Immune organoids: from tumor modeling to precision oncology

Abstract

Cancer immunotherapies, particularly immune checkpoint inhibitors, are rapidly becoming standard-of-care for many cancers. The ascendance of immune checkpoint inhibitor treatment and limitations in the accurate prediction of clinical response thereof have provided significant impetus to develop preclinical models that can guide therapeutic intervention. Traditional organoid culture methods that exclusively grow tumor epithelium as patient-derived organoids are under investigation as a personalized platform for drug discovery and for predicting clinical efficacy of chemotherapies and targeted agents. Recently, the patient-derived tumor organoid platform has evolved to contain more complex stromal and immune compartments needed to assess immunotherapeutic efficacy. We review the different methodologies for developing a more holistic patient-derived tumor organoid platform and for modeling the native immune tumor microenvironment.

Keywords: Patient-derived tumor organoids; immune checkpoint inhibitors; precision oncology.

Figure 1.. Patient-derived tumor organoid (PDO) platforms that recapitulate the immune tumor microenvironment.

The immune tumor microenvironment can be constructed in PDOs via several approaches. (A) In the assembloid PDO platform, organoids containing exclusively tumor cells, often from physically and enzymatically dissociated tissues, are cultured in an extracellular matrix dome (Matrigel or BME) and submerged beneath tissue culture medium. In parallel, immune cells are isolated from peripheral sources (i.e., peripheral blood, lymph node) or from the tumor (i.e., tumor infiltrating lymphocytes, TIL) and subsequently co-cultured with the tumor organoid. (B) Alternatively, these isolated immune cells can be combined with physically and enzymatically dissociated tumors before submerging in an extracellular matrix dome. (C) Several PDO platforms have incorporated native tumor-infiltrating immune cells. In the patient- and murine-derived organotypic tumor spheroid (PDOTS/MDOTS) platform, tumors are physically and enzymatically dissociated, filtered to obtain appropriately sized spheroids, resuspended in a collagen matrix, then the spheroid-collagen mixture is injected into a 3D microfluidic culture device. (D) In the air-liquid interface (ALI) platform, physically dissociated tumor fragments are embedded in a collagen matrix on top of a transwell insert that is exposed to air with culture medium below it. (E) In the patient-derived tumor fragment (PDTF) platform, 1–2 mm³ tumor fragments are cut from different regions within a tumor and individually embedded into a collagen-based extracellular matrix with culture medium placed on top. Figure created with BioRender.com.