Insight into the effect of mitochondrial function on immune function in the context of tumor infiltrating lymphocyte therapy.
2Ella Lemelbaum Institute for Immuno-Oncology, Sheba Medical Center, Israel
3Sackler Faculty of Medicine, Tel Aviv University, Israel
4Department of Pathology, Sackler School of Medicine, Tel Aviv University, Israel
During the last decades, an accumulation of literature has shown a link between mitochondrial function and the immune system such as in T cell differentiation. However, the underlying mechanism of immune cell regulation by mitochondrial function is still poorly understood. Preliminary data from our lab suggested a critical role of mitochondrial haplotype on determining T cell functions. Recently, our institute reported that mitochondrial function in tumor samples correlates with response to immunotherapy in melanoma patients. Melanoma is a malignant transformation of melanocytes. The first-line treatment for melanoma is immune checkpoint inhibitors (CPI), however, up to 70% of patients progress despite treatment. Adoptive cell therapy (ACT) with Tumor Infiltrating Lymphocytes (TIL), is offered as salvage treatment in these cases. Despite TIL therapy showing up to 55% response rate in ICP-naïve patients, the response rate in pretreated patients is as low as 24%. A potential explanation for the differences in response to primary CPI therapy and salvage TIL therapy could be the TILs` mitochondrial state. Based on the above our hypothesis is that the mitochondrial function of T cells determines immune function and response to immunotherapy in melanoma.
To explore our hypothesis, we identified and classified archival TIL samples from patients demonstrating complete, partial, and non-response to ACT (both CPI naïve and pretreated). We optimized a protocol for evaluating mitochondrial function of TILs by using Seahorse xf96 analyzer. Utilizing our protocol, we assessed the classified samples for mitochondrial function, and correlated it to their immunological profile. Our preliminary testing showed a difference in basal respiratory rate between responders (n=3) and non-responders (n=3) (1.3±0.8 vs 0.7±0.3, p<0.001, respectively).
Results of our study could deepen our understanding of the effects of mitochondrial function on T cell activity.
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