Written by | Sister Salty
In eukaryotic cells, DNA polymerases Polδ and Polε (controlled base incorporation and proofreading) and mismatch repair (MMR) systems (for post-replication monitoring) ensure precise DNA replication. Germline and somatic mutations in POLD1 and THE POLAR or MMR genes (MLH1, MSH2, MSH6, PMS2) can lead to DEFECTS IN DNA replication repair, called polymerase proofreading defects (PPD) and MMR defects (MMRD), respectively. This is a major driver of hyper-mutation and microsatellite instability (MSI) in some adult and pediatric cancers, and affected individuals often develop cancer at a very young age, and because of their inherent resistance to chemoradiotherapy, such cancers are often fatal and patient survival is extremely short [1-3].
Some reports have shown that immune checkpoint inhibitors (ICI) against programmed death 1 (PD-1) signals have anti-tumor effects on hypermutant adult cancers like melanoma and lung cancer, but these responses persist only in a subset of patients. Currently, an understanding of the relative importance and variable cut-off values for tumor mutation burden (TMB) in determining the nature and duration of the ICI response is still evolving. It is worth noting that most cancers (including hypermutated adult brain tumors) are considered "immune-cold" tumors that do not respond to ICI. What's more, in multiple large pediatric clinical trials, ICI did not produce a significant response and was considered ineffective in the treatment of solid tumors in children and adolescents. In addition, for all solid tumors receiving immunotherapy, distinguishing between true tumor progression and inflammatory pseudo-progression (tumor "flickering") is a major challenge and an obstacle to effective treatment.
While the results of previous studies on how pediatric cancer patients respond to ICI are disappointing, there are still those who wonder: Could cancers that originate from defects in reproductive dna replication repair potentially benefit from ICI because of their excessive mutant load? This group is the Uri Tabori team from the Canadian Children's Hospital, who published an article titled Genomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency on January 6, 2022 on Nature Medicine. Using an international joint registration study, ICI treatments for progressing or relapsing tumors were reported in 45 of 38 patients, evaluating true outcomes and response predictors of anti-PD-1 therapy in children with cancer caused by defects in reproductive DNA replication repair. Both mmRD and PPD mechanisms were shown to be associated with increased immune infiltration, contributing to the occurrence of favorable ICI responses, and improved survival in patients with some tumor types previously unknown to ICI treatment was found, and the dual role of mutation burden and microsatellite insertion/deletion (MS-indel) in predicting sustained response to immunotherapy was identified.
Between May 2015 and March 2019, the International Federation for Replication Repair Defects (IRRDC) followed up 38 patients with 45 cancers who had received PD-1 inhibitors. All patients had a defect in reproductive system replication repair (RRD), were diagnosed with congenital MMRD, Lynch syndrome, or PPD, contained 7 cancer types, and were divided into 3 broad categories: central nervous system (CNS) tumors (n=31), non-CNS solid tumors (n=11), and hematologic malignancies (n=3). The researchers used this retrospective and prospective systematic data to conduct a large, observational, registration-based study.
The findings showed that while there were significant differences in response to ICI treatment in the three classes of tumors, with non-CNS solid tumors having the highest response (100%), followed by CNS tumors (64%), and hematologic tumors with the lowest responsiveness (0%), overall, reactive or stable disease progression was observed in 55.5% of patients, with most responses persisting after 1.87 years (median) follow-up. And the patients had a 3-year overall survival rate (OS) of 41.4%, with 18 patients still alive at the last follow-up. However, analysis by cancer type showed that the survival rate of non-CNS solid tumors was significantly higher than that of CNS tumors, although the OS (39.3%) and progression-free survival rates (PFS, 26.9%) in patients with recurrent/progressive CNS tumors in this study were still a significant improvement compared with the results of rapid death in history.
To better understand the molecular determinants of response to ICI, this study collected biopsy specimens and blood samples from patients for intensive analysis before and during treatment. Tumor whole exome analysis showed a high degree of variability in the number of single nucleotide variants (SNV), including ultra-high mutations associated with tumor genotypes, and that MMRD cancers alone had significantly fewer SNV than MMRD+PPD cancers. At the same time, the results after COSMIC profiling (imprints reflecting the underlying mutation process) show that mutant signatures have a unique diagnostic and prognostic role in replication-repair defective cancers. Since tumor intrinsic features (such as mutational loads of SNV, indel, and microsatellite-specific indels) have different effects on the ICI response, do these genomic features and their underlying driving mechanisms play an independent role? The results of the study showed that high SNV/Mb was significantly associated with patient response and survival to ICI; it is worth noting that replication repair defect states predict response and survival rates, and patients with MMRD+PPD cancer had a higher mutational load and a larger proportion of those who responded to ICI. At the same time, total MS-indel also predicted tumor response and patient survival across the cohort. It is worth mentioning that since there is no significant correlation between MS-indel and SNV, the researchers found that although SNV and MS-indel have independent immunogenicity in all replication repair-deficient cancers, MS-indel is particularly important for determining the prognosis of MMRD-only cancers with relatively low SNV. Predictive models combining two replication-repair defective cancers (MMRD and MMRD+PPD only) showed that high SNV and total MS-indel together showed a correlation with improved prognosis. Overall, SNV and MS indel have dual roles in determining the immunotherapy response to replication-repair-deficient cancers, including CNS tumors.
Subsequently, the researchers explored whether tumor subtypes influenced tumor microenvironments and responses to treatment. The findings showed that all non-CNS solid tumors in the cohort, including only MMRD, contained high MSI, exhibited high CD8+ T cell infiltration, responded well to ICI, and improved survival. CNS tumors with high mutational burden and MMRD+PPD not only increased CD8+ T cell infiltration, but also significantly increased PD-L1 expression, thus showing an increase in response and survival to ICI. This shows that in an ultra-high mutation environment driven by a combination of MMRD+PPD and high genomic MS-indel, increased activation of the immune microenvironment is associated with a strong CD8+ T cell response, thus explaining the significant response seen even in CNS tumors.
It is very noteworthy in this study that the early imaging manifestations of 12 (27%) tumors were edema and enhancement, suggesting peri-tumor inflammation or tumor progression. This phenomenon occurs at a median 34 days (ranging from 7-74 days) after the start of treatment and is called tumor "flickering". Depending on the location of the tumor, these patients presented with acute clinical exacerbations such as headache, bone pain, or abdominal pain, of which 8 patients stopped treatment early and eventually died, but the other 4 patients continued to receive ICI treatment and showed an objective response to treatment after receiving adequate supportive treatment. Studies of patients who develop tumor "flicker" have found that when "flicker" occurs, there is a pre-existing (specific) immune response and further ICI-driven (non-specific and specific) tumor-directed immune dilation. Further systematic observations suggest that tumor "flickering" after PD-1 blockade is the result of inflammation response and proliferation of tumor antigen-reactive T cells, while the authors note that over-activation of this immune microenvironment can also be harmful because it may be misinterpreted as tumor progression and lead to premature abandonment of treatment.
In summary, this study is the first to elucidate the significant efficacy of PD-1 blockade in children and young adults with reproductive line DNA replication repair defects with recurrent/refractory high-mutation cancers, and can improve associated survival rates. The complex interactions between tumor genomic states, microenvironments, and systemic immune responses are revealed, especially in the context of extreme mutations and MS indel burden. The important role of studying hereditary cancer syndromes in understanding the general cancer process and having a direct therapeutic impact on patients was also emphasized.
Original link:
https://doi.org/10.1038/s41591-021-01581-6
Model Maker: Eleven
bibliography
1. Campbell, B. B. et al. Comprehensive analysis of hypermutation in human cancer. Cell 171, 1042–1056 (2017).
2. Chung, J. et al. DNA polymerase and mismatch repair exert distinct microsatellite instability signatures in normal and malignant human cells. Cancer Discov. 11, 1176–1191 (2021).
3. Tabori, U. et al. Clinical management and tumor surveillance recommendations of inherited mismatch repair deficiency in childhood. Clin. Cancer Res. 23, e32–e37 (2017).