Abstract 2662: Mitochondrial genetics appear to alter immune cell development/trafficking
Authors: Beadnell Thomas C. , Brinker Amanda E. , Fain Cori , Vivian Carolyn J. , Welch Danny R. 
Published: September 2020

Background Metastatic burden is the leading cause of cancer deaths; however, it remains unclear why some patients are more susceptible to metastatic disease. While the nuclear genome's role in tumor progression and metastasis is known, the role of mitochondrial DNA (mtDNA) polymorphisms (SNP) has only recently been explored. Using mitochondrial nuclear exchange (MNX) mice, we previously showed that mtDNA strongly influences mammary carcinoma progression and metastasis both intrinsically and via non-cell autonomous mechanisms. We hypothesized that mtDNA SNP alter immune cell development/trafficking which, in turn, could influence metastasis efficiency.

Methods Peritoneal exudate, and splenocytes were collected from male and female wild-type C57BL/6J (CC) and C3H/HeN (HH), and MNX mice - C57BL/6-mtMNX(C3H/HeN) (CH) and C3H/HeN-mtMNX(C57BL/6J) (HC) mice [first letter=nuclear; second letter=mitochondrial]. Lung metastases were established from tail-vein injection of E0771 (CC/CH) or K1735-M2 (HH/HC) cell lines.

Results Lung metastases derived from histocompatible (i.e. nDNA matched) tumor cell injection into wild-type or MNX mice increased in C3H/HeN mtDNA backgrounds (HH and CH). No significant differences were observed in seeding, suggesting that mtDNA mediated differences in metastatic microenvironments likely impact metastatic outgrowth. No significant changes in broad immune cell populations were observed in naïve animals, but selective changes in differentiation markers were observed. The most significant change was lower CD11c+ peritoneal macrophages in HH (3%) versus CC (16%) mice (p &lt; 0.001). C57BL/6 mtDNA (HC) increased the percentage of macrophages (9%) compared to wild-type (HH) (p &lt; 0.001). We next confirmed a role for mitochondrial derived ROS mediating immune microenvironmental regulation of metastasis, as mtDNA mediated metastatic differences are abrogated upon treatment with the anti-oxidant MitoTEMPO. Tumor infiltrating CD8+ lymphocytes (TIL) increased 1.5-fold in CH (1.7%) compared to wild-type CC (1.2%) (p = 0.07) while no differences were observed between HH and HC mice. Consistent with changes in metastasis in the HH background, MitoTempo treatment reduced CD4+ TIL &gt;1.5-fold (1.5%), compared to the vehicle control (2.8%) (p = 0.029).

Discussion Our data support the hypothesis that mitochondrial SNP modulate immune cell development and/or trafficking, providing a plausible explanation for how metastatic potentials of syngeneic tumor cells injected into MNX mice are altered. That is, mtDNA contributions to immune function affect metastasis and may provide insight as to why some immune therapies succeed/fail.

Support: DOD BCRP BC171381 and Kansas INBRE P20 GM103418 (TCB); Susan G. Komen for the Cure SAC110037; National Foundation for Cancer Research and NIH CA168524 (DRW)

Citation Format: Thomas C. Beadnell, Amanda E. Brinker, Cori Fain, Carolyn J. Vivian, Danny R. Welch. Mitochondrial genetics appear to alter immune cell development/trafficking [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2662.