Abstract 1813: The genetic makeup of patient-derived xenografts shapes the immune landscape of humanized mice tumors
Authors: Maneesh Singh, Laura Bradshaw, Laura B. Prickett, Griffin Matthew, Maryann San Martin, Noel Monks, Lisa Drew, Simon T. Barry, Corinne Reimer, Theresa Proia
Journal: Cancer Research (2021)

Abstract The complex interplay between the immune system and cancer cells is challenging to model in preclinical species. Many commonly mutated genes that influence tumorigenesis actively participate in the activation, recruitment or suppression of the immune system. A growing body of clinical findings indicates that defined oncogenic driver mutations correlate with immune contexture and associated immunotherapy responses. The goal of this study was to generate a hematopoietic stem cells (HSCs) transplanted humanized mice model using patient-derived xenografts with defined mutations to understand whether genetic alterations in the cancer cells can influence the tumor's immune landscape. Loss of function in the tumor suppressor gene STK11/LKB1 are observed in 5-30% of NSCLC. Patients with STK11 mutations do not typically respond to immune checkpoint blockade, and analysis of patient tumor biopsies indicates that these tumors are poorly infiltrated by immune cells such as T cells and dendritic cells, but with higher density of suppressive myeloid cells and associated cytokines. Therefore, there is an interest to understand ways to improve IO responses in these patients. To determine whether we could recapitulate this biology in a preclinical model, we implanted three STK11mut and one wild type PDX on humanized mice generated from six cord blood donors, and compared the immune infiltration in these tumors. Our results demonstrate efficient engraftment of human immune cells in the peripheral blood (53.1%), spleen (64.2%), and bone marrow (59.3%) of humanized mice (n=29, animals). Along with T and B cells, myeloid immune populations such as monocytes, macrophages and dendritic cells, which are absent in the previous generation of humanized mice, were present in the peripheral blood (monocytes 4.7%, dendritic cells 7.2% ) and bone marrow (macrophage 27.8%, neutrophils 21.6% and 10.2% dendritic cells ) of humanized mice. Tumor human immune subpopulation cells were significantly different (One-way Anova analysis) between the STK11mut (n=3) vs. wild type (n=1) humanized PDXs models (n=7 animals/PDX model). Three STK11mut tumors had low percentage of human CD45+ leukocytes infiltration (STK11mut; 0.9, 1.1 and 2.3% vs. wt; 6.6%) We also found a significantly reduced percentage of CD8+ cytotoxic T cells (STK11mut; 5.6, 3.2, 3.1% vs. wt; 9.6%) and dendritic cells subsets (STK11mut; 3.6, 2.2, 3.1% vs. wt; 5.6%) in the STK11mut PDXs implanted on humanized mice. We have shown efficient engraftment of a multilineage human immune system in immunodeficient mice and a selective infiltration of human immune cells subsets in PDXs representing a key genetic segment of NSCLC. Our novel humanized PDX model can recapitulate human tumor immune reconstitution, providing a valuable opportunity to evaluate the benefit of immunomodulatory therapies and personalize immune intervention strategies. Citation Format: Maneesh Singh, Laura Bradshaw, Laura B. Prickett, Griffin Matthew, Maryann San Martin, Noel Monks, Lisa Drew, Simon T. Barry, Corinne Reimer, Theresa Proia. The genetic makeup of patient-derived xenografts shapes the immune landscape of humanized mice tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1813.