Immune Checkpoint Inhibitors in Tumors Harboring Homologous Recombination Deficiency: Challenges in Attaining Efficacy

Abstract

Cancer cells harbor genomic instability due to accumulated DNA damage, one of the cancer hallmarks. At least five major DNA Damage Repair (DDR) pathways are recognized to repair DNA damages during different stages of the cell cycle, comprehending base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), homologous recombination (HR), and non-homologous end joining (NHEJ). The unprecedented benefits achieved with immunological checkpoint inhibitors (ICIs) in tumors with mismatch repair deficiency (dMMR) have prompted efforts to extend this efficacy to tumors with HR deficiency (HRD), which are greatly sensitive to chemotherapy or PARP inhibitors, and also considered highly immunogenic. However, an in-depth understanding of HRD's molecular underpinnings has pointed to essential singularities that might impact ICIs sensitivity. Here we address the main molecular aspects of HRD that underlie a differential profile of efficacy and resistance to the treatment with ICIs compared to other DDR deficiencies.

Keywords: DNA damage repair; homologous recombination; immune checkpoint inhibitors; mismatch repair; oncology.

Figure 1

Increased rate of DNA double strands breaks due to deficiency in HR might evolve with molecular events that lead to challenges in restoring immune responses through immune checkpoint inhibitors. (1) DNA double-strand breaks association with CNV and large structural genetic alterations contribute to an increased flux of unstable mRNA and, ultimately, proteins that may saturate critical chaperones and the proteasome complex, thus leading to a dysfunctional tumor antigen presentation. (2) ATM plays a central role in recognizing DNA strand breaks but can also upregulate glycolysis and PPP to replenish nucleotides and NADPH supply for the upcoming anabolic reactions to restore DNA damages. This metabolic regulation might deprive glucose in the tumor microenvironment and export acid lactic, impacting immune responses. (3) CHK1 is crucial to repair strands breaks but may also activate the STAT1-STAT3-IRF1 signaling pathway that contributes to upregulating PD-L1 expression. (4) Cytosolic DNA censoring can lead to STING-IRF3 production of IFN-I, which might recruit monocytes that will be further exposed to a range of tolerogenic stimuli in the tumor microenvironment. Moreover, the STING signaling pathway might induce IDO1, and the expression of IFN-I might upregulate CD73, thus contributing to producing inhibitory molecules in the tumor microenvironment. Created with BioRender.com.