Transient activation of tumoral DNA damage tolerance pathway coupled with immune checkpoint blockade exerts durable tumor regression in mouse melanoma

Abstract

Major advances in cancer therapy rely on engagement of the patient’s immune system and suppression of mechanisms that impede the antitumor immune response. Among the most notable is immune checkpoint blockade (ICB) therapy that releases immune cells from suppression. Although ICB has had significant success particularly in melanoma, it eradicates tumors in subsets of patients and sequencing data across different cancers suggest that tumors with high mutational loads are more likely to respond to ICB. This is consistent with the premise that greater tumoral mutational loads contribute to formation of neoantigens that spur the body’s antitumor immune response. Prompted by strong evidence supporting the therapeutic benefits of neoantigens in the context of ICB, we have developed a mouse melanoma combination treatment, where intratumoral administration of DNA‐damaging drug transiently activates intrinsic mutagenic DNA damage tolerance pathway and improves success rates of ICB. Using the YUMM1.7 cells melanoma model, we demonstrate that intratumoral delivery of cisplatin activates translesion synthesis DNA polymerases‐catalyzed DNA synthesis on damaged DNA, which when coupled with ICB regimen, elicits durable tumor regression. We expect that this new combination protocol affords insights with clinical relevance that will help expand the range of patients who benefit from ICB therapy.

Enhanced Antitumor Response to Immune Checkpoint Blockade Exerted by Cisplatin-Induced Mutagenesis in a Murine Melanoma Model

“…Importantly, in the YUMM1.7-CM tumor-bearing mice/ ICB treatment group, nearly all tumors regressed, while growth of YUMM1.7 tumors was not suppressed by the ICB regimen (Figure 8B). This is consistent with our earlier findings, that demonstrated that a combination protocol that includes ICB in conjunction with intratumoral cisplatin delivery is required for eradication of YUMM1.7 melanoma tumors (13).…”

“…Female 8–10-week-old C57BL/6 mice were purchased from Envigo (USA) and acclimated for 2 weeks. YUMM1.7 or YUMM1.7-CM tumors were generated by subcutaneous inoculation of 5 × 10 4 cells suspended in a 2:1 PBS/solubilized Matrigel Membrane Matrix (#354234 Corning) into upper left hindlimb as we described ( 13 ). Tumor dimensions were recorded 3×/week using vernier calipers and the formula: volume = ([length] × [width] 2 )/2 to calculate the volume ( 19 ).…”

“…Activation of the DNA damage tolerance pathway involves recruitment of error-prone translesion synthesis (TLS) DNA polymerases ( 6 , 11 ). Using the YUMM1.7 melanoma mouse model ( 12 ), we have previously demonstrated that tumoral TLS polymerases are transiently elevated following intratumoral delivery of the DNA damaging chemotherapeutic drug, cisplatin ( 13 ) and that the anti-CTLA-4/anti-PD-1 ICB regimen ( 14 , 15 ), given in conjunction with intratumoral cisplatin, leads to complete tumor regression in the mouse ( 13 ). These findings are consistent with the notion that low-dose chemotherapeutic treatments that increase tumoral mutation burden contribute to formation of immunogenic neoantigens and thereby provide a plausible path for enhancing the host’s antitumor immune response and improving immunotherapy outcomes.…”

Translesion Synthesis or Repair by Specialized DNA Polymerases Limits Excessive Genomic Instability upon Replication Stress

“…In line with this possibility, a previous report has highlighted an important role of Polκ in sustaining resistance to the alkylating agent temozolomide in glioblastoma through activation of the ATR/Chk1 pathway [ 89 ], confirming a previous observation implicating Polκ in Chk1 phosphorylation [ 38 ]. Finally, upregulation of TLS Pols coupled with immunocheckpoint blockade has been reported to improve tumor regression upon treatment with cisplatin [ 90 ]. Altogether, these observations put TLS as an emerging appealing pathway to sensitize cancer cells to the therapy.…”

Activation of DNA Damage Tolerance Pathways May Improve Immunotherapy of Mesothelioma

“…This partial response may be explained by the low mutational burden encountered in MM. According to data available in other cancers, such as melanoma or non-small cell lung cancer (NSCLC), responders to ICI therapy typically present high numbers of somatic mutations in genomic coding regions [25,26]. The underlying prediction is that mutated genes generate altered-self proteins that can be processed in the form of small peptides, referred to as neoantigens, and presented on the major histocompatibility complex I (MHC-I) molecules at the surface of tumor cells.…”