Cancer chemotherapy: insights into cellular and tumor microenvironmental mechanisms of action

Abstract

Chemotherapy has historically been the mainstay of cancer treatment, but our understanding of what drives a successful therapeutic response remains limited. The diverse response of cancer patients to chemotherapy has been attributed principally to differences in the proliferation rate of the tumor cells, but there is actually very little experimental data supporting this hypothesis. Instead, other mechanisms at the cellular level and the composition of the tumor microenvironment appear to drive chemotherapy sensitivity. In particular, the immune system is a critical determinant of chemotherapy response with the depletion or knock-out of key immune cell populations or immunological mediators completely abrogating the benefits of chemotherapy in pre-clinical models. In this perspective, we review the literature regarding the known mechanisms of action of cytotoxic chemotherapy agents and the determinants of response to chemotherapy from the level of individual cells to the composition of the tumor microenvironment. We then summarize current work toward the development of dynamic biomarkers for response and propose a model for a chemotherapy sensitive tumor microenvironment.

Keywords: cancer chemotherapy; cell death; chemotherapy; immune response; mechanism of action; tumor microenvironment.

Figure 1

Clinical responses to chemotherapy in a range of cancer types. Patients might experience no response (continuous progression) or a partial response followed by progression [e.g. non-small cell lung cancer (9), colorectal cancer (10) breast cancer (11), mesothelioma (12) and pancreatic cancer (13)]; a complete response followed by progression [e.g. small cell lung cancer (14) and acute myeloid leukemia (15)]; or a complete durable response [e.g. germ cell tumors (16)].

Figure 2

Mechanisms of action of conventional chemotherapies. (A) Primary mechanisms of action. Alkylating agents induce DNA breaks, anti-metabolites are incorporated into DNA or RNA and interfere with DNA and RNA synthesis, topoisomerase (Top) inhibitors damage the Top I or Top II enzymes halting DNA replication and anti-microtubule agents damage microtubules and affect mitosis. (B) Secondary mechanisms of action of chemotherapies. Alkylating agents can bind to RNA or induce protein-DNA crosslinks, antimetabolites can inhibit enzymes crucial for DNA or RNA synthesis and topoisomerase inhibitors can impair mitochondria biogenesis or generate reactive oxygen species. For more see Table 1. Figure created with BioRender.com.

Figure 3

Reported clinical studies testing a correlation between Ki67 expression and chemotherapy response. Number of studies assessing Ki67 expression using immunohistochemistry with reported correlation between Ki67 expression and response rate or survival. Full dataset in Supplementary Table 1.

Figure 4

Characteristics of a chemotherapy sensitive TME. An inflammatory, immune infiltrated ‘hot’ tumor is associated with response to classical chemotherapies. These tumors are characterized by the infiltration of immune cells, particularly increased CD8⁺ T cells. release of inflammatory mediators such as IFNs and TNFα and decreased levels of immunosuppressive cells. Additionally, tumor vasculature can have both positive and negative effects on chemotherapy response while CAFs are primarily associated with chemotherapy resistance. Figure created with BioRender.com.