In a paper, published in the journal Blood, Dr Shipp’s team demonstrated that PCNSL tumors had increased expression of programmed cell death ligand 1 (PD-L1) ligands. These proteins,2 of course, are important modulators of the immune system and indicate the cancer might be treated with checkpoint inhibitor drugs. In the study, 5 patients were treated with a PD-L1 blocking antibody nivolumab and all 5 showed responses to the treatment. Subsequent research from other labs broke this research down into even smaller subgroups, further demonstrating the genetic heterogeneity of these cancers.3,4

“Because we know a little bit more about the genomics, we know a little bit better how to how to target these CNS lymphomas rather than just giving huge doses of chemotherapy and radiation,” said Justin Kline, MD, hematologist and associate professor of medicine at the University of Chicago, Illinois.

Now, researchers are adding this new information about the background immune landscape to the pool of genetic knowledge. In the preprint, the research team obtained tumor samples from 20 newly diagnosed patients who underwent surgery and performed transcriptomic and human leukocyte antigen (HLA) status-related analysis to find immune signatures.

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They found downgraded HLA class 1 and 2 expression in the immune-poor group, meaning that these types were likely to evade responses from the T cells in the patient’s immune system. They also found HIPPO, NOTCH, and WNT/β-catenin activation. The WNT/β-catenin pathway inhibits the recruitment of immune cells into tumors in other cancers like melanoma, making them difficult to treat.5

And in the immune-rich group, they found active pathways involved in the immune response like STAT3, IFNγ, IL-10, TNF-α, and NF-κB. STAT3 and IFNγ are typically linked to PD-L1 expression, which hints that this subtype of cancer might be vulnerable to checkpoint inhibitors. 

This research is still correlative and more work needs to be done to show any kind of therapeutic benefit. The paper also has yet to undergo the peer-review process so the results should be interpreted carefully. But scientists think it is an important step in furthering our understanding of these cancers that have lagged behind in the precision medicine revolution.

“The dichotomy between inflamed cancers and noninflamed cancers is really important because we know from solid tumors like melanomas and lung cancers that these inflamed tumors have somehow stimulated an immune response spontaneously in the person. These are the ones that respond to checkpoint blockade therapy,” said Dr Kline.


  1. Alame M, Cornillot E, Cacheux V, Rigau V, Costes-Martineau V, Lacheretz-Szablewski V, Colinge J. The immune landscape of primary central nervous system diffuse large B cell lymphoma. Biorxiv. Published /17/2020.
  2. Nayak L, Iwamoto AL, Srinivasan M, Roemer MGM, Chapuy B, Armand SJR, Shipp MA. PD-1 blockade with nivolumab in relapsed/refractory primary central nervous system and testicular lymphoma. Blood. 2017;129(23):3071–3073. doi:10.1182/blood-2017-01-764209
  3. Schmitz R, Wright GW, Huang DW, et al. Genetics and pathogenesis of diffuse large B-cell lymphoma. N Engl J Med. 2018;378(15):1396-1407 doi:10.1056/NEJMoa1801445
  4. Wright GW, Huang DW, Phelan JD, Wilson WH, Scott DW. A probabilistic classification tool for genetic subtypes of diffuse large B cell lymphoma with therapeutic implications. Cancer Cell. 2020;37(4):551-568. doi:10.1016/j.ccell.2020.03.015
  5. Spranger S, Bao R, Gajewski TF. Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature. 2015;523(7559):231-235. doi:10.1038/nature14404