Abstract 2051: Precision immune phenotyping from primary tumor and metastatic lesions reveals novel insights into therapeutic intervention in cancer immunotherapy
Authors: Roller Andreas , Ferreira Claudia , Jarassier Laura , Heller Astrid , Dietmann Gabriele , Korski Konstanty , Gomes Bruno , Cannarile Michael A. 
Published: September 2020

Abstract
A key question in cancer immunotherapy is the general immune status of the patient's tumor-microenvironment (TME) prior to therapy. A patient's underlying tumor immune-contexture may therefore a) guide the therapeutic intervention and b) help to identify potential resistance mechanisms to immunotherapies. The most commonly used classification of the patients' immune status is based on the CD8 tumor infiltrating lymphocytes (TIL) status referring to either “cold”- or “hot” tumors. Patients in early clinical development programs will mostly present with late metastatic disease and therefore the immune phenotypes from these lesions may more relevant to determine the actual tumor-immune contexture status than the currently used characterization based on the primary tumor type. In this study, we systematically analyzed the CD8 immune phenotype (CD8 IP) in 454 patients from various Phase 1 clinical trials using the commonly applied CD8 immnohistochemistry (IHC)-based classification into cold (CD8 deserts) and hot (CD8 excluded and inflamed) tumors and matched gene expression profiling. In total, we observed 116 inflamed, 95 excluded, and 243 desert phenotypes from 25 different indications. The main sources of tumor biopsy tissues were liver metastasis (N=151), lymph node (N=73) as well as lung (N=59). Overall, we identified a significant overrepresentation of the desert phenotype in liver metastasis (p=1e-05). In patients with metastatic disease, we compared the predominant CD8 IP in metastatic lesions to that of the primary tumor. The overall distribution for tumor types such as UBC, NSCLC or OvCa did not change, whereas PDAC, GC, and CRC revealed a significant change towards the desert phenotype for metastatic lesions. Beyond the predominant CD8 IP assessment via IHC, we characterized each CD8 subtype further using specific immune gene signatures. We could identify a reverse correlation of inflammatory and suppressive immune signatures along the CD8 phenotypes in metastatic lesions such as M2-like macrophages, MDSC, or Dendritic Cells. Further zooming into the desert phenotype, we were also able to show that liver metastasis have a more significant immunosuppressive tumor environment compared to other tumor biopsies. In summary, our data provide essential insights about the importance of the origin of the tissue biopsy to reduce impaired decision making based on the underlying tumor-immune contexture of cancer patients. Precision immune phenotyping beyond CD8 TIL infiltration is needed to identify specific resistance mechanisms to cancer immunotherapy and can be used for efficient patient enrichment and thus increase the probability of success for early clinical trials in immuno-oncology.
Citation Format: Andreas Roller, Claudia Ferreira, Laura Jarassier, Astrid Heller, Gabriele Dietmann, Konstanty Korski, Bruno Gomes, Michael A. Cannarile. Precision immune phenotyping from primary tumor and metastatic lesions reveals novel insights into therapeutic intervention in cancer immunotherapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2051.