Immunotherapies including immune checkpoint blockade (ICB) and adoptive T cell therapy (ACT) have demonstrated durable responses in many patients with solid tumor malignancies. To maximize the clinical benefit of immunotherapy in cancer patients, it is important to identify molecular determinants in non-responders to cancer immunotherapy and understand how these molecular determinates govern antitumor immune responses. However, advancements in this field are hindered by a lack of high-throughput approaches to comprehensively evaluate the role of tumor intrinsic factors in controlling tumor sensitivity to the immune attack. To address this emerging challenge, we aim to develop a new genetic s...

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Immunotherapies including immune checkpoint blockade (ICB) and adoptive T cell therapy (ACT) have demonstrated durable responses in many patients with solid tumor malignancies. To maximize the clinical benefit of immunotherapy in cancer patients, it is important to identify molecular determinants in non-responders to cancer immunotherapy and understand how these molecular determinates govern antitumor immune responses. However, advancements in this field are hindered by a lack of high-throughput approaches to comprehensively evaluate the role of tumor intrinsic factors in controlling tumor sensitivity to the immune attack. To address this emerging challenge, we aim to develop a new genetic screen platform by integrating the functional immune screen system established in our previous studies with single cell RNA sequencing technology. By using this genetic screen platform, the potential immunosuppressive effects of candidate genes which were selected from our genome-wide screens using murine and human tumor cell lines, will be characterized in multiple clinically relevant murine tumor models. The success of this project will not only provide a valuable tool to rapidly screen genes/pathways for their potential to sensitize tumors to immunotherapy, but also reveal a mechanistic blueprint of immune evasion among non-responders to cancer immunotherapy. The potential benefits of the proposed studies include identifying novel biomarkers to predict patients who are most likely to benefit from immunotherapies, and the development of personalized combinations to overcome immune resistant mechanisms for application in future clinical interventions.

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