Skull bone marrow as a source for immune cells in glioma

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Anna Salamero Boix

The tumor microenvironment has emerged as a potential therapeutic target in cancer therapy. Within the tumor microenvironment, tumor-associated immune cells regulate tumor progression and immune evasion (1). While most research has focused on targeting immune cell activity, fewer studies have interrogated the origin of tumor-associated immune cells. Expanding the knowledge of the origin of tumor-associated immune cells might shed light into how to promote their recruitment into the tumor. This is of particular importance in cancers such as glioblastoma that, compared to peripheral tumors, present lower amounts of immune cells (2). Moreover, patients with glioblastoma do not respond to current therapies, highlighting the need to discover new therapeutic avenues.

The authors of the recently published study titled “Cranioencephalic functional lymphoid units in glioblastoma” in Nature Medicine interrogated the cranial bones in patients with glioma for the presence of immune cells (3). The cranial bones were chosen for interrogation due to their near spatial proximity to glioma. The presence of immune cells was assessed by positron emission tomography based on a radioligand known to bind to CXCR4, a protein enriched in the hematopoietic and immune cell niches. By applying positron emission tomography based on CXCR4, the scientists found a clear presence of immune cells in the cranial bones of patients with glioblastoma before surgery. 

With the aim to delve into the cellular complexity of immune cells to characterize their function, the authors employed single cell RNA sequencing of immune cells from craniotomy-derived fresh surgical bone, peripheral bone marrow cells and fresh glioblastoma tissue. Abundant T cell fractions, which correlate with the establishment of an immune response against the tumor, were detected among the immune cells derived from cranial bones. 

More detailed analysis of T cells revealed the accumulation of a cell subpopulation, referred to as effector-type CD8+ T cell, in both cranial bones and glioblastoma. The authors proved that this effector-type CD8+ T cell population derived from cranial bones and, detected at lower levels in glioblastoma tumors, was effective against glioma tumor cells. In contrast to that, CD8+ T cell populations derived from peripheral blood did not react against the glioma tumor cells.

T cells play a major role in the adaptive immune response by responding to a specific antigen, which is dictated by their clonotype. It is well known that T cells that receive a stimulatory signal divide, resulting in T cell clonal expansions. The analysis of the clonotype repertoire of T cells revealed the presence of shared clonotypes between glioblastoma and cranial bones, suggesting that those clones were tumor reactive and that the T cells present in the glioma tumor might originate from the cranial bones.

Although there were shared clones between the T cells in the cranial bone and in the glioma, they were associated with different T cell subsets. In the cranial bones, the shared clones were detected in activated and effector cell types, that is subsets with increased properties related to T cell activation and functionality. In contrast, the shared clones were present in exhausted T cells in the glioma tissue. In line with this, the authors observed that tumor-derived CD8+ T cells had lost their functionality based on their lack of expansion upon repeated stimulation. Contrary to that, CD8+ T cells from blood and from the cranial bones could expand on repeated stimulation. This finding goes in line with the described CD8+ T cell exhaustion and dysfunctionality within the tumor microenvironment. 

Since previous research has described the sphingosine 1-phosphate receptor S1PR1 expression in lymphocytes that egress from lymphoid organs, the authors of this study interrogated the expression of S1PR1 on T cells. The authors found increased levels of S1PR1 on T cells from cranial bones, above all in T cells associated with an effector phenotype. S1PR1 levels were not increased in peripheral blood. At this point, the authors decided to interrogate whether there was a correlation between immune cell infiltration based on CXCR4 expression on the glioma tissue and the cranial bones and glioma prognosis. Both cranial and calvarial enhancement of the CXCR4 radiolabel -which detects immune cell presence- correlated with improved patient outcome. 

In summary, this research suggests that, at least part of, the source of the immune cells detected in glioma is the cranial bone. Although the findings may shed light on the path of how to increase the recruitment of those immune cells into the tumor, as well as how to manipulate them, it is worth mentioning that the amount of patients studied was limited. Another point worth considering is that the clinical glioma specimens were obtained at the time of initial diagnosis from patients that were naïve to treatment. Thus, how treatment affects the lymphoid populations in the cranial bones is one more factor which needs to be studied. Nonetheless, based on these findings, it can be speculated that the preservation of the cranial bones -and therefore the tumor reactive immune cells- could benefit the response to treatment, particularly those treatment regimens where an immune response is required for achieving the most response. Should that be the case, the integrity of the cranial bone should be preserved during craniotomy where current guideline-based standards require the transient removal of the proximal bone. 

Header Image Source: https://unsplash.com/photos/a-plastic-model-of-a-human-head-with-a-blue-brain-ooyFfGRACOw

Edited by Karli Norville

References

1.     Quail DF, Joyce JA. The Microenvironmental Landscape of Brain Tumors. Cancer Cell. 2017 Mar 13;31(3):326-341. doi: 10.1016/j.ccell.2017.02.009. PMID: 28292436; PMCID: PMC5424263.

2.     Klemm F, Maas RR, Bowman RL, Kornete M, Soukup K, Nassiri S, Brouland JP, Iacobuzio-Donahue CA, Brennan C, Tabar V, Gutin PH, Daniel RT, Hegi ME, Joyce JA. Interrogation of the Microenvironmental Landscape in Brain Tumors Reveals Disease-Specific Alterations of Immune Cells. Cell. 2020 Jun 25;181(7):1643-1660.e17. doi: 10.1016/j.cell.2020.05.007. Epub 2020 May 28. PMID: 32470396; PMCID: PMC8558904.

3.     Dobersalske, C., Rauschenbach, L., Hua, Y. et al. Cranioencephalic functional lymphoid units in glioblastoma. Nat Med 30, 2947–2956 (2024). https://doi.org/10.1038/s41591-024-03152-x