Study of adenocarcinoma microenvironment important in ICI therapy

The body's immune system can recognize and fight tumor cells. However, tumor cells can escape attack by inhibiting the immune system. In this inhibition, the tumor cells specifically exploit a natural brake of the immune system that prevents an exuberant immune response. By binding tumor-derived proteins to cell receptors on immune cells ("checkpoints"), the tumor cells activate this brake, and, as a result, immune cells are prevented from attacking the tumor. Immune checkpoint inhibitors (ICIs) are drugs that prevent activation of the brake and thus suppression of the immune response, allowing the immune system to increase its attack on the tumor.

ICIs have dramatically expanded therapeutic options. However, only a portion of patients responds to treatment. Because ICIs can cause adverse health effects, drug use of these agents would be desirable only in those patients whose tumors can be successfully treated with them. To date, however, there are no clear signs ("predictive markers") that predict which patients will benefit from ICI treatment.

In search of such predictive markers, an interdisciplinary team of pathologists, basic scientists, and physicians at the DZL TLRC site studied immune cells in tumor samples from patients with metastatic lung adenocarcinoma. Of these patients, one group responded well to therapy with ICI for at least one year, while another group responded for less than two months until disease progression occurred. The tumor-infiltrating immune cells could be classified into 14 different types of immune cells based on the differential activity of 60 selected genes important for the immune response to the tumor. Depending on the number and type of different immune cells, tumors removed before the start of therapy were classified into immunologically "hot" and immunologically "cold" tumors. It was striking that the immunologically "hot" tumors with particularly high numbers and types of immune cells were predominantly from those patients who had a lengthy response to subsequent ICI therapy (52%). In contrast, among the immunologically "cold" tumors, the proportion of these patients with a long-term response was significantly lower (20%).

Another finding of this work was that the abundance of B lymphocytes (a subclass of white blood cells that produce antibodies) was associated with a higher likelihood of long-term response to ICI therapy, as well as with a prolonged progression-free period after ICI therapy.

The work, published in the journal Oncoimmunology, shows that in addition to studying the genes of tumor cells, analysis of the cells surrounding the tumor cells, known as the tumor microenvironment, is important in identifying patients who are most likely to benefit from ICI therapy. The work performed in this study was done on tumor samples collected as part of routine diagnostic procedures. These analyses were shown to be easily integrated into clinical workflows without the need for further tissue collection or special workup beyond already established workflows. Confirmation of the clinical relevance of these initial results is now required in other multicenter studies.

Further information:

Original publication: Budczies et al., 2021 / Oncoimmunology