Abstract LB-191: Spatiotemporal changes in effector immunity in response to checkpoint blockade immune therapy in acute myeloid leukemia
Authors: David Harris , Usher Lindsay , Bui Thi , Belle Ian , Rainbolt Elizabeth , Kidder Shasta , Meshaw Kay , Hall Chassidy , Mahajan Vivek 
Published: August 2019

To prevent uncontrolled immune cell activation and limit the potential for auto reactivity, T cell responses are subject to multiple levels of regulatory control. In peripheral tissues, tolerance is maintained by regulatory networks and immunosuppressive mechanisms which restrict T cell activity. These same mechanisms can however contribute to failure to mount productive and sustained anti-tumor responses. Therapeutic intervention with immune checkpoint blockade therapy (ICT) restrains negative regulation, re-engages the immune system and promotes enhanced effector responses. Following the success of immunotherapy in certain solid tumors, Nivolumab was the first checkpoint inhibitor approved for treatment of lymphoma, and this approach is now being evaluated in other types of hematological malignancies. Therefore, we developed and characterized an immunocompetent disseminated mouse model for AML using CD11blo CD49b+ PD-L1+, luciferase-transduced C1498 tumor cells. Tumor growth, evidenced by luciferase expression, was progressive and widespread with metastatic development in peripheral organs and tissues and led to increased myeloid (gMDSC, mMDSC, Macrophage, DC) populations in the tumor bearing tissues, characteristic of myeloid leukemia. An efficacious response to therapy was observed, with anti-PD-L1 showing greater overall efficacy than anti-PD-1 and enhancement with combination anti-CTLA-4 therapy. To gain a mechanistic understanding of efficacy, we performed an extensive spatial (blood, spleen, bone marrow, and ovaries) and temporal (after 1st, 3rd and 5th dose of ICT) immune cell profile analysis using flow cytometry, immuno-histochemistry and microarray gene expression in response to mono and combination ICT. In blood, the response to combination immunotherapy was characterized by an initial increase in CD4 T cells (conventional and Tregs), consistent with early priming events after 1st dose of ICT. As the response developed, T cells in blood and spleen expressed elevated Ki67, Granzyme B and CTLA-4 after 3rd and 5th dose of ICT, consistent with development of an established activated effector response. Correspondingly, the NK cell population decreased in spleen and increased in the blood correlating with mobilization of effector response. Similarly, we observed a decrease in CD4 and CD8 cells in spleen, suggesting egress from blood into the sites of neoplasm e.g. ovaries and liver. Besides the lymphoid effector response, we also observed an increase in inhibitory feedback in response to ICT in both blood and spleen. This reflected in increased mMDSC and macrophages population in the blood and an increased PD1+ and CTLA4+ CD4 and CD8 cells in spleen.

Citation Format: Harris David, Lindsay Usher, Thi Bui, Ian Belle, Elizabeth Rainbolt, Shasta Kidder, Kay Meshaw, Chassidy Hall, Vivek Mahajan. Spatiotemporal changes in effector immunity in response to checkpoint blockade immune therapy in acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-191.