The immune contexture of primary central nervous system diffuse large B cell lymphoma associates with patient survival and specific cell signaling

Abstract

Rationale: Primary central nervous system diffuse large B-cell lymphoma (PCNSL) is a rare and aggressive entity that resides in an immune-privileged site. The tumor microenvironment (TME) and the disruption of the immune surveillance influence lymphoma pathogenesis and immunotherapy resistance. Despite growing knowledge on heterogeneous therapeutic responses, no comprehensive description of the PCNSL TME is available. We hence investigated the immune subtypes of PCNSL and their association with molecular signaling and survival. Methods: Analysis of PCNSL transcriptomes (sequencing, n = 20; microarrays, n = 34). Integrated correlation analysis and signaling pathway topology enabled us to infer intercellular interactions. Immunohistopathology and digital imaging were used to validate bioinformatic results. Results: Transcriptomics revealed three immune subtypes: immune-rich, poor, and intermediate. The immune-rich subtype was associated to better survival and characterized by hyper-activation of STAT3 signaling and inflammatory signaling, e.g. , IFNγ and TNF-α, resembling the hot subtype described in primary testicular lymphoma and solid cancer. WNT/β-catenin, HIPPO, and NOTCH signaling were hyper-activated in the immune-poor subtype. HLA down-modulation was clearly associated with a low or intermediate immune infiltration and the absence of T-cell activation. Moreover, HLA class I down-regulation was also correlated with worse survival with implications on immune-intermediate PCNSL that frequently feature reduced HLA expression. A ligand-receptor intercellular network revealed high expression of two immune checkpoints, i.e. , CTLA-4/CD86 and TIM-3/LAGLS9. TIM-3 and galectin-9 proteins were clearly upregulated in PCNSL. Conclusion: Altogether, our study reveals that patient stratification according to immune subtypes, HLA status, and immune checkpoint molecule quantification should be considered prior to immune checkpoint inhibitor therapy. Moreover, TIM-3 protein should be considered an axis for future therapeutic development.

The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms

“…This new entity now combines the previous entity of primary DLBCL of CNS with DLBCL of the vitreoretina and testis that were previously included among DLBCL, NOS. They arise in immune sanctuaries created by their respective anatomical structures (e.g., the blood-brain, blood-retinal, and blood-testicular barriers), and immune regulation systems within their respective primary sites, and share immunophenotypic and molecular features [ 137 – 139 ] (Table 4 ). Information on this group of tumours is rapidly accruing: it appears that some lymphomas arising at other distinct sites such as the breast and skin share some of these features, and thus, this group of ‘immune-privileged lymphomas’ might expand in future classifications.…”

Intratumor heterogeneity and T cell exhaustion in primary CNS lymphoma

“…Genomic alterations may also affect genes that are involved in immune evasion mechanisms, including deletions in the HLA locus (6p21), copy-number loss of B2M (15q21.2), or copy-number gain of CD274 /PD-L1 (9p24.1) [ 12 ]. Accordingly, immune checkpoint molecules (PD-1, CTLA-4, TIM-3) have emerged as potential therapeutic targets in PCNSL [ 13 ]. Prospective trials of the checkpoint blockade with PD-1 inhibitors have been initiated in PCNSL (NCT02779101, NCT02857426), but no results have been published yet.…”

Identification of mRNA Signature for Predicting Prognosis Risk of Rectal Adenocarcinoma

“…Additionally, unlike the B cells, LGALS9C exhibited a negative correlation with immune infiltrates. High LGALS9 scores were found in every immune subtype, although they were higher in the immune-rich tumors ( Alame et al, 2021 ).…”