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Immune Signatures of Murine and Human Cancers Reveal Unique Mechanisms of Tumor Escape and New Targets for Cancer Immunotherapy

Authors' Affiliation: Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California

Requests for reprints: Alan L. Epstein, Department of Pathology, University of Southern California, Keck School of Medicine, 2011 Zonal Avenue, HMR 205, Los Angeles, CA 90033. Phone: 323-442-1172; Fax: 323-342-3049; E-mail: aepstein{at}usc.edu.

Purpose: Despite lymphocyte infiltration of tumors and the activation of tumor-draining lymph nodes, malignant tumors are able to "escape" from both innate and adaptive immune responses. For immunotherapy to be successful, it must reverse these escape mechanisms, which necessitates explicit and tumor-specific elucidation of tumor escape strategies.

Research Design: To identify relevant escape mechanisms in murine tumors and in two corresponding human cancers, real-time reverse transcription-PCR was used to measure a panel of genes associated with T-cell activation and inhibition pathways.

Results: Comparative analysis of the expression levels of these immunomodulatory genes showed astonishing similarities in expression patterns between murine and human breast cancers but profound variability in the expression of immunomodulatory genes in colorectal cancers. For human ductal adenocarcinoma of the breast, down-regulation of dendritic cell maturation marker CD83 and T-cell activation gene CD28 was observed as well as a notable increase in the expression of the immunoinhibitory gene B7-H4. By contrast, colorectal adenocarcinoma cases showed high variability in tumor escape mechanisms, indicating a need to produce immune signatures for individual patients to identify appropriate immunotherapeutic targets.

Conclusions: These results show that certain tumors, such as ductal carcinoma of the breast, show consistent immunologic abnormalities that can be used as targets for immunotherapy. These findings also show the importance and feasibility of determining the immune signatures of patients' tumors to select appropriate immunotherapeutic strategies. Ultimately, these results advocate for the determination of immune signatures as part of the customary repertoire of clinical diagnostics for cancer.