For many people with various kinds of most cancers, immune checkpoint inhibitors can successfully enhance their immune system to combat their illness, however not all sufferers profit from these drugs. Now a crew led by investigators at Massachusetts General Hospital (MGH) and Harvard Medical School (HMS) has developed an strategy to assist establish potential medical markers that may point out which sufferers will reply to immune checkpoint inhibitors and which must be handled with different methods. The findings are printed within the Proceedings of the National Academy of Sciences.
For the research, the scientists developed an strategy whereby they implanted breast most cancers tumors into mice after which handled the animals with immune checkpoint inhibitors.
We first developed a resection and response bilateral tumor mannequin wherein we put one breast tumor in all sides of the mouse breast. We then take away one tumor to consider the tumor microenvironment and we monitor the response of the opposite, non-resected, tumor to immune checkpoint blockade, figuring out the mouse as a responder or a non-responder.”
Ivy X. Chen, PhD, lead creator, former postdoctoral fellow at MGH’s E.L. Steele Laboratories for Tumor Biology
Using this mannequin system, the researchers discovered that the responding tumors contained increased numbers of cancer-killing “cytotoxic” T immune cells and fewer numbers of sure immune suppressor cells early after the beginning of remedy.
Gene expression analyses of the cytotoxic T cells throughout the tumors revealed distinct gene signatures distinguishing responders from non-responders–specifically, the presence of T cell activation indicators in responding tumors and T cell exhaustion indicators in non-responding tumors. “Importantly, we found that these gene signatures for responder and non-responder tumors significantly correlated with responder and non-responder gene signatures derived from patients with melanoma who were treated with immune checkpoint inhibitors, as well as with overall survival in a group of patients with breast cancer,” mentioned co-senior creator Meromit Singer, PhD, an Assistant Professor within the Department of Data Science on the Dana-Farber Cancer Institute and the Department of Immunology at Harvard Medical School.
The affect of this research may transcend the identification of novel markers to predict patient response to immune checkpoint inhibitors. “Our study highlights the importance of investigating the dynamic immune modulation of the tumor microenvironment to understand the potential benefit of immunotherapy,” mentioned co-senior creator Rakesh Jain, PhD, director of the Steele Laboratories at MGH and the A.W. Cook Professor of Radiation Oncology at Harvard Medical School. “We hope to extend our approach to study and discover resistance mechanisms and biomarkers of response to immune checkpoint inhibitors in other tumor types.”
Co-senior creator Arlene Sharpe, MD, PhD, the George Fabyan Professor of Comparative Pathology at Harvard Medical School, added, “Ultimately, our goal is to utilize this method to develop combination therapies to boost the effectiveness of immune checkpoint inhibitors and to identify new treatments for patients who are unlikely to respond to these agents.”