Abstract B01: Microphysiological systems as a next-generation precision immunotherapy tool: From patient heterogeneity to memory-like natural killer cells
Authors: McBain Catherine A , Farooqui Mehtab A , Virumbrales-Muñoz María , Sanchez-de-Diego Cristina , Teertam Sireesh Kumar , Schmitz Rebecca , Skala Melissa , Beebe David J , Ayuso Jose M 
Published: December 2022

Immunotherapy is transforming cancer treatment for thousands of patients worldwide. However, treatment response relies on the patients’ immune system, eliciting heterogeneous results. Numerous parameters contribute to immunotherapy response, including tumor-intrinsic factors such as an immunosuppressive microenvironment characterized by nutrient depletion, acidic pH, or waste products; and tumor-extrinsic factors including genetic immunodeficiencies, or immunosuppressive disorders like HIV infection or organ transplant medication. Consequently, predicting response to immunotherapy remains challenging. Thus, we designed a microphysiological system (MPS) that allows us to incorporate these factors to evaluate patient-specific immunotherapy efficacy. We used our MPS to assess memory-like natural killer (mNK) cell efficacy against solid tumors, as well as evaluated NK cell exhaustion in a tumor-induced suppressive environment. Focusing upon head and neck squamous cell carcinoma (HNSCC), we evaluated risk/benefit ratios and mNK cell responses, including mNK cell extravasation; tumor penetration/killing; and synergy with therapeutic antibodies. We observed that the tumor-induced microenvironment led to gradual erosion of natural killer (NK) cells’ cytotoxicity and upregulation of exhaustion markers. Interestingly, NK cells exhibited a limited capacity to recover from tumor-induced exhaustion, and checkpoint inhibitors and immunomodulatory agents (e.g., PD-1, IDO-1 inhibitors) partially prevented NK cell exhaustion. We also infected T cells with HIV to evaluate whether immunocompromised patients would benefit from mNK cell therapy in the same fashion. In this context, mNK cells exhibited promising immunotherapeutic potential for these populations as they retained tumor killing capacity even in the absence of T cells; mNK cells exhibited extravasation and migration towards patient-derived tumor spheroids, suggesting that mNK cells alone are capable of extravasation. However, CD4 T cells enhanced mNK responses and elicited overexpression of NK survival and function-associated genes, suggesting that future guidelines for people living with HIV and cancer should consider the progression of the disease when considering mNK cell-based therapies. Our MPS may also help to identify CD4 T cell-secreted factors with therapeutic potential to increase mNK cell responses, which could be provided ex vivo in immunocompromised patients. In summary, MPSs offer a precision tool to assess treatment responses in a patient-specific fashion and may help identify next-generation immunotherapies for hitherto excluded cohorts.

Citation Format: Catherine A McBain, Mehtab A Farooqui, María Virumbrales-Muñoz, Cristina Sanchez-de-Diego, Sireesh Kumar Teertam, Rebecca Schmitz, Melissa Skala, David J Beebe, Jose M Ayuso. Microphysiological systems as a next-generation precision immunotherapy tool: From patient heterogeneity to memory-like natural killer cells [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr B01.