Immunotherapy has become a buzzword in the cancer research field. Immunotherapy can take many forms but ultimately seeks to leverage the human immune system to target and kill cancer cells. While there have been promising therapeutic advances in this field it remains painfully obviously that scientists are only beginning to understand how the immune system detects cancer cells and how cancer evades that detection. A key to mobilizing the immune system is to understand how its response changes based on cancer type. The Houghton and MacPherson labs (Clinical Research and Human Biology Divisions) recently published a collaborative study in the Journal of Immunology that compares the immune response not only between lung adenocarcinoma (ADCA) and small cell lung cancer (SCLC), but also between specific oncogenic mutations that drive ADCA.
Researchers utilized three genetically engineered mouse models of ADCA. The first model induced ADCA by expressing a hyperactive mutant of the common oncogene epidermal growth factor (EGFR) in all tissues of an adult mouse (referred to as EGFR). The second model of ADCA was generated by replacing the natural KRAS gene with a hyperactive oncogenic mutant KRAS (referred to as KRAS). The final model consisted of the KRAS mutation and the deletion of tumor suppressor genes p53 and Rb specifically in lung tissue (referred to as Kp53). These well established models have been used for many studies; however, the immune response to these tumors has not yet been characterized. For this study researchers dissociated whole lung tissue to single cells and used a stepwise flow cytometry scheme to identify relative levels of immune cells. The types of immune cells included macrophages, granulocytes, monocytes, eosinophils, natural killer, B, and T cells.
In all of the models macrophages dominated the immune makeup; however, this is likely a limitation of the murine system as this response is rarely observed in human disease. If ignoring the macrophage response the most striking difference was that EGFR mice recruited far fewer mature T and B cells to the lung tissue. Further characterization of the T cell response revealed that KRAS and Kp53 mice recruited similar levels of CD4+ and CD8+ T cells while EGFR mice not only recruited fewer T cells, but they were primarily CD4+. This finding was validated in tissue samples of human ADCA tumors known to harbor EGFR or KRAS mutations, again KRAS driven tumors showed higher levels of CD8+ cells.
For tumors to evade the immune system they commonly activate PDL-1 mediated immune blockade which inhibits T cell activity. One class of cancer therapies works by preventing this inhibitory process and allowing T cells to function correctly; thus researchers characterized the PDL-1 expression in these ADCA models. Interestingly PDL-1 levels were lower in EGFR and KRAS models than control mice, and indistinguishable from one another, suggesting immune blockade is not preventing T cell activation. Consistently, when healthy control T cells were treated with lung derived lysates from control mice they proliferated however both KRAS and EGFR lysates inhibited T cell growth.
To further understand the value of targeting immune blockade in ADCA cells researchers tested an anti-CTLA4 antibody. This antibody weakly stimulated the immune response consistent with previous findings suggesting alternative aspects of the tumor microenvironment provides ADCA cells with anti-immune properties. While these findings are specific to mouse models it may suggest that anti-immune blockade therapy will not be successful in ADCA. Yet further testing is important. Finally researchers compared the difference between ADCA and SCLC in mice. Interestingly SCLC generated an immune response that emphasized T cells over macrophages.
Ultimately this study emphasized the importance of understanding the native tumor microenvironment before employing immunotherapy. This field is new and exciting but not a fix all for cancer. We look forward to further characterizations from these labs.
Busch SE, Hanke ML, Kargl J, Metz HE, MacPherson D, Houghton AM. 2016. Lung Cancer Subtypes Generate Unique Immune Responses. J Immunol. doi: 10.4049/jimmunol.1600576
Funding for this research was provided by the National Heart, Lung, and Blood Institute (NIH) and European Commission