Homologous Recombination Repair Deficiency and Implications for Tumor Immunogenicity

Abstract

Homologous recombination repair deficiency (HRD) can be observed in virtually all cancer types. Although HRD sensitizes tumors to DNA-damaging chemotherapy and poly(ADP-ribose) polymerase (PARP) inhibitors, all patients ultimately develop resistance to these therapies. Therefore, it is necessary to identify therapeutic regimens with a more durable efficacy. HRD tumors have been suggested to be more immunogenic and, therefore, more susceptible to treatment with checkpoint inhibitors. In this review, we describe how HRD might mechanistically affect antitumor immunity and summarize the available translational evidence for an association between HRD and antitumor immunity across multiple tumor types. In addition, we give an overview of all available clinical data on the efficacy of checkpoint inhibitors in HRD tumors and describe the evidence for using treatment strategies that combine checkpoint inhibitors with PARP inhibitors.

Keywords: cancer; homologous recombination repair deficiency; immune checkpoint inhibitors.

Figure 1

Homologous recombination repair (HR). HR commences with the recognition of double-strand DNA breaks by ATM and ATR. ATM and ATR activate BRCA1, which plays a key role in the recruitment of repair proteins needed for DNA end resection. DNA end resection generates a long 3′ single-strand DNA tail that can invade the homologous DNA strand (sister chromatid). After end resection, RAD51 is loaded on the single-strand DNA tail with the help of BRCA2 and PALB2. The strand then invades the homologous DNA strand where the actual DNA repair is performed. Since a sister chromatid is used as a template for DNA repair, HR is considered a relatively error-free process. Of note, besides the proteins depicted here, many other proteins are involved in HR.

Figure 2

The genomic landscape of BRCA-mutated and BRCA-wildtype tumors. The depicted circos plots were generated using whole genome sequencing data of CPCT-02 study participants treated in the Radboudumc. Results of the CPCT-02 have previously been published elsewhere [30]. The outer first circle shows the chromosomes. The darker areas represent large gaps in the human reference genome, i.e., regions of centromeres. The second circle shows all somatic single nucleotide variants (SNVs) across the genome. Tumor purity-adjusted allele frequencies are scaled from 0% to 100%. SNVs are colored according to the type of base change in concordance with coloring used in previous literature [31]. Base substitutions that frequently occur in HRD are displayed in blue (C > A) and black (C > G). The third circle depicts short insertions (yellow) and deletions (red, indels). The fourth circle shows all copy number changes. Losses and gains are indicated in red and green, respectively. The scale ranges from 0 (complete loss) to 6 (high-level gains). Absolute copy numbers above 6 are indicated by a green dot on the diagram. The fifth circle represents the observed minor allele copy numbers. The scale ranges from 0 to 3, with losses (<1) shown in orange and gains (>1) shown in blue. The innermost circle displays the structural variants within or between the chromosomes. Translocations are indicated in blue, deletions are indicated in red, insertions are shown in yellow, tandem duplications are indicated in green, and inversions are shown in black. The figure shows that BRCA-mutated tumors generally have higher numbers of SNVs, small indels, deletions, and tandem duplications (the latter is only more frequent in BRCA1-mutated tumors).

Figure 3

Telomeric allelic imbalance (TAI), loss of heterozygosity (LOH), and large-scale state transitions (LSTs). (a) Genomic scars characteristic for homologous recombination repair deficiency (HRD) include TAI, LOH, and LSTs. Allelic imbalance is the imbalance in paternal and maternal alleles with or without changes in the overall copy number of that region. Characteristic for HRD is AI at the telomeric end of a chromosome (TAI). LOH refers to the situation where one of the two alleles that was originally present in the cell is lost. LSTs are defined as chromosomal breaks between adjacent regions of at least 10 mb. (b) CNV profile of an HRD tumor. The plot was generated using whole genome sequencing data of a CPCT-02 study participant treated in the Radboudumc [30]. Dots represent regions of 10 mb. As LSTs lead to copy number changes, dots with a log ratio ≠ 0 indicate LSTs.