The Importance of the Tumor Microenvironment for Immunotherapy
Immunotherapy (IO Therapy) has proven to be a unique and successful way to fight certain cancers, and the analysis of the tumor microenvironment has been increasingly recognized as an important aspect of therapy success. Written by Bryan Kaplan, Alex Kernagis, Mira Amin, and Kesavan Venkatesh
Cancer immunotherapy leverages the body’s immune system to control the growth of cancer cells and ultimately eliminate them. IO therapy programs the immune system to recognize and attack cancer cells through various characteristics, such as the differentiation of biomarkers (i.e. proteins, hormones, DNA, etc.).. This form of cancer treatment can also increase the number of immune cells that play a role in fighting off cancerous ones. Immunotherapies come in a variety of different forms for different cancers, including immune checkpoint inhibitors, cancer vaccines, targeted antibodies, tumor-infecting viruses, and more. Specifically, in immune checkpoint inhibitors, the role of PD-L1, a protein involved in the immune response, is crucial. PD-L1 functions as an “inhibitor” and a control measure for the immune system. The protein can be found in some normal cells but will be found in higher levels in specific cancer cells. PD-L1 usually binds to another protein called PD-1, which is found on T cells (cells that attack specific foreign antigens). This then prevents T cells from eliminating cells that contain PD-L1, including cancer cells. Immunotherapy drugs can target and bind to PD-L1, preventing PD-1 from binding to the protein, and thus allowing T cells to freely attack cancer cells.
Some of the primary biomarkers for studying the efficacy of IO therapy are tumor mutational burden (TMB) and microsatellite instability (MSI). TMB is a measurement of the total non-inherited mutations per million bases of the genomic sequence, commonly acquired via next-generation sequencing (NGS). While this is a decent measure of whether or not a cancerous cell is present, it is insufficient for dictating how treatable a cancer will be on its own. MSI measures how “stable” or predisposed to mutating a segment of DNA may be and, in contrast to TMB, can serve alone as an indicator of cancer presence and treatment potential. The larger the MSI value, the more likely treatment will lead to a positive outcome for the patient.
When looking at the IO therapy industry as a whole, across the only seven FDA-approved IO therapy drugs, a majority of the approvals have been for cancers in the metastatic first-line and second-line stages. Approximately 70% of approvals have been in these categories when compared to 30% of approvals in the adjuvant and neoadjuvant settings. Although there are many current nuances to IO therapy approval in the adjuvant and neoadjuvant settings, the disparity in approvals highlights a clear upcoming need in the future.
In addition, the tumor microenvironment has increasingly become emphasized as an important element to consider when adopting IO therapy. The tumor microenvironment is generally characterized by elements such as myeloid-derived suppressor cells (MDSC), tumor infiltrating lymphocytes (TIL), and tumor angiogenesis. MDSCs suppress the immune system and inhibit the effects of immunotherapies; a microenvironment with a large population of MDSCs is evidently a poor candidate for IO therapy. TILs are cells that move from the bloodstream into the tumor to exterminate it. TILs can be removed from the patient, cultured, and then reinserted into the patient, leading to more efficient IO therapy. Neovascularization (angiogenesis) allows a tumor to grow new blood vessels, helping promote tumor growth by stimulating the spread of pro-angiogenic factors. In the 1950s, suburban America faced great amounts of “urban sprawl” due to the development of highways into less populated areas. We can explain this relationship by comparing the tumor to the town center and the blood vessels to the roads and highways. By targeting the vascularity of a tumor, we can effectively remove the highways that allow it to spread rapidly and starve it of resources.
Down the line, drug developers will need to make important considerations with regard to the tumor’s microenvironment to better predict a patient’s response to immunotherapy treatment. Patients with higher levels of angiogenesis/MDSCs and low immune responses/TILs will be far less likely to respond to immunotherapy when compared to patients with low angiogenesis/MDCs and high immune responses/TILs. However, these effects can lead to bias in drug development as pharmaceutical companies may seek to screen clinical trial candidates that are less favorable towards treatment to skew the results and r probability of approval in their favor. Similarly, many tumors typically exhibit higher or lower levels of angiogenesis, MDSCs, and TILs. To have higher clinical trial success, drug developers may seek to put more research into analyzing a tumor’s microenvironment before picking a specific tumor to target for an IO drug trial.