Abstract 959: Cellular dynamics of productive anti-tumor response mediating long-term rejection of disseminated lung tumors after systemic therapy with oncolytic adenovirus
Authors: Yao Jia , Atasheva Svetlana , Young Cedrick B. , Shayakhmetov Dmitry M. 
Published: September 2020

Currently, some of the most advanced and clinically effective solid cancer treatment approaches are based on counteracting immune checkpoint inhibitory pathways (ICI) to activate cytotoxic activity of tumor antigen-specific CD8+ T cells. Unfortunately, the use of ICI targeting drugs provides clinical benefits only to a minority of cancer patients. Although major efforts are put forth to improve understanding of CD8+ T cell-centric adaptive immune mechanisms to increase the the proportion of cancer patients responding to this therapy, the effector functions of innate immunity in mediating tumor rejection remain poorly understood. Using a CD8+ T cell-deficient mouse model and a disseminated human lung cancer model, allowing for a productive replication of human oncolytic adenovirus, AVID-317, in this study we analyzed the recruitment and activation states of hematopoietic and stromal cells that enter the lungs of tumor-bearing mice after systemic oncolytic virus therapy and their correlation with the efficacy of anti-tumor response. Intravenous administration of AVID-317 resulted in a significant suppression of tumor growth and extension of survival of mice with disseminated tumors in the lungs. However, the longitudinal analyses showed that two distinct cohorts of mice could be identified within 21 days after the beginning of the therapy - one where mice responded by a complete rejection of disseminated lung tumors (complete responders) and the other, where mice exhibited unimpeded tumor progression (non-responders). Multi-dimensional flow cytometry analysis revealed that after oncolytic virus treatment, there were quantitative and qualitative differences in tumor-infiltrating cells recovered from the lungs of responder and non-responder mice. After oncolytic virotherapy, the tumor infiltrating cells in non-responder mice were significantly enriched for inflammatory myeloid Ly-6G-, Ly6C-, and CD11b-expressing cells, which also expressed high levels of CD80/CD86 and MHC class II proteins, indicating their highly activated state. In contrast, in responder mice, the tumor infiltrating cells were significantly enriched for B cells, NKT cells, and Ly-6C- and Sca-1-positive stromal cells. The influx of B cells, NK, and NKT cells in the lungs after systemic AVID-317 therapy significantly correlated with tumor burden reduction. Although the relative abundance of NK cells was not different between responder and non-responder mice, the single cell transcriptomics analysis showed that NK cells in responder mice expressed higher levels of KLRG1 and KLRC1 terminal effector markers and perforin. Taken together, our data provides evidence that a systemic therapy with oncolytic adenovirus promotes significant alteration of the tumor microenvironment, leading to the recruitment of lymphocytes, namely B cells, NK cells, and NKT cells, with effector functions, which mediate long-lasting rejection of disseminated lung tumors via innate immune mechanisms.

Citation Format: Jia Yao, Svetlana Atasheva, Cedrick B. Young, Dmitry M. Shayakhmetov. Cellular dynamics of productive anti-tumor response mediating long-term rejection of disseminated lung tumors after systemic therapy with oncolytic adenovirus [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 959.