Molecular Pathology Abstracts, 7/17

Create PDF

Editors: Donna E. Hansel, MD, PhD, chief, Division of Anatomic Pathology, and professor, Department of Pathology, University of California, San Diego; John A. Thorson, MD, PhD, associate professor of pathology, director of the Clinical Genomics Laboratory, Center for Advanced Laboratory Medicine, UCSD; Sarah S. Murray, PhD, professor, Department of Pathology, and director of genomic technologies, Center for Advanced Laboratory Medicine, UCSD; and James Solomon, MD, PhD, resident, Department of Pathology, UCSD.

Mutational burden in gliomas and implications for immune checkpoint immunotherapy

Immune checkpoint inhibition therapy, such as blockage of PD-1/PD-L1 interaction, has proven effective in many types of cancers. The mechanism underlying this therapy is postulated to involve “disinhibition” of tumor-infiltrating lymphocytes that respond to neoantigens expressed by tumor cells. In theory, the larger the number of neoantigens expressed, the greater the immune response resulting from disinhibition. Extension of this reasoning leads to the conclusion that a large number of tumor mutations and, consequently, a large number of neoantigens may be indicative of a better response to immune checkpoint inhibition. Therefore, assessments that measure tumor mutational load (TML) or mechanisms that result in a high level of mutations, such as mismatch repair (MMR) defects, increasingly are used as markers of responsiveness to immune checkpoint inhibition. The frequency of these biomarkers in gliomas has not been well studied. The authors conducted a study in which they profiled the frequency of shared biomarker phenotypes in gliomas. They studied 327 consecutive glioma patients for whom TML data were available. The cohort comprised predominantly grade 4 glioblastomas but also smaller numbers of grades 1, 2, and 3 gliomas. High, moderate, and low TML was defined as more than 20, 11 to 20, and 10 or fewer nonsynonymous missense mutations per 1.4 Mb, respectively. Immunohistochemistry was used to assess the number of CD8+ tumor-infiltrating lymphocytes as well as expression of PD-1 on such lymphocytes and PD-L1 on tumor cells for a subset of the cases. Immunohistochemistry and next-generation sequencing were used to assess expression and mutational status of the MMR system—MLH1, MSH2, MSH6, and PMS2. The authors found that a high TML was present only in high-grade gliomas and in only a small percentage of those tumors (15 of 327; 4.6 percent). Of those 15 gliomas with a high TML, 40 percent (six of 15) were newly diagnosed and 60 percent (nine of 15) were recurrent. The presence of a high TML was associated with loss of expression of MLH1, MSH2, MSH6, and PMS2. All cases with high TML showed loss of at least one of the four proteins analyzed. However, no association was found between high TML and the presence of one or more mutations in the MMR genes, which the authors suggest may be due to the inability of mutations to always alter protein activity. Interestingly, although a high TML and the likely increased neoantigen number might be expected to result in a greater influx of tumor-infiltrating lymphocytes, neither the gliomas with moderate nor high TML showed a significant association with CD8+ T-cell influx. Similarly, no association was found between a high TML and PD-1 or PD-L1 expression. The authors pointed out that previous studies of lung tumors have demonstrated that neoantigens induced via chemotherapy exposure are poor indicators of response to immune checkpoint inhibition. This may also be true for recurrent gliomas, which accounted for a significant percentage of the samples in this study, as radiation and chemotherapy may induce subclonal mutations that are less effective at stimulating an immune response. The authors concluded that it is unlikely that a single biomarker will predict responsiveness to immune checkpoint inhibition. Although additional studies with outcome information are needed to fully gauge the effectiveness of immune checkpoint blockade in gliomas, this study suggests that only a small subset of these tumors may show a durable response.

Hodges TR, Ott M, Xiu J, et al. Mutational burden, immune checkpoint expression, and mismatch repair in glioma: implications for immune checkpoint immunotherapy [published online ahead of print March 24, 2017]. Neuro-oncol. doi:10.1093/neuonc/nox026.

Correspondence: Dr. Amy B. Heimberger at aheimber@mdanderson.org