Cancer immune evasion is a major hurdle for effective anticancer therapy. According to a recent study published in Blood, different large B-cell lymphoma subtypes use distinct immune evasion strategies. Therefore, different approaches (checkpoints inhibitors) should be used depending on the immune evasion strategy of each cancer type.
Key strategies of tumour cells to avoid T-cell recognition include downregulation of major histocompatibility complex (MHC) molecules and activation of immune checkpoints. Remarkably, the immune checkpoint protein programmed cell death 1 (PD-1) and its ligands, PD-L1 and -L2, play a key role in repressing T-cell activity in the tumour microenvironment, not only in solid cancers but also in haematological malignancies. Specifically in advanced classic Hodgkin lymphoma (cHL), blockade of the PD-1/PD-L1/L2 axis yields outstanding clinical responses. Most cHLs are infiltrated by PD-1+ T cell. The tumour cells show strong expression of PD-L1/PD-L2 related to copy-number alterations (CNAs) at chromosome 9p24.1, containing the loci for PD-L1/PD-L2, or alternatively, driven by Epstein-Barr virus (EBV) infection.
In the current study, the authors revisited the immune evasion mechanisms operating in primary testicular lymphomas (PTLs) and primary central nervous lymphomas (PCNSLs). In order to do this, they assessed HLA class I and II expression, PD-L1 expression, and 9p24.1/PD-L1/2 CNAs in a panel of lymphomas diagnosed as PTLs (n = 25) or PCNSLs (n = 22) according to the World Health Organization classification, using immunohistochemistry and fluorescence in situ hybridization (FISH), respectively To validate the techniques used to detect PD-L1 expression and 9p24.1/PD-L1/2 CNAs, a series of primary mediastinal B-cell lymphomas (PMBCLs; n = 25) were studied.
The results of this study indicate that different large B-cell lymphoma subtypes use distinct immune evasion strategies. PTLs and PCNSLs seem to rarely use the PD1/PD-L1/2 checkpoint (with the exception of EBV+PCNSLs). Instead, they seem to use the loss of MHC expression as a major mechanism of immune evasion. In contrast, in PMBCLs, PD-L1 overexpression, often caused by 9p24.1/PD-L1/2 CNAs, appears to play a major role.
These findings suggest that patients with PBMCL, but not those with PTL or PCNSL, are likely to benefit from treatment with PD-1/PD-L1 immune checkpoint inhibitors. Therefore, the authors believe that a critical reappraisal of the prevalence of PD-L1 expression and 9p24.1 alterations in these lymphomas is of crucial importance in order to choose the best therapeutic approach.
Minderman M, Amir A, Kraan W et al. Immune evasion in primary testicular and central nervous system lymphomas: HLA loss rather than 9p24.1/PD-L1/PD-L2 alterations. Blood. 2021 Sep 30;138(13):1194-1197.