cell lymphoma

Mansoor

Akhter

Shabani‐Rad

et al. 2023

Hematological Oncology

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“…A possible explanation of these contradictory findings lies in the fact that the frequency of genetic alterations encompassing PD-1 ligands in PCNSL appears to be much lower than the one initially reported [38 ▪▪ ,68,69]. In addition, recurrent deletion of HLA genes [38 ▪▪ ,68,69] and presence of multiple inhibitory receptors on T cells infiltrating PCNSL [70] might represent additional reasons why T cells unleashed upon PD-1 blockade did yield the expected benefit.…”

Section: Novel Approaches For Relapsed/refractory Primary Central Ner...mentioning

confidence: 94%

New hopes in relapsed refractory primary central nervous system lymphoma

Calimeri

Steidl

Fiore

et al. 2023

Current Opinion in Oncology

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Purpose of review Patients with relapsed/refractory primary central nervous system lymphoma (rrPCNSL) have poor prognosis, with a median survival after relapse of 6.8 months. In this review, we discuss the evolving landscape and the possible future directions related to this important unmet clinical need. Recent findings The modern two-phase approach for newly diagnosed PCNSL based on an induction using high-dose methotrexate (HD-MTX) combinations and a subsequent consolidation, has significantly improved the outcome in this setting. However, this strategy is able to cure more or less 50% of patients. rrPCNSL patients have a very poor prognosis with a reported 5-year overall survival of 18%. Late relapses (after third year) and use of high-dose chemotherapy and autologous stem cell transplantation (HDT-ASCT) represent important factors associated with a better outcome in this setting. On the basis of the growing acquisition of knowledge on the molecular characteristics of PCNSL, the use of non-chemotherapeutic drugs such as bruton tyrosine kinase inhibitors (BTK-is), immunomodulatory drugs (IMiDs) and immune checkpoint blockers (ICBs) is increasing in the last years along with the introduction of novel approaches (CAR-T cells and blood--brain barrier disruption). However, despite high responses in some cases, durations are often short, translating in outcome results still unsatisfactory. Summary Treatment of rrPCNSL patients is challenging. As no standard of care exist in this setting, it is of paramount importance to acquire new knowledge related to this condition and start multidisciplinary collaboration in order to improve pts outcome.

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“…Instead, HLA deletions were common in their PTL cohort. Their article suggests that the mechanism of immune escape in PTL and CNS lymphoma is primarily HLA loss rather than the use of the PD1/PD-L1/2 checkpoint [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

Genomic landscape and distinct molecular subtypes of primary testicular lymphoma

Zhang,

Yang,

Yang

et al. 2024

J Transl Med

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Primary testicular lymphoma (PTL) is a rare lymphoma predominantly occurring in the elderly male population. It is characterized by a limited response to treatment and a heightened tendency towards relapse. Histologically, approximately 90% of PTL cases are classified as diffuse large B-cell lymphomas (DLBCL). Genetic features of PTL were delineated in a limited scope within several independent studies. Some of the articles which analyzed the genetic characterization of DLBCL have incorporated PTL samples, but these have been constrained by small sample sizes. In addition, there have been an absence of independent molecular typing studies of PTL. This report summarizes the common mutational features, copy number variations (CNVs) and molecular typing of PTL patients, based on whole-exome sequencing (WES) conducted on a cohort of 25 PTL patients. Among them, HLA, CDKN2A and MYD88 had a high mutation frequency. In addition, we found two core mutational characteristics in PTL including mutation in genes linked to genomic instability (TP53 and CDKN2A) and mutation in immune-related genes (HLA, MYD88, CD79B). We performed molecular typing of 25 PTL patients into C1 subtype with predominantly TP53 mutations and C2 subtype with predominantly HLA mutations. Notably, mutations in the TP53 gene predicted a poor outcome in most types of lymphomas. However, the C1 subtype, dominated by TP53 mutations, had a better prognosis compared to the C2 subtype in PTL. C2 subtype exhibited a worse prognosis, aligning with our finding that the mechanism of immune escape in PTL was primarily the deletions of HLA rather than PD-L1/PD-L2 alterations, a contrast to other DLBCLs. Moreover, we calculated the tumor mutation burden (TMB) and identified that TMB can predict prognosis and recurrence rate in PTL. Our study underscores the significance of molecular typing in PTL based on mutational characteristics, which plays a crucial role in prognostication and guiding therapeutic strategies for patients.

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Immune evasion in primary testicular and central nervous system lymphomas: HLA loss rather than 9p24.1/PD-L1/PD-L2 alterations

Cited by 10 publications

References 18 publications

Primary testicular lymphoma demonstrates overexpression of the Wilms tumor 1 gene and different mRNA and miRNA expression profiles compared to nodal diffuse large B‐cell lymphoma

Primary testicular lymphoma demonstrates overexpression of the Wilms tumor 1 gene and different mRNA and miRNA expression profiles compared to nodal diffuse large B‐cell lymphoma

New hopes in relapsed refractory primary central nervous system lymphoma

Genomic landscape and distinct molecular subtypes of primary testicular lymphoma

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