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

Falih M Gorgun,Douglas S Tyler,Steven G Widen,Ella W Englander

doi:10.3389/fonc.2021.701968

Falih M Gorgun, Douglas S Tyler + Show 2 more

Open Access

https://doi.org/10.3389/fonc.2021.701968

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Abstract

Sequencing data from different types of cancers including melanomas demonstrate that tumors with high mutational loads are more likely to respond to immune checkpoint blockade (ICB) therapies. We have previously shown that low-dose intratumoral injection of the chemotherapeutic DNA damaging drug cisplatin activates intrinsic mutagenic DNA damage tolerance pathway, and when combined with ICB regimen leads to tumor regression in the mouse YUMM1.7 melanoma model. We now report that tumors generated with an in vitro cisplatin-mutagenized YUMM1.7 clone (YUMM1.7-CM) regress in response to ICB, while an identical ICB regimen alone fails to suppress growth of tumors generated with the parental YUMM1.7 cells. Regressing YUMM1.7-CM tumors show greater infiltration of CD8 T lymphocytes, higher granzyme B expression, and higher tumoral cell death. Similarly, ex-vivo, immune cells isolated from YUMM1.7-CM tumors-draining lymph nodes (TDLNs) co-incubated with cultured YUMM1.7-CM cells, eliminate the tumor cells more efficiently than immune cells isolated from TDLNs of YUMM1.7 tumor-bearing mice. Collectively, our findings show that in vitro induced cisplatin mutations potentiate the antitumor immune response and ICB efficacy, akin to tumor regression achieved in the parental YUMM1.7 model by ICB administered in conjunction with intratumoral cisplatin injection. Hence, our data uphold the role of tumoral mutation burden in improving immune surveillance and response to ICB, suggesting a path for expanding the range of patients benefiting from ICB therapy.

Highlights

Differences in tumoral mutational burden have emerged as predictors of clinical outcomes of immune checkpoint blockade (ICB) therapies across different cancers [1, 2]
Considered together, our findings show that the in vitro cisplatin-mutagenized YUMM1.7-CM melanoma clone-generated tumors respond to ICB regimen to the parental YUMM1.7-generated tumors, subjected in vivo to intratumoral cisplatin injection, supporting a pivotal role for increases in tumoral mutational loads in augmentation of the host’s antitumor immune response
Our study demonstrates that tumors generated with in vitro mutagenized YUMM1.7-CM cells elicit a productive antitumor immune response in vivo, in the mouse (Figure 9)

Summary

Introduction

Differences in tumoral mutational burden have emerged as predictors of clinical outcomes of immune checkpoint blockade (ICB) therapies across different cancers [1, 2]. 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 antiCTLA-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 lowdose 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. This targeted approach affords an important advantage over conventional chemotherapy, because tightly calibrated intratumoral delivery of a chemotherapeutic drug allows for significant dose reduction limiting debilitating generalized toxicity, while achieving durable desired antitumor effect via revitalized immune response

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