The microenvironment of most tumors is not really a place where you’d want to be. Quite often, indeed, nutrients are limited and oxygen is scarce, which renders cancer cell survival and proliferation not particularly easy. Moreover, a variety of toxic agents delivered as part of cancer therapy may be just around the corner.
Bottom line, cancer cells die all the time — which, by the way, is great news! For a long time, though, it was believed that dying cancer cells would never be able to initiate a specific immune response because of their similarity to normal cells and because cancer cells generally die through a rather physiological process that is known as “apoptosis.”
Apoptosis is the main mechanism through which normal cells die as part of tissue homeostasis. This involves billions of cells every day, but our bodies are perfectly fine with it. Over the past decades, considerable efforts have, therefore, been devoted to the development of therapeutic regimens that would be as toxic as possible for cancer cells (in the attempt to kill them all) while sparing normal tissues (to minimize side effects). In the majority of cases, however, conventional treatments such as chemotherapy and radiation therapy are unable to eliminate 100% of cancer cells and are quite toxic for (at least some) healthy tissues.
By the early 2000s, researchers had begun to realize that cancer cells are quite dissimilar from normal cells, so much that the immune system has the potential to recognize them and (in the best-case scenario) even eliminate them. Why, then, would tumors form, progress, and ultimately kill patients if the immune system has the potential to detect and kill cancer cells? Because cancer cells are very good at hiding from the immune system, both when they are alive and when they die. Restoring the ability of the immune system to recognize and kill cancer cells has, therefore, become a major therapeutic approach that has become known as “immunotherapy.”
A variety of molecules that target immune cells to activate them (rather than cancer cells to kill them) have been generated, and some of them have already entered the clinical practice for the treatment of multiple tumors (e.g., melanoma, lung cancer). Additionally, efforts are being refocused on the development of agents that kill cancer cells by mechanisms other than apoptosis.
Cancer cells can indeed die in ways that are not immunologically silent (as apoptosis is), which potentially results in the activation (or reactivation) of tumor-targeting immune responses. Such immunogenic variants of cell death depend on the emission of specific signals from dying cancer cells, which are interpreted by the immune system as a sign of danger and a green light for the elicitation of tumor-specific responses. Importantly, multiple chemotherapeutics, as well as radiation therapy (when employed according to precise doses and schedules), are able to cause the immunogenic demise of cancer cells, followed by the activation of tumor-targeting immune responses that have the potential to control not only cancer cells that resisted treatment, but also the emergence of metastases.
In summary, since most conventional treatments cannot kill 100% of cancer cells, and even a few residual cancer cells can drive disease relapse, the amount of cancer cell death may not be as important as the mechanisms cancer cells actually die. That is, quality beats quantity. Our research aims at deconvoluting the processes that are activated in cancer cells exposed to therapeutic agents, understanding how such processes are connected to the immunogenicity of cell death, and tweaking them to maximize the efficacy of treatment.
These notions are further elaborated in the articles Modeling Tumor Immunology and Immunotherapy in Mice and Immunogenic Cell Death in Cancer and Infectious Disease, recently published in the journals Trends in Cancer and Nature Reviews – Immunology, respectively. These lines of investigation are actively pursued by Aitziber Buqué, Takahiro Yamazaki and Lorenzo Galluzzi from Weill Cornell Medical College.
Author Disclosure: L.G. provides remunerated consulting to AstraZeneca, VL47 and OmniSEQ, is a member of the Scientific Advisory Board of OmniSEQ, and receives research funding from Lytix and Phosplatin.
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