Impact of Radiochemotherapy on Immune Cell Subtypes in High-Grade Glioma Patients

Abstract

Glioblastoma is a dreadful disease with very poor prognosis, median overall survival being <2 years despite standard-of-care treatment. This has led to the development of alternative strategies, among which immunotherapy is being actively tested. In particular, many clinical trials of therapeutic vaccination using peptides or tumor cells are ongoing. A major issue in implementing therapeutic vaccines in patients with high-grade glioma is that immune responses have to be elicited in the context of immunosuppressive treatments. Indeed, radiotherapy, chemotherapy, and steroids, which are part of the standard of care for patients with glioblastoma, are known to deplete leukocytes. Whether lymphopenia is beneficial or detrimental to elicitation of efficient immune responses is still debated. Here, in order to determine the impact of standard radiochemotherapy on immune cell subsets, we analyzed the phenotype and function of immune populations in 25 patients with high-grade glioma along concomitant radiochemotherapy and adjuvant chemotherapy with temozolomide. Thirteen healthy individuals were studied along the same period. We show that absolute T and B cell counts are reduced upon concomitant radiochemotherapy. Importantly, T cell counts were not restored long-term after discontinuation of treatment. In addition, the percentage of T regulatory cells among CD4 T cells was increased during the same period and was not decreased upon treatment discontinuation. Finally, we show that the ability of T cells to proliferate is transiently reduced after concomitant radiochemotherapy but is restored at the time of adjuvant TMZ cycles. Although not experimentally validated, transient reduction in proliferation associated with strong lymphopenia during radiochemotherapy may suggest that vaccine-induced T cell stimulation would be suboptimal in that period and that therapeutic vaccination should be performed outside radiochemotherapy administration. In addition, strategies aiming at depleting Treg cells should be implemented in future trials.

Randomized Controlled Immunotherapy Clinical Trials for GBM Challenged

“…General blood counts and immune cell counts and functioning, as analyzed in the routine clinical laboratory, are shown in Figure 2 A. A large proportion of patients were lymphopenic at that time—caused by the radiochemotherapy—a finding compatible with published data [ 39 ].…”

“…It is already well-known that neurosurgical removal of the tumor transiently “relieves” the systemic immune system from tumor-induced immunosuppression [ 34 ], which returns upon disease progression [ 35 ]. Both radiotherapy and TMZ have effects on inflammation and the systemic immune compartment but may also influence the tumor microenvironment [ 36 , 37 , 38 , 39 , 40 ].…”

“…Moreover, there is a definite influence of the tumor and the response to treatment on the systemic immune and inflammatory compartments [ 34 ]. Finally, steroids, radiotherapy, and chemotherapy all influence antitumor immune responses [ 39 ]; this, again, differs from patient to patient. A strong correlation was found between OS and the systemic immune profile after neurosurgical resection and after radiochemotherapy when the extent of resection and timing of immunotherapy were taken into account [ 40 ].…”

Considering the Experimental Use of Temozolomide in Glioblastoma Research

“…In such cases, it is indicated that patients should be monitored for opportunistic infections [190]. Furthermore, it was demonstrated that concomitant standard radiation and TMZ (RT/TMZ) provokes a strong reduction in lymphocytes but numbers of lymphocytes slowly come back to normal when treatment with TMZ is stopped [191]. Another study showed that the frequency and absolute numbers of natural killer (NK) cells, which are known to destroy tumour cells by their ability to initiate apoptosis in target cells with reduced levels of MHC molecules ('missing-self' recognition), are decreased in RT/TMZ-treated GB patients [189].…”

Molecular Mechanisms of Treatment Resistance in Glioblastoma

“…In a mouse model, administration of systemic bis-chloroethylnitrosourea induced lymphodepletion, decreased the number of TILs, and reduced the survival benefit from PD-1 blockade [ 186 ]. Furthermore, during concurrent chemoradiation with temozolomide, the absolute T and B cell counts were reduced and remained low even after the completion of treatment, and the composition of these immune cells shifted toward persistent increased Treg expression with concomitant decreased expression of naïve CD4+ T cells [ 187 ]. Interestingly, PD-1/PD-L1 checkpoint inhibition in temozolomide-resistant tumors also led to increased immunosuppressive macrophage infiltration in tumors [ 188 ] which was resolved by the co-administration of a PI3Kγ inhibitor.…”