Single-cell Characterization of Acute Myeloid Leukemia and its Microenvironment Following PD-1 Blockade Based Therapy

Abbas, H. A.; Hao, D.; Tomczak, K.; Baroodia, P.; Im, J.; Reville, P. K.; Alaniz, Z.; Wang, W.; Wang, R.; Wang, F.; Al-Atrash, G.; Takahashi, K.; Ning, J.; Ding, M.; Matthews, J.; Little, L.; Zhang, J.; Basu, S.; Konopleva, M.; Garcia-Manero, G.; Green, M. R.; Sharma, P.; Allison, J.; Kornblau, S.; Rai, K.; Wang, L.; Daver, N.; Futreal, A.

doi:10.1101/2020.09.03.278309

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bioRxiv · 10.1101/2020.09.03.278309

Single-cell Characterization of Acute Myeloid Leukemia and its Microenvironment Following PD-1 Blockade Based Therapy

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Abstract

Acute myeloid leukemia (AML) and effector cells of immune checkpoint blockade (ICB) therapy co-reside in a complex bone marrow (BM) milieu. The interplay of tumor intrinsic and microenvironment (TME) mechanisms that influences the response to ICB-based therapies in AML have not been elucidated. Here we report our analyses of single cell RNA profiling of more than 127,000 BM cells from healthy donors and relapsed/refractory (R/R) AML patients at pre/post treatment with azacitidine/nivolumab, paired with single cell T cell receptor (TCR) repertoire profiles, to uncover factors impacting response and resistance. Loss of chromosome 7/7q conferred an immunosuppressive TME and was associated with resistance to ICB-based therapy in R/R AML. Our trajectory analysis revealed a continuum of CD8+ T cell phenotypes, characterized by differential expression of granzyme B (GZMB) and GZMK. GZMK expression defined a BM residing memory CD8+ T cell subset with stem-like properties likely an intermediary between naive and cytotoxic lymphocytes. Responses to ICB-based therapy were primarily driven by novel and expanded T cell clonotypes. Our findings support an adaptable T cell plasticity in response to PD-1 blockade in AML. Disentangling AML cells from their complex, immune-rich microenvironment revealed characteristics that shaped resistance to ICB-based therapy and could inform strategies to target AML vulnerabilities. SignificanceDetermining the cellular and molecular underpinnings of response and resistance to PD-1 blockade based therapy in AML can guide immune-based therapeutic strategies. Our results reveal AML intrinsic characteristics (chromosome 7/7q status and oxidative stressors) and tumor microenvironment to modulate responses to checkpoint blockers. CD8 cells exist in the bone marrow in a continuum with GZMK expression defining a memory, stem-like T cell population that could play a role in response to therapy.

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Abbas, H. A., Hao, D., Tomczak, K., Baroodia, P., Im, J., Reville, P. K., Alaniz, Z., Wang, W., Wang, R., Wang, F., Al-Atrash, G., Takahashi, K., Ning, J., Ding, M., Matthews, J., Little, L., Zhang, J., Basu, S., Konopleva, M., Garcia-Manero, G., Green, M. R., Sharma, P., Allison, J., Kornblau, S., Rai, K., Wang, L., Daver, N., Futreal, A.. 2020-09-03. Single-cell Characterization of Acute Myeloid Leukemia and its Microenvironment Following PD-1 Blockade Based Therapy. https://doi.org/10.1101/2020.09.03.278309

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