ID #280 Organ-specific immune editing affects mutational burden and response to immunotherapy in replication repair deficient cancers
Zoya Aamir, Melissa Galati, Owen Crump, Lucie Stengs, Emma Gattoni, Jose Dimayacyac, Yuan Chang, Nuno Nunes, Taylor Bridge, Sumedha Sudhaman, Brian Chung, Susie Wang, Dar’ya Semenova, Dana Elshaer, Vanessa Bianchi, Melissa Edwards, Magimairajan Issai Vanan, Anirban Das, Cynthia Hawkins, Uri TaboriAbstract
Introduction
Replication repair deficiency (RRD) is a pan-cancer mechanism characterized by hypermutagenesis and variable response to immunotherapy. Total tumor mutational burden (TMB) is a potential predictor for cancer response to immunotherapy, however, whether organ-specific immune regulation of mutation accumulation during tumorigenesis is present, remains unclear.
Methods
To address this question and gain understanding on differential immune surveillance in intracranial and extracranial tumors, we created a novel RRD (MMRD/ POLE mutant) glioma mouse model. We then performed a trans-species analysis comparing RRD mutagenesis of murine and human cancers from intracranial and extracranial origins to study tumor kinetics, clonal evolution, and the effects of immunotherapy on TMB and immunogenic neoantigens during tumorigenesis.
Results
In humans, CNS tumors exhibited lower immune cell infiltration (p = 0.001) and survival (p = 0.03) than extracranial tumors, similar to our observations in immunocompetent mice, where intracranial tumors equally displayed low immune infiltration and worse survival outcomes (p = 0.002) compared to extracranial tumors. Interestingly, despite obligatory mutagenesis, TMB was reduced during tumor relapse in human cancers and upon re-implantation in immunocompetent mice (p < 0.05). In contrast, TMB dramatically increased in human RRD cell glioma cell lines grown in vitro and in tumors reimplanted in immunocompromised mice, particularly in the CNS (p < 0.05). In immunocompetent mice, the tumor-growth driving ability of RRD glioma cell lines with different TMB exhibited an association between higher TMB, lower penetrance, higher immune infiltration (p = 0.0005), and improved survival outcomes over lower TMB (p = 0.01). Finally, neoantigen analysis in mouse and human gliomas pre- and post-immunotherapy revealed fewer immunogenic neoantigens after therapy (p < 0.05). Longitudinal human biopsies revealed an initial increase in neoantigen burden during immunotherapy response, followed by a marked loss of neoantigens at relapse.
Significance
This trans-species analysis confirms CNS as an immune “sanctuary” site and highlights continuous organ-specific immunoediting, which determines tumor progression and response to immunotherapy.