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Tumor immunity following radiopharmaceutical + checkpoint blockade varies with treatment sequence, radioisotope, and tumor immunogenicity

ABSTRACT: Radiopharmaceutical therapy (RPT) enhances tumor response to immune checkpoint inhibitors (ICI) in preclinical models, but the effects of different radioisotopes have not been compared. To evaluate mechanisms of response to RPT+ICI, we used NM600, an alkylphosphocholine selectively taken up by most tumors. Effects of 90Y-, 177Lu-, and 225Ac-NM600 + ICIs were compared in syngeneic murine models, B78 melanoma (poorly immunogenic) and MC38 colorectal cancer (immunogenic). 90Y-/177Lu-/or 225Ac-NM600 delivering 2 Gy mean tumor dose promoted tumor regression and improved survival when combined with ICIs in syngeneic mice bearing B78 or MC38 tumors. Regardless of the administered isotope, this combination was optimized with early ICI administration (days -3/0/3) relative to day 1 RPT. 90Y-NM600+ICI produced the greatest anti-tumor response for MC38, whereas high linear energy transfer (LET) alpha particle radiation from 225Ac-NM600+ICI was most effective against poorly immunogenic B78 tumors. Flow cytometry and single cell RNA and T cell receptor (TCR) sequencing illuminated distinct mechanisms of 90Y- or 177Lu-NM600 in promoting expansion of existing adaptive immunity and of 225Ac-NM600 in promoting immune priming when combined with ICI. Antitumor immune response can be achieved with appropriate application of α- or β- emitting RPT in combination with ICIs in diverse murine tumor models.

ORGANISM(S): Mus musculus

PROVIDER: GSE275609 | GEO | 2025/11/10

REPOSITORIES: GEO

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Project description:Murine syngeneic tumor models have been extensively used for cancer research for several decades. These tumor models are very simplistic cancer models, but recent reports have, however, indicated that the different inoculated cancer cells can lead to the formation of very different tumor microenvironments (TMEs). Importantly, these types of tumor models have been instrumental in driving the discovery and development of cancer immunotherapies. In order to gain more knowledge from studies based on syngeneic tumor models it is essential to know in more details the cellular and molecular composition of the TME in the different models. It is also important to know about other parameters such as the mechanical tumor stiffness of the different models. This type of knowledge can be used for the rational selection of tumor models for specific studies and for studying the correlation between different tumor-promoting parameters. Here, we compare the tumor microenvironment (TME) of tumors derived from six different commonly used syngeneic tumor models. Using flow cytometry and transcriptomic analyses we show that strikingly different TMEs are formed by the different cancer cell lines. The differences are reflected as changes in abundance and phenotype of myeloid, lymphoid and stromal cells in the tumors. The gene expression profile of tumors from the different models supported the different cellular composition of the TMEs and indicate that different mechanisms of immune suppression are employed in the different tumor models. Cancer-associated fibroblasts also acquire very different phenotypes in the different tumor models. These differences include differential expression of genes encoding ECM proteins, MMPs, and immunosuppressive factors. In consistence with these observations, the mechanical stiffness of the tumors from different models do not simply correlate to the number of infiltrating CAFs even though collagen produced by stromal cells is an important reason for the increased stiffness of tumors. The gene expression profiles suggest that CAFs can contribute to the formation of an immunosuppressive TME and flow cytometry analyses show CAFs express high levels of PD-L1 in the immunogenic tumor models MC38 and CT26. Comparison with CAF subsets identified in other studies show that CAFs from the different models are skewed towards specific subsets. CAFs from CT26 tumors show similarities to iCAFs and myCAFs, and in athymic mice without infiltrating cytotoxic T cells, CAFs express lower levels of PD-L1 and lower levels of fibroblast activation markers.

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Tumor immunity following radiopharmaceutical + checkpoint blockade varies with treatment sequence, radioisotope, and tumor immunogenicity

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